Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:16][C@@H:17]1[O:19][CH2:18]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C([O-])(=O)C.[NH4+].S(C1C=CC([N+]([O-])=O)=CC=1)(OCC1OC1)(=O)=O>C(#N)C.CN(C)C=O>[N:7]1[C:8]2[C:3](=[C:2]([O:1][CH2:16][C@@H:17]3[O:19][CH2:18]3)[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: Oc1cccc2ncccc12
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc(S(=O)(=O)OCC2CO2)cc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: c1cc(OC[C@H]2CO2)c2cccnc2c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
A mixture of 5-hydroxyquinoline (5.60 g, 38.6 mmol), (R)-glycidyl nosylate (10.0 g, 38.6 mmol), powdered potassium carbonate (11.7 g, 84.9 mmol), and N,N-dimethylformamide (100 mL) was stirred at ambient temperature until HPLC analysis (40% acetonitrile/60% of a 0.5% aqueous ammonium acetate solution, 1 mL/min, 1=230 nm, Zorbax RX-C8 25 cm×4.6 mm column) indicated complete disappearance of glycidyl nosylate (approximately 6 hours). The reaction mixture was filtered through paper and the filter cake was washed with 200 mL of a 3:1 mixture of MTBE and methylene chloride. The filtrate was washed with 200 mL of water and the aqueous layer was extracted four times with 100 mL of 3:1 MTBE/methylene chloride. The combined organic layers were dried over 30 grams of magnesium sulfate and the dried solution was then stirred with 50 grams of basic alumina for 30 minutes. The alumina was removed by filtration and the filter cake was washed with 200 mL of 3:1 MTBE/methylene chloride. The filtrate was concentrated to a volume of 100 mL. 300 mL of MTBE was added, and the solution was again concentrated to 80 mL. After heating to 50° C., the solution was treated with 160 mL of heptane drop-wise over 15 minutes, allowed to cool to 40° C., and seeded, causing the formation of a crystalline precipitate. The mixture was stirred for two hours at ambient temperature and then at 0-5° C. for an additional 2 hours. The crystals were filtered, washed with cold heptane, and dried to provide 5.68 g (73.2%) of (2R)-1-(5-quinolinyloxy)-2,3-epoxypropane as white needles.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](Cl)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[C:25]([Cl:27])[N:24]=[CH:23][N:22]=1>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:18])[NH:20][C:21]2[CH:26]=[C:25]([Cl:27])[N:24]=[CH:23][N:22]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Nc1cc(Cl)ncn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cc(Cl)ncn1)C1CCN(C(=O)OCc2ccccc2)CC1
Yield: 97.2 %

Procedure:
A mixture of 4-chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (VII) (5.70 g, 20.2 mmol), 4-amino-6-chloropyrimidine (I) (2.10 g, 16.2 mmol) and 4-(N,N-dimethylamino)-pyridine (2.90 g, 23.7 mmol) in dichloromethane (50 ml) was heated to reflux temperature for 18 hours. The progress of the reaction was monitored by TLC, then dichloromethane was completely distilled off. Aqueous sodium bicarbonate solution was added to the residue and the mixture was extracted with ethyl acetate (3×100 ml). The organic layers were separated, dried over sodium sulfate and concentrated to obtain 4-(6-chloro-pyrimidin-4-ylcarbamoyl)-piperidine-1-carboxylic acid benzyl ester (VIII) (5.9 g, 79%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH2:4]Cl.[NH2:12][C:13]1[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][N:14]=1>[OH-].[Na+].ClCCl.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[NH2:12][C:13]1[C:18]([O:19][CH2:4][C:3]2[C:2]([CH3:1])=[CH:9][C:8]([CH3:10])=[CH:7][C:6]=2[CH3:11])=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: Nc1ncccc1O
Reactant: Cc1cc(C)c(CCl)c(C)c1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C)c(COc2cccnc2N)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.5 %

Procedure:
A mixture of 2,4,6-trimethylbenzyl chloride (50 g, 0.296 mol) and 2-amino-3hydroxypyridine (29.6 g, 0.269 mol) in 40% aqueous sodium hydroxide solution (200 ml) and dichloromethane (200 ml) was treated with Adogen 464 (5 ml) and stirred vigorously at room temperature for 16 hours. The product was extracted into dichloromethane and purified by flash chromatography (silica, chloroform) to yield a solid (10.1 g, 14%), m.p. 160°-166° C.
