Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH2:2]([O:9][C:10]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:11]=1[CH2:12][CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[C:41]([O:45][C@@H:46]([C:52]1[C:53]([CH3:95])=[N:54][C:55]2[N:56]([N:90]=[C:91]([CH:93]=O)[CH:92]=2)[C:57]=1[N:58]1[CH2:63][CH2:62][C:61]([O:65][CH2:66][CH2:67][CH2:68][CH2:69][C@H:70]([O:72][Si:73]([C:86]([CH3:89])([CH3:88])[CH3:87])([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)[C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)[CH3:71])([CH3:64])[CH2:60][CH2:59]1)[C:47]([O:49][CH2:50][CH3:51])=[O:48])([CH3:44])([CH3:43])[CH3:42]>C1COCC1>[CH2:2]([O:9][C:10]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:11]=1[CH2:12][CH:13]=[CH:93][C:91]1[CH:92]=[C:55]2[N:54]=[C:53]([CH3:95])[C:52]([C@H:46]([O:45][C:41]([CH3:44])([CH3:43])[CH3:42])[C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:57]([N:58]3[CH2:63][CH2:62][C:61]([O:65][CH2:66][CH2:67][CH2:68][CH2:69][C@H:70]([O:72][Si:73]([C:86]([CH3:87])([CH3:88])[CH3:89])([C:74]4[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=4)[C:80]4[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=4)[CH3:71])([CH3:64])[CH2:60][CH2:59]3)[N:56]2[N:90]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=O)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Reactant: Fc1cc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(OCc2ccccc2)cc1F
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=CCc3cc(F)c(F)cc3OCc3ccccc3)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83.7 %

Procedure:
To a suspension of (2-(benzyloxy)-4,5-difluorophenethyl)triphenylphosphonium iodide salt (289 mg, 0.454 mmol) in THF (4 ml) at 0° C. was added NaH (18.61 mg, 0.465 mmol) and the resulting mixture was stirred at rt for 45 min. The mixture was cooled to 0° C. and (S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-formyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (175 mg, 0.227 mmol) dissolved in THF (4 ml) was added dropwise and the mixture was stirred at 0° C. for 1 h then warmed to rt and stirred 2 h. The reaction was quenched with water and the product was extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage; 0%-30% EtOAc/hexane) to afford (S)-ethyl 2-(2-(3-(2-(benzyloxy)-4,5-difluorophenyl)prop-1-en-1-yl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (190 mg, 0.190 mmol, 84% yield) as mixture of E and Z isomers. LCMS (M+H)=1002.0.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:4][CH:5]=[CH:6][CH:7]=[CH:8][C:9](Cl)=[O:10].[C:20]1([NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:26].CN1CCOCC1>C(Cl)Cl>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:27][C:9](=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH2:4][CH:3]([O:2][CH3:1])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1
Reactant: COc1ccc(C(CC=CC=CC(=O)Cl)OC)cc1
Reactant: Nc1ccccc1N
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(C(CC=CC=CC(=O)Nc2ccccc2N)OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 14.5 %

Procedure:
To a stirred solution of acid chloride 5 (115 mg,0.41 mmol) in CH2Cl2 (5 mL) at 0° C. was added 1,2-phenylenediamine (133 mg,1.23 mmol) followed by N-methylmorpholine (49 μL, 0.45 mmol). The mixture was stirred at 0° C. for 1 h, and then was allowed to warm to rt over 1 h. After being stirred for an additional 1 h at rt, the reaction mixture was partitioned between CHCl3 (2×15 mL) and water (15 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by flash silica gel chromatography (50% ethyl acetate in hexane) afforded the desired benzamide 18 (21 mg, 15% yield): 1H NMR (300 MHz, CDCl3) δ 6.65-7.40 (m, 9H), 5.96-6.20 (m, 2H), 5.92 (d, J=15.3 Hz, 1H), 4.18 (m, 1H), 3.82 (br s, 2H), 3.81 (s, 3H ), 3.19 (s, 3H), 2.61 (m, 1H), 2.43 (m, 1H); 13CNMR (75.4 MHz,CDCl3) δ 41.7, 55.2, 56.4, 82.7, 113.8, 118.2, 119.5, 121.8, 124.4, 125.0, 127.0, 127.8, 130.1, 133.1, 139.5, 140.7, 142.4, 159.2, 164.6.
Reaction SMILES: [N+]([C:4]([CH3:17])=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:8][CH:7]=1)([O-])=O.C[OH:19].O.Cl>[Fe].C(Cl)Cl>[N:12]1([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C:4](=[O:19])[CH3:17])=[CH:7][CH:8]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: CO
Reactant: CC(=Cc1ccc(-n2ccnc2)cc1)[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)Cc1ccc(-n2ccnc2)cc1
Temperature: 25 °C

