Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.[CH2:18]([C@H:25]1[CH2:29][O:28][C:27](=[O:30])[N:26]1[C:31](=[O:41])[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:42]([O:49][C:50]1[CH:57]=[CH:56][C:53]([CH:54]=[O:55])=[CH:52][CH:51]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[Cl-].[Na+].OO>ClCCl.C(N(CC)CC)C.CO>[CH2:18]([C@H:25]1[CH2:29][O:28][C:27](=[O:30])[N:26]1[C:31](=[O:41])[C@@H:32]([O:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1)[C@@H:54]([C:53]1[CH:56]=[CH:57][C:50]([O:49][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:51][CH:52]=1)[OH:55])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(OCC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: OO
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1ccc(O[C@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)[C@H](O)c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
A 1M solution of dibutylboron triflate in dichloromethane (33.2 ml) and triethylamine (5.12 ml) were added at 0° C. to a solution of (S)-4-benzyl-3-[(4-methylphenoxy)acetyl]oxazolidin-2-one (9.00 g) obtained from Reference example 20(a) in dichloromethane (90 ml), and the mixture was stirred at 0° C. for 1 hour. A solution of 4-benzyloxybenzaldehyde (6.46 g) in dichloromethane (6 ml) was added dropwise at −78° C. to the reaction solution, and then the reaction solution was stirred at 0° C. for 2 hours. A mixed solution (20 ml) of a saturated aqueous sodium chloride solution and methanol (1:1) and a mixed solution (100 ml) of an aqueous solution of hydrogen peroxide (31%) and methanol (2:1) were added thereto, and the resulting reaction solution was stirred for 1 hour. After the methanol was evaporated under reduced pressure, the residue was extracted with ethyl acetate. The ethyl acetate layer was washed successively with an aqueous solution of hydrochloric acid (1N), a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant; hexane/ethyl acetate=3/1˜1/1) to afford the target compound (9.80 g) as a foam.
Reaction SMILES: C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[F:17][CH:18]([CH:24]([OH:27])[CH2:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20].[C:28](Cl)(=[O:32])[C:29]([CH3:31])=[CH2:30].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C1COCC1>[F:17][CH:18]([CH:24]([O:27][C:28](=[O:32])[C:29]([CH3:31])=[CH2:30])[CH2:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C(F)C(O)CC
Reactant: C=C(C)C(=O)Cl
Agent: CN(C)c1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC(CC)C(F)C(=O)OCC
Reaction time: 2 h
Yield: 71.9 %

Procedure:
Under a nitrogen atmosphere, 50 mL of dehydrated THF, 4.63 g (45.8 mmol) of triethylamine and 0.466 g (3.82 mmol) of dimethylaminopyridine were added to 6.27 g (38.2 mmol) of the ethyl 2-fluoro-3-hydroxypentanoate at a room temperature. Thereafter, 4.39 g (42.0 mmol) of methacrylic acid chloride was added dropwise over 10 min, and then the mixture was stirred for 2 hrs. After disappearance of the raw material was confirmed by thin layer chromatography (TLC), an aqueous sodium bicarbonate solution was added to stop the reaction. Thereafter, ethyl acetate was added to the reaction liquid and extraction was carried out three times. The organic layer thus obtained was washed with water and saturated brine each once, and dried by adding anhydrous sodium sulfate. Thereafter, the product obtained by distilling off the solvent under a reduced pressure was purified by column chromatography to give 6.38 g (yield: 60%) of ethyl 2-fluoro-3-(methacryloyloxy)pentanoate represented by the following formula.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[N:19]=[C:18]([C:20]3[O:28][C:27]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[C:21]=3[O:29]CC3C=CC=CC=3)[O:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.C(Cl)Cl.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]2[N:19]=[C:18]([C:20]3[O:28][C:27]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[C:21]=3[OH:29])[O:17][N:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2noc(-c3oc4ccncc4c3OCc3ccccc3)n2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Cc2noc(-c3oc4ccncc4c3O)n2)CC1