Reaction SMILES: [C:1]([O:5][CH:6]([CH3:17])[CH2:7][CH2:8][CH2:9][CH:10]1[O:15][CH:14]([OH:16])[CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[CH:18]([Mg]Cl)=[CH2:19].CCOCC.[Cl-].[NH4+]>O1CCCC1>[OH:16][CH:14]([CH2:13][CH2:12][CH2:11][CH:10]([OH:15])[CH2:9][CH2:8][CH2:7][CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:17])[CH:18]=[CH2:19]
Reactant: C=C[Mg]Cl
Reactant: CC(CCCC1CCCC(O)O1)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(O)CCCC(O)CCCC(C)OC(C)(C)C

Procedure:
4.5 G. of 6-[4-tertiarybutoxypentyl]-2-tetrahydropyranol produced in Example 120 was dissolved in 200 ml. of tetrahydrofuran and added slowly over a 20 minute period to a solution of 300 ml. of vinyl magnesium chloride in tetrahydrofuran at 0°. After agitation for an additional hour at room temperature, 200 ml. of ether was added which was followed by the addition of 100 ml. of a 20 per cent aqueous solution of ammonium chloride. Extraction with ether yielded a waxy solid, 3,7-dihydroxy-11-tertiarybutoxydodec-1-ene.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:15][C:16]2[N:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][N:17]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:29](I)[CH3:30].O>CN(C=O)C>[CH2:29]([N:15]([C:16]1[N:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][N:17]=1)[C:7]1[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=1)[CH3:30]
Reactant: CCOC(=O)c1cnc(Nc2cc(C(C)(C)C)cc(C(C)(C)C)c2)nc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc(N(CC)c2cc(C(C)(C)C)cc(C(C)(C)C)c2)nc1
Yield: 99 %

Procedure:
Ethyl 2-[N-(3,5-di-tert-butylphenyl)amino]pyrimidine-5-carboxylate (50 mg) was dissolved in dry DMF (2 ml), and the solution was added with a suspension of NaH (45 mg) in DMF (1 ml). The mixture was then added with ethyl iodide (0.3 ml) and stirred. After the disappearance of the materials was observed with TLC, the reaction mixture was poured into water, and extracted with CH2Cl2. The organic layer was dried over Na2SO4, and the solvent was evaporated. The residue was purified by silica gel flash column chromatography (n-hexane: AcOEt=10:1) to obtain white crystals of ethyl 2-[N-ethyl-N-(3,5-di-tert-butylphenyl)amino]pyrimidine-5-carboxylate (53 mg, 99%).
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](SC2C=CC(S(O)(=O)=O)=CC=2)=[CH:4][C:3]=1OC1C=CC(S(O)(=O)=O)=C(N)C=1.N1C(Cl)=NC(Cl)=NC=1Cl.NC1C=C(S(O)(=O)=O)C=CC=1.[Cl-].[Na+]>>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cc(Oc2cc(Sc3ccc(S(=O)(=O)O)cc3)c3c(c2N)C(=O)c2ccccc2C3=O)ccc1S(=O)(=O)O
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: Nc1cccc(S(=O)(=O)O)c1
Agent: [Cl-]
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
1-Amino-2-(3'-amino-4'-sulfophenoxy)-4-(4'-sulfophenylthio)anthraquinone (6 parts) and cyanuric chloride (1.8 parts) were subjected a to condensation reaction in an aqueous medium in a conventional manner, followed by a condensation reaction with 3-aminobenzenesulfonic acid (1.7 parts) at 20° to 40° C. under a weak acid condition. Thereafter, salting out of the reaction mixture with sodium chloride gave an anthraquinone compound of the following formula (free acid form). ##STR215##
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:20])[CH2:16][C:17](N)=[O:18])=[CH:11][CH:10]=1.Cl.C(O)(=[O:24])C>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:20])[CH2:16][C:17]([OH:24])=[O:18])=[CH:11][CH:10]=1
Reactant: CC(=O)O
Reactant: CC(CC(N)=O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: Cl
Solvent: O
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
A mixture of 1 g. of 3-(2',4'-difluoro-4-biphenylyl)butyramide, 2 ml. of concentrated hydrochloric acid and 2 ml. of acetic acid is heated under reflux for 48 hours and, after addition of water, is worked up in the customary manner to give 3-(2',4'difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[C:23]([N:27]=[C:28]=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(CC)CC)C>C1COCC1>[C:23]([NH:27][C:28]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)N=C=O