Procedure:
A 5.0 liter 3-neck flask fitted with a condenser, addition funnel, and mechanical stirrer is charged with a mixture of 218.4 g (0.954 mole) of 1-[4-(2-nitro-1-propenyl)phenyl-1H-imidazole, 449 g (8.04 mole) of iron powder (325 mesh), 6.4 g of FeCl3.6H2O, 350 ml of methanol and 760 ml of water. The mixture is heated to reflux with stirring and 450 ml of concentrated hydrochloric acid is added dropwise over a period of 2.5 hours. Refluxing is continued for two to three hours. The reaction mixture is cooled to room temperature, 1.9 liter of CH2Cl2 was added, and the mixture stirred rapidly for one hour. This is filtered, the inorganic solid is washed three times with 500 ml portions of CH2Cl2, and the layers separated. The CH2Cl2 layer is dried over MgSO4, then filtered through a bed of silica gel (600 g, 70-230 mesh), which is washed with 5 liters of CH2Cl2 and then with 13 liters of 10% methanol in methylene chloride. Evaporation of the solvent gave 126.7 g of a brown oil which crystallized on standing. The product is purified via the sodium bisulfate addition product to give a product having a mp of 71.5°-72.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39].[CH3:40][N:41]([CH3:46])[CH2:42][CH2:43][NH:44][CH3:45]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:44]([CH2:43][CH2:42][N:41]([CH3:46])[CH3:40])[CH3:45])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39]
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CNCCN(C)C
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(N(C)CCN(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 24.6 %

Procedure:
To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (50 mg, 0.09 mmol) in DCM (10 mL) was added N,N,N′-trimethyl-1,2-ethanediamine (0.057 mL, 0.44 mmol). The resultant mixture was stirred at room temperature overnight. The mixture was concentrated under vacuo. Flash chromatography (90% CH2Cl2/7% MeOH/3% NH4OH) then provided the title compound (13 mg, 25%). LC-MS (ES) m/z 587 (M+H)+; 1H-NMR (MeOD) δ 2.09 (s, 3H), 2.24 (s, 3H), 2.38 (s, 3H), 2.41 (m, 1H), 2.59 (m, 1H), 2.91 (s, 1H), 3.22 (s, 2H), 3.52 (m, 1H), 3.88 (m, 1H), 6.38 (d, 1H), 7.13 (m, 2H), 7.25 (m, 2H), 7.52 (d, 1H), 7.62 (m, 2H), 7.71 (m, 2H), 7.92 (s, 1H), 8.06 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>>[CH2:16]([O:15][C:13](=[O:14])[NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[F:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Product: O=C(Nc1ccc(F)cc1F)OCc1ccccc1
Reaction time: 2 h