Procedure:
A solution of 4-[5-(3-benzyloxyfuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]-piperidine-1-carboxylic acid tert-butyl ester (Example 120, 200 mg, 500 μmol) and Pd (10% on C, 10 mg) in EtOH (10 mL) was stirred under a H2 atmosphere for 2.5 h. The mixture was diluted with CH2Cl2, to solubilise the product, before being filtered through celite. The filtrate was concentrated to furnish the title compound: RT=2.87 min; m/z (ES+)=401.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[NH:12][CH:11]=1.[C:20]1(=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:8][C:6]2[CH:5]=[CH:4][C:3]([CH2:9][C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=4)[NH:12][CH:11]=3)=[C:2]([F:1])[N:7]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1cnc2[nH]cc(Cc3ccc(N)nc3F)c2c1
Reactant: O=C1CCCCC1
Product: Cc1cnc2[nH]cc(Cc3ccc(NC4CCCCC4)nc3F)c2c1

Procedure:
Cyclohexyl-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine P-3008 is prepared in one step from 6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine 49 and cyclohexanone 67 as shown in Scheme 10.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:15]=[CH:14][O:13][CH:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.B(O)(O)[C:17]1[CH:22]=[CH:21][C:20]2[O:23][CH2:24][O:25][C:19]=2[CH:18]=1.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[O:23]1[C:20]2[CH:21]=[CH:22][C:17]([C:2]3[CH:3]=[C:4]4[C:10]([C:11]5[CH:15]=[CH:14][O:13][CH:12]=5)=[CH:9][NH:8][C:5]4=[N:6][CH:7]=3)=[CH:18][C:19]=2[O:25][CH2:24]1
Reactant: Brc1cnc2[nH]cc(-c3ccoc3)c2c1
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1cc(-c2c[nH]c3ncc(-c4ccc5c(c4)OCO5)cc23)co1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.4 %

Procedure:
Bromide 14 (17.6 mg, 0.07 mmol), 3,4-(methylenedioxy)phenylboronic acid (16.7 mg, 0.10 mmol), LiCl (8.4 mg, 0.20 mmol), PdCl2(Ph3P)2 (4.6 mg, 0.007 mmol) in 1 M aqueous Na2CO3 (0.17 mL, 0.17 mmol), PhMe (1.5 mL) and EtOH (1.5 mL) was heated at 105° C. After 5 h the mixture was allowed to cool to r.t. and then purified by PTLC with AcOEt:hexane=1:1 as eluent to afford azaindole 15 (15.2 mg, 76%) as a white solid. 1H NMR (400 MHz; CDCl3) δ 6.04 (s, 2H), 6.72 (dd, J=0.8 and 1.8 Hz, 1H), 6.94 (dd, J=7.9, 0.3 Hz, 1H), 7.08-7.12 (m, 2H), 7.48 (d, J=2.3 Hz, 1H), 7.54 (t, J=1.6 Hz, 1H), 7.82 (t, J=1.1 Hz, 1H), 8.15 (d, J=2.1 Hz, 1H), 8.52 (d, J=2.1 Hz, 1H), 9.61 (brs, NH).
Reaction SMILES: [OH:1][CH:2]1[CH:19]([CH2:20][CH2:21][CH:22]([O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:5]2[CH2:6][C:7]3[C:12]([CH2:13][CH:4]2[CH2:3]1)=[C:11]([O:14][CH2:15][C:16]([OH:18])=[O:17])[CH:10]=[CH:9][CH:8]=3.[CH2:35](O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl.COC(C)(C)C>[CH2:35]([O:17][C:16](=[O:18])[CH2:15][O:14][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][CH:4]1[CH2:3][CH:2]([OH:1])[CH:19]([CH2:20][CH2:21][CH:22]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:5]1[CH2:6]2)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCCCCC(CCC1C(O)CC2Cc3c(cccc3OCC(=O)O)CC21)OC1CCCCO1
Reactant: OCc1ccccc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CCCCCC(CCC1C(O)CC2Cc3c(cccc3OCC(=O)OCc3ccccc3)CC21)OC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of {2-hydroxy-1-[3-(tetrahydropyran-2-yloxy)octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy}acetic acid (Compound B) (2 g, 4.21 mmol), benzyl alcohol (2.47 g, 22.9 mmol) and triethylamine (7.2 g, 71.3 mmol) in dichloromethane (DCM) (20 mL) was treated with bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP—Cl) (7.8 g, 30.7 mmol) at 0° C. and stirred at room temperature (RT) for 2 hr. The reaction mixture was diluted with methyl-tert-butyl ether (MTBE) and washed with water and then brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography to provide Compound C. MS: m/z 587 [M+Na]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]([OH:27])[CH2:25][OH:26])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[N:11](COCC[Si](C)(C)C)[N:10]=1.FC(F)(F)C(O)=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]([OH:27])[CH2:25][OH:26])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[NH:11][N:10]=1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(O)CO)c3)cc12
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(O)CO)c3)cc12
Yield: 12.5 %