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 40 °C
Yield: 33.4 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.00 g, 3.10 mmol) and t-butylisocyanate (0.31 g, 3.10 mmol) in THF (35 mL), was added triethylamine (0.88 mL, 6.20 mmol) at room temperature under nitrogen. The mixture was heated to 40° C. for 18 h then cooled to rt. The mixture was filtered and the filtrate diluted with EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (100 mL), water (2×100 mL), dried (MgSO4) and concentrated. The crude product was purified by prep-HPLC (35/65 CH3CN/H2O). The product fractions were combined, concentrated and dried in vacuo to give 1-tert-butyl-3-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.40 g, 84% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 4.89 min (97.00%); mp: 202-204° C.; 1H NMR (DMSO-d6) δ 1.24 (s, 9H), 1.97-2.14 (m, 1H), 2.53-2.71 (m, 2H), 2.79-3.02 (m, 1H), 4.34 (d, J=5.9 Hz, 2H), 5.14 (dd, J=5.4, 12.9 Hz, 1H), 5.89 (s, 1H), 6.34 (t, J=6.0 Hz, 1H), 7.65-7.79 (m, 2H), 7.87 (d, J=7.7 Hz, 1H), 11.08 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 29.2, 30.9, 42.3, 48.9, 49.2, 121.4, 123.4, 129.5, 131.5, 133.0, 149.6, 157.3, 167.0, 167.2, 169.8, 172.7; Anal Calcd for C19H22N4O5+0.3H2O: C, 58.24; H, 5.81; N, 14.30. Found: C, 58.15; H, 5.52; N, 14.16.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[C:17]3[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=3[O:15][N:14]=2)[CH2:9][CH2:8]1)(=O)C.[OH-].[Na+].Cl.[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30]>C(O)C>[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[F:22][C:20]1[CH:19]=[CH:18][C:17]2[C:13]([CH:10]3[CH2:11][CH2:12][N:7]([CH2:6][CH2:5][OH:4])[CH2:8][CH2:9]3)=[N:14][O:15][C:16]=2[CH:21]=1.[F:22][C:20]1[CH:19]=[CH:18][C:17]2[C:13]([CH:10]3[CH2:11][CH2:12][N:7]([CH2:6][CH2:5][OH:4])[CH2:8][CH2:9]3)=[N:14][O:15][C:16]=2[CH:21]=1
Reactant: CC(=O)OCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CCO
Product: OCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl acetate (10.58 g, 34.6 mmol), 15% NaOH (100 ml) and ethanol (100 ml) was heated at reflux for 4 hours. The solution was cooled (~5° C.) and neutralized with HCl to pH~7. The ethanol was removed under reduced pressure. The aqueous solution was basified with NaHCO3 and extracted with DCM (2×200 ml). The DCM solution was washed with brine and dried over MgSO4 and evaporated to give a white solid: 6.88 g (75%). A sample (2.03 g) was dissolved in ethanol and treated with fumaric acid (660 mg, 1.0 eq). Crystallization was induced with drops of isopropyl ether to yield off-white crystals: 1.43 g, m.p.=159°-161° C. ANALYSIS: Calculated for C14H17FN2O2.0.5C4H4O4 : 59.62%C 5.94%H 8.69%N Found: 59.55%C 5.95%H 8.53%N
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)=[CH:16][C:15]([O:26]CC1C=CC=CC=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.C(O)C.[C].[Pd]>[C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:37])[CH3:38])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)=[CH:16][C:15]([OH:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccc(F)c2)c2cc(OCc3ccccc3)ccc2c1=O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccc(F)c2)c2cc(O)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A suspension of tert-butyl[6-benzyloxy-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (3.18 g, 6 mmol) and 5% palladium carbon (1.0 g) in tetrahydrofuran (20 mL) and ethanol (20 mL) was stirred, under a hydrogen atmosphere at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-n-hexane to give tert-butyl[4-(3-fluorophenyl)-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (2.54 g, 96.2%) as crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]([CH:13]2[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[CH:4][CH:3]=1.[F:16][C:17]([F:38])([F:37])[C:18]1[CH:19]=[C:20]([C:28]2([C:33]([F:36])([F:35])[F:34])[CH2:32][CH2:31][NH:30][CH2:29]2)[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(OCC)(=O)C>[F:26][C:24]([F:25])([F:27])[C:22]1[CH:21]=[C:20]([C:28]2([C:33]([F:36])([F:34])[F:35])[CH2:32][CH2:31][N:30]([C:2]3[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]([CH:13]4[CH2:15][CH2:14]4)=[O:12])[CH3:9])=[CH:4][CH:3]=3)[CH2:29]2)[CH:19]=[C:18]([C:17]([F:16])([F:37])[F:38])[CH:23]=1