Procedure:
The 2,4 difluoro aniline (5.06 ml, 49.6 mmole) put into a solution of 10% NaOH (76 ml). Cooled in an ice bath and added benzyl chloroformate (7.85 ml, 55 mmole). After stirring for for 2 hours the product was filtered, stirred with hexane, dried. Yield 9.4 g
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:25])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC.OS([O-])(=O)=O.[K+]>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:25])[C@@H:15]([CH3:26])[CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C(CCCCc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: C[C@@H](CCCc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
To a stirring solution consisting of (S)-4-benzyl-3-(5-phenylpentanoyl)oxazolidin-2-one (21ma, 1.24 g, 3.68 mmol) in THF (20 mL) at −78° C. was slowly added lithium bis-(trimethylsilyl)amide solution (4.41 mL, 4.41 mmol, 1 M solution in THF). The reaction mixture was stirred at −78° C. for one hour, after which time iodomethane (0.27 mL, 4.2 mmol) was slowly added. The resulting reaction mixture was allowed to rise to room temperature with stirring overnight. The mixture was acidified with 5% KHSO4 and extracted twice with ethyl acetate. The organic layer was washed twice with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography. Elution with ethyl acetate-heptane (25:75 v/v) afforded the title compound (563 mg, 43.6%) as a clear oil; TLC Rf 0.53 (solvent system: 25:75 v/v ethyl acetate-heptane; MS (ESI+) m/z 352.3 (M+H)+374.2 (M+Na)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.C[O:16][C:17](=O)[NH:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([CH3:27])[N:20]=1.C[Al](C)C.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:26][O:25][C:23]1[CH:22]=[C:21]([CH3:27])[N:20]=[C:19]([NH:18][C:17]([NH:14][S:11]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[NH:3][CH:2]([CH3:1])[CH2:10]3)(=[O:13])=[O:12])=[O:16])[N:24]=1
Reactant: COC(=O)Nc1nc(C)cc(OC)n1
Reactant: CC1Cc2cccc(S(N)(=O)=O)c2N1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc3c2NC(C)C3)n1
Yield: 11.2 %

Procedure:
To a solution of 2,3-dihydro-2-methyl-1H-indole-7-sulfonamide (1.0 g) and (4-methoxy-6-methylpyrimidin-2-yl)carbamic acid methyl ester (1.0 g) in methylene dichloride (100 ml) was added trimethylaluminum (3.0 ml of a 2.0 M solution in toluene). The mixture was heated at reflux for 18 hours under a nitrogen atmosphere. Work-up was achieved by careful addition of 100 ml of 1N HCl followed by separation of the organic layer. The methylene chloride was dried over MgSO4 and evaporated to dryness. The residue was chromatographed on a silica gel column to give the pure product (0.2 g, m.p. 175°-177° C.).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26].[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Fc1ccccc1Br
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1ccccc1-c1cccc2[nH]ccc12
Temperature: 75 °C
Reaction time: 15 h
Yield: 63.9 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 2.431 g, 10.0 mmol), and 2-bromofluorobenzene (1.75 g, 10.1 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (0.347 g, 0.30 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30.0 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 1.35 g (64%) of the product 4-(2-fluoro-phenyl)-1H-indole as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][C:16](=[O:18])[NH:15][C:14]([CH3:19])=[C:13]1[C:20]([O:22][CH3:23])=[O:21].[H-].[Na+].[CH3:26]OS(OC)(=O)=O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][C:16](=[O:18])[N:15]([CH3:26])[C:14]([CH3:19])=[C:13]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)C1=C(C)NC(=O)CC1c1ccc(C(F)(F)F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)N(C)C(=O)CC1c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 48 %

Procedure:
The product of Example 21, Step 1 (3.0 g, 9.056 mmol, 1.0 equiv) was dissolved in 100 mL DMF and NaH (725 mg, 18.11 mmol, 2.0 equiv) was added slowly to the reaction mixture. Me2SO4 (1.72 mL, 18.11 mmol, 2.0 equiv) was added and the reaction was stirred at room temperature for 45 min. The reaction was quenched with water and diluted with EtOAc. After the phases were separated, the organic phase was washed once with satd. NaHCO3 and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was triturated with Et2O and filtered to provide 1.5 g (48%) of the title compound as a light yellow solid. MS (ES+) m/e 346 [M+H]+
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23]C(=O)CCl)=[CH:19][CH:18]=2)[CH:8]=[C:9]([O:11][C:12](=[O:14])[CH3:13])[CH:10]=1)(=[O:3])[CH3:2].Cl>N1C=CC=CC=1>[C:12]([O:11][C:9]1[CH:8]=[C:7]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:6]=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:10]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Oc1cc(C=Cc2ccc(OC(=O)CCl)cc2)cc(OC(C)=O)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(C=Cc2ccc(O)cc2)cc(OC(C)=O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.7 %