Procedure:
1-{3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-ethane-1,2-diol (114 mg, 0.232 mmol) was treated with 2 mL trifluoroacetic acid for 5 h. The solution was concentrated and co-evaporated with tetrahydrofuran (2×), then dissolved in ethyl acetate, washed with saturated sodium bicarbonate (1×), brine (1×), and dried over sodium sulfate. The material was purified by preparative HPLC and shown to contain hydroxymethyl attached to the product (28 mg). Therefore, the material was treated with 100 mg PS-trisamine (Argonaut Technologies, Inc.) in tetrahydrofuran at 50° C. for 15 h., filtered and the resin was washed with tetrahydrofuran/methanol and concentrated to afford 1-{3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-ethane-1,2-diol (10.5 mg, 12.5%). 1H-NMR (500 MHz, dimethylsulfoxide-d6) δ 3.45 (t, J=6.0 Hz, 2H), 3.79 (s, 3H), 4.56 (q, J=5 Hz, 1H), 4.67 (t, J=6 Hz, 1H), 5.23 (d, J=4 Hz, 1H), 7.03 (t, J=7.0 Hz, 1H), 7.15 (d, J=8 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.37 (t, J=7.5 Hz, 1H), 7.40 (t, J=8.5 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.58 (dd, J=7.5 Hz, J=2.0 Hz, 1H), 7.62 (s, 1H), 8.24 (d, J=2.5 Hz, 1H), 8.75 (d, J=2.5 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-])=O)=[C:6]([S:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:10])=[O:9])[CH:7]=1.[H][H]>CO.[Pd]>[NH2:16][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][C:6]=1[S:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:10])=[O:9]
Reactant: [H][H]
Reactant: COC(=O)CS(=O)(=O)c1cc(C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CS(=O)(=O)c1cc(C)ccc1N
Yield: 98.8 %

Procedure:
Palladium (10%) on carbon is added to a solution of methyl ((5-methyl-2-nitro-phenyl)sulfonyl)acetate (Preparation 37, 2.0 g) in MeOH (60 mL) and the solution is shaken on a Parr apparatus under 30 psi of hydrogen. After 3 hours the solution is filtered through Celite and the filter cake eluted with MeOH (60 mL). The combined MeOH eluant is evaporated and the remaining residue placed under high vacuum overnight to obtain 1.76 g (99%) of the title compound as a dark solid. Physical characteristics: MS (ESI+) m/z 244 (M+H).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(C(C)=O)C(C)C.O>[C:19]1([CH2:18][N:3]2[CH2:4][CH2:5][S:1][C:2]2=[O:6])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1NCCS1
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=C1SCCN1Cc1ccccc1
Yield: 55.2 %

Procedure:
A mixture containing 3.09 g (0.03 mol) of 2-thiazolidinone, 11.2 g of potassium carbonate, 1.8 g of potassium hydrogen carbonate, 0.5 ml of water, 30 ml of methyl isobutyl ketone and 3.0 ml (0.033 mol) of benzyl bromide is refluxed for 7 hours. After cooling down, the reaction mixture is washed twice with 30 ml of water each, the organic phase is dried and evaporated. The yellow oily product (which solidifies on standing) may be purified by column chromatography (by using Kieselgel 60 of 230-400 mesh as sorbent and chloroform as eluent) to give 3.2 g (55.2%) of the title compound, m.p.: 50°-51° C.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:4][C@H:3]1[NH:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:26][CH:25]=1)=[O:22].[H-].[Na+].Br[CH2:40][C:41]([C:43]([CH3:46])([CH3:45])[CH3:44])=[O:42]>CN(C)C=O>[C:43]([C:41]([CH2:40][N:8]1[C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:4][C@@H:3]([NH:20][C:21]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][CH:29]=2)=[O:22])[C:2]1=[O:1])=[O:42])([CH3:46])([CH3:45])[CH3:44]
Reactant: Cc1ccc2c(c1)NC(=O)[C@H](NC(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)CN2C1CCCCC1
Reactant: CC(C)(C)C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)[C@H](NC(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)CN2C1CCCCC1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 33.4 %