Reactant: FC(F)(F)c1cc(C(F)(F)F)cc(C2(C(F)(F)F)CCNC2)c1
Reactant: C[C@H](NC(=O)C1CC1)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@H](NC(=O)C1CC1)c1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1
Yield: 100 %

Procedure:
To a reaction vessel, N-[(1S)-1-(4-bromophenyl)ethyl]cyclopropanecarboxamide (134 mg), 3-[3,5-bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidine (211 mg), sodium t-butoxide (96 mg), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (10 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (18 mg) and toluene (6 ml) were added, and reacted in a microwave reactor (Initiator™, manufactured by Biotage) for 10 minutes at 120° C. Upon the completion of the reaction, ethyl acetate was added and the precipitates were filtered by using silica gel. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain N-[(1S)-1-(4-{3-[3,5-bis-(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}phenyl)ethyl]cyclopropanecarboxamide (269 mg). 1H-NMR (CDCl3) as given in Table 2
Reaction SMILES: IC.[CH3:3][C:4]([C:7]1[CH:8]=[C:9]([CH:18]=[C:19]2[NH:23][C:22](=[S:24])[NH:21][C:20]2=[O:25])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:6])[CH3:5].[CH:26](N(C(C)C)CC)(C)C.O>C(O)C>[CH3:17][C:14]([C:11]1[CH:10]=[C:9]([CH:18]=[C:19]2[NH:23][C:22]([S:24][CH3:26])=[N:21][C:20]2=[O:25])[CH:8]=[C:7]([C:4]([CH3:3])([CH3:5])[CH3:6])[C:12]=1[OH:13])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1cc(C=C2NC(=S)NC2=O)cc(C(C)(C)C)c1O
Reactant: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CI
Solvent: CCO
Product: CSC1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)N1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
Iodomethane (0.5 mL, 8 mmols) is added to a stirred suspension of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2-thioxo-4-imidazolidinone (2.5 g, 7.5 mmols) and diisopropylethylamine (1.35 mL, 7.7 mmols) in ethanol (25 mL), and the mixture is stirred under an inert atmosphere at room temperature. After 5 hours the resultant solution is stirred into water (150 ml). After a hour the precipitate is filtered off, rinsed three times with water and dried to afford the 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-1,5-dihydro-2-(methylthio)-4H-imidazol-4-one (2.6 g), mp 248°-249° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][CH2:19]O)=[C:7]([Si:11]([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:12][CH3:13])[NH:8]2)=[CH:4][C:3]=1[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:41]C(Br)(Br)Br>C1COCC1>[Br:41][CH2:19][CH2:18][C:6]1[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[C:3]([CH3:21])[CH:4]=2)[NH:8][C:7]=1[Si:11]([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:12][CH3:13]
Reactant: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(C)cc2c1CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(C)cc2c1CCBr
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