Procedure:
A solution of 3,5-diacetoxy-4′-chloroacetoxy stilbene (0.388 g, 1 mmol) in 50% aqueous pyridine, which was adjusted to pH 6.7 with hydrochloric acid, was stirred for 6 h at room temperature. The mixture was concentrated and diluted with EtOAc. The mixture was washed with 1 N aqueous HCl, saturated NaHCO3 and water. Then the EtOAc solution was dried and concentrated. After purification by radial chromatography, the product (0.28 g, 90%) was obtained. Data are: 1H NMR (Aceton-d6, 300 MHz) δ 8.55 (bs, 1H), 7.47 (m, 2H), 7.25-7.00 (m, 4H), 6.86 (m, 2H), 6.82 (t, 1H, J=2.1 Hz), 2.27 (s, 3H); 13C NMR (Aceton-d6, 75 MHz) δ 169.5, 158.7, 152.7, 141.2, 131.4, 129.5, 129.2, 124.8, 117.5, 116.6, 115.1, 21.0; HRMS (EI+) found 312.0993 M+, calcd 312.0998 for C18H16O5.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]([F:20])([F:19])[C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>>[F:10][C:11]([F:19])([F:20])[C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[N:7]=[C:6]([NH:16][C:15]3[CH:17]=[CH:18][C:12]([C:11]([F:10])([F:19])[F:20])=[CH:13][CH:14]=3)[C:5]([F:9])=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Nc2ccc(C(F)(F)F)cc2)nc1Nc1ccc(C(F)(F)F)cc1

Procedure:
In a manner similar to the preparation of N2-N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidineamine, the reaction of 2,4-dichloro-5-fluoropyrimidine with 4-trifluoromethylaniline gave N2,N4-bis(4-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.06 (bs, 1H), 7.75 (d, 2H, J=9 Hz), 7.67 (d, 2H, J=9 Hz), 7.63 (d, 2H, J=9 Hz), 7.54 (d, 2H, J=9 Hz), 7.19 (bs, 1H), 6.96 (s, 1H); 19F NMR (CDCl3): δ −17598 (s, 3F), −17676 (s, 3F), −46549 (s, 1F); HPLC: 85% pure.
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:22]2[C:27]([Cl:28])=[CH:26][N:25]=[C:24](Cl)[N:23]=2)(=[O:14])=[O:13])[CH2:8]1)(C)(C)C.[NH2:32][C:33]1[CH:34]=[CH:35][C:36]2[CH2:42][CH:41]([NH:43][CH2:44][CH2:45][OH:46])[CH2:40][CH2:39][CH2:38][C:37]=2[C:47]=1[O:48][CH3:49]>>[Cl:28][C:27]1[C:22]([NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:12]([N:9]2[CH2:10][CH2:11][C@H:7]([OH:6])[CH2:8]2)(=[O:13])=[O:14])=[N:23][C:24]([NH:32][C:33]2[CH:34]=[CH:35][C:36]3[CH2:42][CH:41]([NH:43][CH2:44][CH2:45][OH:46])[CH2:40][CH2:39][CH2:38][C:37]=3[C:47]=2[O:48][CH3:49])=[N:25][CH:26]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCN(S(=O)(=O)c2ccccc2Nc2nc(Cl)ncc2Cl)C1
Reactant: COc1c(N)ccc2c1CCCC(NCCO)C2
Product: COc1c(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CC[C@H](O)C3)n2)ccc2c1CCCC(NCCO)C2

Procedure:
The title compound was prepared from {2-[(S)-3-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1-sulfonyl]-phenyl}-(2,5-dichloro-pyrimidin-4-yl)-amine (150 mg, 0.30 mmol) and 2-(2-Amino-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylamino)-ethanol (75 mg, 0.30 mmol) in an analagous manner to Example 946 to afford a white foam. Mp: 92-5° C. LCMS (m/e) 603 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.36 (s, 1H), 8.50 (m, 1H), 8.18 (s, 1H), 8.00 (m, 2H), 7.62 (m, 1H), 7.50 (br s, 1H), 7.29 (m, 1H), 6.81 (m, 1H), 4.37 (m, 1H), 3.74 (s, 3H), 3.61 (m, 2H), 3.43 (m, 3H), 3.30 (m, 1H) 2.98-2.70 (m, 7H), 2.03 (m, 1H), 1.86 (m, 2H), 1.63 (m, 6H).
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].[Li+].[OH-].O.Cl>CCO>[CH3:8][C:2]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)c1cccnc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C(=O)O)c1cccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
Ethyl α,α-dimethyl-3-pyridylacetate (disclosed in EP Application 0 288 279, published Oct. 26, 1988) (2.67 grams, 13.8 mmoles) was dissolved in EtOH (11.1 ml.) and a 1.0M LiOH in water (33.3 ml.) (33.4 mmoles) was added. The mixture was stirred at 25° C. for 4 hours. 1N HCl (38.73 ml.) was added and after 5 minutes the mixture was evaporated to dryness to give the title compound (Yield: 100%).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:33][CH2:34][N:29]([C:23]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=3[CH3:21])[CH2:30][CH2:31]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4ccc(C)cc4C)CC3)nn2C(C)(C)C)cc1