Procedure:
(R)-1-(2-oxo-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(4-tert-butoxycarbonylphenyl)urea (500 mg) was dissolved in N,N-dimethylformamide (5 ml), the solution was cooled to internal temperature 5° C. Under argon atmosphere, 60% sodium hydride (49 mg) was added, the mixture was stirred at internal temperature 5° C. for 30 minutes. Bromomethyl tert-butylketone (218 mg) was added thereto, stirred at internal temperature 5° C. for one hour. The reaction mixture was poured into ice-water, extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform), to thereby obtain 200 mg of the title compound.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH:5]1([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=2[CH:17]=[O:18])[CH2:7][CH2:6]1>C1COCC1>[CH:5]1([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=2[CH:17]([OH:18])[CH2:1][CH3:2])[CH2:6][CH2:7]1
Reactant: O=Cc1cc(C(=O)O)ccc1C1CC1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1cc(C(=O)O)ccc1C1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.9 %

Procedure:
Into a 250-mL 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen and containing THF (60 mL), was placed a solution of ethylmagnesium bromide (3 M in diethyl ether) (24.6 mL, 73.8 mmol). A solution of 4-cyclopropyl-3-formylbenzoic acid (compound 10.4, 3.5 g, 18.4 mmol) in THF (40 mL) was added drop-wise at room temperature over 45 min. The resulting mixture was stirred for 1.5 h at room temperature, then carefully quenched with water/ice (50 mL). The mixture was diluted with EtOAc (100 mL) and the organic layer was washed with aqueous NH4Cl (sat., 2×100 mL) and the aqueous layers combined. The pH of the aqueous phase was adjusted to 3-4 with aqueous hydrogen chloride (2 M) and extracted with ethyl acetate (2×150 mL). The combined organic extracts were washed with brine (30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate:PE (1:10-2:1) as the eluent to yield 3.4 g (84%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[CH3:11][C:12]1[CH:17]=[C:16](B(O)O)[CH:15]=[CH:14][N:13]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[F:10][C:4]1[CH:3]=[C:2]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([CH3:11])[CH:17]=2)[C:8]([CH3:9])=[CH:7][C:5]=1[NH2:6]
Reactant: Cc1cc(N)c(F)cc1Br
Reactant: Cc1cc(B(O)O)ccn1
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: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(-c2cc(F)c(N)cc2C)ccn1
Temperature: 25 °C

Procedure:
To a round bottom flask charged with 4-bromo-2-fluoro-5-methylaniline 191-1 (2.04 g, 10 mmol), 2-methylpyridin-4-ylboronic acid 191-2 (1.37 g, 10 mmol) and Pd(PPh3)4 (0.4 g, 0.35 mmol) was added toluene (30 mL), ethanol (10 mL) and saturated sodium carbonate (10 mL). The flask was flushed with nitrogen and the reaction was heated to reflux for 10 hours. After the reaction was cooled down to room temperature, it was partitioned between ethyl acetate and saturated NaHCO3 and the organic phase was washed with brine and dried over Na2SO4. The solvent was removed by rotary evaporation and the residue was purified by silica gel flash chromatography, eluted with 50% ethyl acetate in hexane to give 2-fluoro-5-methyl-4-(2-methylpyridin-4-yl)aniline 191-3. MS m/z 217.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.N1C=CN=C1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19].CCCCCC>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
200 g 6-bromonaphthalen-2-ol, 143 g imidazole and 151 g tert.-butylchlorodimethylsilane were dissolved in 1,000 ml dimethylformamide, stirred for two hours at ambient temperature, the solution largely concentrated (506 g), the residue dissolved in ethyl acetate and water, 1,500 ml saturated sodium chloride solution added, the phases separated, the aqueous phase extracted twice with ethyl acetate and the organic phases combined and concentrated. The crude product obtained was dissolved in boiling hexane and subsequently kept overnight at 4° C. After filtration, 158 g (6-bromonaphthalen-2-yloxy)-tert.-butyldimethylsilane were isolated. Repeated concentration of the mother liquor and recrystallisation from methanol yielded a further 54 g (6-bromonaphthalen-2-yloxy)-tert.-butyldimethylsilane.
Reaction SMILES: CO[CH:3]=[CH:4][C:5](=[O:7])[CH3:6].[F:8][C:9]([F:19])([F:18])[C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][NH2:14]>>[F:8][C:9]([F:18])([F:19])[C:10]1[CH:11]=[C:12]([CH2:13][NH:14][CH:3]=[CH:4][C:5](=[O:7])[CH3:6])[CH:15]=[CH:16][CH:17]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: COC=CC(C)=O
Product: CC(=O)C=CNCc1cccc(C(F)(F)F)c1

Procedure:
The title compound 66 is prepared according to the procedure reported in step A of Example 18 with 4-methoxy-3-buten-2-one (0.2 g, 2 mmol) and 3-trifluoromethylbenzylamine (0.35 g, 2 mmol) as reactants. Yellow oil. (Yield 0.48 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:12](O)[CH2:13][OH:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:7]2[O:14][CH2:13][CH2:12][O:8]2)[CH:9]=1
Reactant: COc1ccc(Br)cc1C=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(Br)cc1C1OCCO1
Yield: 62.3 %

Procedure:
To a stirred solution of 5-bromo-2-methoxybenzaldehyde (5.0 g, 23.25 mmol) in toluene (50 mL) was added ethylene glycol (2.6 mL, 46.5 mmol) and p-toluenesulfonic acid monohydrate (0.45 g, 2.32 mmol) and the reaction mixture was azeotroped for 2 h, quenched with sat. NaHCO3 (50 mL). Reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate (2×100 mL), washed with water, brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography to furnish 2-(5-bromo-2-methoxy-phenyl)-[1,3]dioxolane (3.75 g).
Reaction SMILES: O.S([O-])([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]C)(=O)=O.[Na+].[CH2:20]=[C:21]1[CH2:26][CH2:25][O:24][C:22]1=[O:23].C=CC1C=CC=CC=1.C(O)(=[O:38])C=C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[OH-].[Na+]>>[CH2:20]=[C:21]1[CH2:26][CH2:25][O:24][C:22]1=[O:23].[CH:9]([CH:8]=[CH:7][C:6]([OH:5])=[O:38])=[CH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Reactant: C=CC(=O)O
Agent: C=C1CCOC1=O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C=Cc1ccccc1
Product: O=C(O)C=CC=Cc1ccccc1
Temperature: 73 °C
Reaction time: 1 h

Procedure:
To a 100 mL round bottom flask equipped with a magnetic stir bar was added 8.825 g (0.490 mol) water and 0.117 g (4.06×10−4 mol) sodium dodecyl sulfate (20% aqueous solution). The mixture was heated under flowing nitrogen to 73° C., at which time a monomer mixture consisting of 3.079 g (3.14×10−2 mol) α-methylene-γ-butyrolactone, 1.082 g styrene (1.04×10−2 mol) and 0.220 g (3.66×10−3 mol) acrylic acid was added via syringe pump over 130 minutes. After 10 minutes of monomer mixture addition, an aqueous mixture consisting of 16.694 g (0.927 mol) water, 0.269 g (9.33×10−4 mol) sodium dodecyl sulfate (20% aqueous solution), 0.033 g (1.39×10−4 mol) sodium persulfate, and 0.041 g of a 20% aqueous sodium hydroxide solution was added via syringe pump over 130 minutes. After both the monomer and aqueous mixtures were added completely, the emulsion was allowed to stir for an additional 60 minutes, after which the reaction was cooled to room temperature and dried under vacuum under vacuum at 90° C. overnight. Size exclusion chromatography yielded a monomodal peak with a weight average molecular weight of 104 kDa and a polydispersity of 1.96, relative to polystyrene standards. Differential scanning calorimetry showed a single first order transition at approximately 167° C.
Reaction SMILES: [NH2:1][C:2]([CH2:7][CH3:8])([CH2:5][CH3:6])[C:3]#[CH:4].[F:9][C:10]1[C:11](I)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[NH2:1][C:2]([CH2:7][CH3:8])([CH2:5][CH3:6])[C:3]#[C:4][C:11]1[C:10]([F:9])=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:20]/[C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26])/[C:14](=[O:19])[NH:15]2
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CC(N)(CC)CC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(N)(C#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2)CC

Procedure:
Using Method C above, 3-amino-3-ethyl-1-pentyne (37.6 mg, 0.34 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (50 mg, 0.135 mmol) using (Ph3P)4Pd (16 mg) and CuI (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 h to give (Z)-4-[3-amino-3-ethyl-1-pentynyl]-1,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 45 mg, 95%).