Procedure:
88 mg (82%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (60 mg, 0.222 mmol), 1-(2,4-dimethylphenyl)piperazine (42 mg, 0.222 mmol), DIPEA (0.06 mL, 0.333 mmol) and NaBH(OAc)3 (141 mg, 0.666 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[CH:7]([N:11]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:44])[NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][NH2:43])=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:46]1(=[O:53])[O:52][C:50](=[O:51])[CH2:49][O:48][CH2:47]1>CN(C)C=O>[C:1]([O:5][C:6](=[O:45])[CH:7]([N:11]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](=[O:44])[NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][NH:43][C:50](=[O:51])[CH2:49][O:48][CH2:47][C:46]([OH:53])=[O:52])=[CH:28][CH:29]=1)[S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH:8]([CH3:9])[CH3:10])([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccc(C(=O)NCCOCCOCCOCCN)cc2)C(C(=O)OC(C)(C)C)C(C)C)cc1
Reactant: O=C1COCC(=O)O1
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(Cc2ccc(C(=O)NCCOCCOCCOCCNC(=O)COCC(=O)O)cc2)C(C(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of the amine (Compound 13*; 60 mg, 0.092 mmol), N, N′-diisopropyl ethylamine (96 μl, 0.55 mmol), and diglycolic anhydride (66 mg, 0.55 mmol) in dimethylformamide (6 ml) was stirred at ambient temperature for 3 hours when monitoring by HPLC indicated complete reaction. The solvent was removed under reduced pressure and the residue dissolved in acetonitrile containing 0.1% TFA. After stirring for 5 minutes, the mixture was evaporated to dryness and the crude product purified by flash chromatography using CHCl3MeOH/H2O, 65:25:4. The product was obtained as white foam. Yield 70.50 mg (99.80%).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:32][C:33]1[NH:34][CH:35]=[C:36]([CH:38]=O)[N:37]=1.CC(O)=O>ClCCCl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH2:38][C:36]4[N:37]=[C:33]([CH3:32])[NH:34][CH:35]=4)[CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCNCC3)co2)C2CC2)c(C)c1
Reactant: Cc1nc(C=O)c[nH]1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCN(Cc4c[nH]c(C)n4)CC3)co2)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-cyclopropyl-4-methoxy-2,6-dimethyl-N-{[4-(piperazin-1-ylcarbonyl)-1,3-oxazol-2-yl]methyl}benzenesulfonamide (30 mg, 0.07 mmol) in DCE (2 mL) were added 2-methyl-1H-imidazole-4-carboxaldehyde (9 mg, 0.08 mmol) and AcOH (3 μL, 0.07 mmol) and the reaction mixture was stirred for 1 h at ambient temperature. STAB (20 mg, 0.09 mmol) was added and the reaction was stirred for 16 h. The reaction mixture was quenched with H2O (2 mL) and extracted with DCM (3×2 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep method D to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][NH2:10])=[O:8])=[CH:5][CH:4]=1.[C:13](Cl)(=[O:15])[CH3:14]>C1COCC1>[C:13]([NH:10][NH:9][C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: COc1ccc(C(=O)NN)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NNC(C)=O)cc1
Reaction time: 1 h

Procedure:
To 40 mL of THF were added 1.8 g (10.8 mmol) of 4-methoxybenzoylhydrazine, 0.9 g (11.5 mmol) of acetyl chloride and 1.1 g of TEA. The reaction mixture was stirred for 1 hour, followed by evaporation off ca. ½ volume of THF. The product was precipitated into methanol, filtered and dried over night under vacuum. Yield was 2.14 g (95%). MS (EI, m/e) calcd for C10H12N2O3 208, found 208 M+, 6.7); mp 146-148° C.