A solution of 2-(6-chloro-5-methyl-2-(triethylsilyl)-1H-indol-3-yl)ethanol (1.44 g; 4.45 mmol) in THF (6 mL) was added to a solution of triphenylphosphine (1.75 g; 6.67 mmol) and perbromomethane (2.21 g; 6.67 mmol) in THF (40 mL) pre-stirred for 30 minutes. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was then filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane) to afford 0.725 g (42%) of the title compound as a brown oil.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]#[CH:14])(OC(C)(C)C)=O.[C:15]([C:18]1[CH:19]=[C:20](/[CH:23]=[C:24]2\[C:25](=[O:35])[NH:26][C:27]3[C:32]\2=[C:31](I)[C:30]([F:34])=[CH:29][CH:28]=3)[NH:21][CH:22]=1)(=[O:17])[CH3:16].O>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.FC(F)(F)C(O)=O.C(Cl)Cl.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:15]([C:18]1[CH:19]=[C:20](/[CH:23]=[C:24]2\[C:25](=[O:35])[NH:26][C:27]3[C:32]\2=[C:31]([C:14]#[C:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[C:30]([F:34])=[CH:29][CH:28]=3)[NH:21][CH:22]=1)(=[O:17])[CH3:16]
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1
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
Solvent: O
Product: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(C#C[C@@H]4CCCN4)c32)c1
Reaction time: 2 h

Procedure:
Using Method C above, (S)-N-Boc-2-Ethynyl-pyrrolidine (220 mg, 1.13 mmol) (Example 87B) was coupled with (Z)-3-[(4-acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (150 mg, 0.38 mmol) (Example 90B) using (Ph3P)4Pd (44 mg, 0.04 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 7 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated and the residue was chromatographed on a silica gel column with a 0-5% MeOH in CH2Cl2 gradient. The intermediate that resulted from this process was dissolved in 6 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.3 mL of H2O at 0° C. and stirred for 2 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. The (S)-(Z)-3-[(4-Acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-[(pyrrolidin-2-yl)ethynyl]-2H-indol-2-one was obtained after silica gel column with a 0-10% MeOH in CH2Cl2 gradient and precipitation out of THF with excess of pentane. (Yield 56 mg, 41%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][C:18]=1B1OC(C)(C)C(C)(C)O1>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:21][C:22]=1[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: COC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: FC(F)(F)c1cc(Br)c2cn[nH]c2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: COC(=O)Cc1ccc(OC)c(-c2cc(C(F)(F)F)cc3[nH]ncc23)c1
Temperature: 140 °C
Yield: 79 %

Procedure:
A vial was charged with a mixture of 4-bromo-6-(trifluoromethyl)-1H-indazole (0.433 g, 1.633 mmol), methyl 2-(4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (0.5 g, 1.633 mmol) and PdCl2(dppf) (0.060 g, 0.082 mmol) in dioxane (10 mL) and aqueous saturated NaHCO3 (3 mL). The resulting light brown suspension was heated at 140° C. for 45 minutes in a microwave reactor. The reaction mixture was subsequently concentrated. The crude residue was dissolved in EtOAc and was washed with water and brine, concentrated, and purified by CombiFlash® chromatography (0-35% MeOH in DCM). The product-containing fractions were combined and concentrated by rotary evaporation to give the title compound (0.47 g, 79%). ESI-MS m/z [M+H]+ calc'd for C18H15F3N2O3, 365.1. found 365.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:14][C:15]([F:18])([F:17])[F:16].[NH2:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]2[N:26]([CH2:34][C:35](O)=[O:36])[N:27]=[C:28]([C:29]3[NH:30][CH:31]=[CH:32][N:33]=3)[C:21]=12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[NH2:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]2[N:26]([CH2:34][C:35]([N:11]3[CH2:12][CH2:13][N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:14][C:15]([F:18])([F:16])[F:17])[CH:4]=4)[CH2:9][CH2:10]3)=[O:36])[N:27]=[C:28]([C:29]3[NH:33][CH:32]=[CH:31][N:30]=3)[C:21]=12
Reactant: Nc1ncnc2c1c(-c1ncc[nH]1)nn2CC(=O)O
Reactant: FC(F)(F)Oc1cc(N2CCNCC2)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnc2c1c(-c1ncc[nH]1)nn2CC(=O)N1CCN(c2ccc(Cl)c(OC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(4-chloro-3-trifluoromethoxyphenyl)piperazine didydrochloride salt (70 mg, 0.198 mmol, 1 equiv), [4-amino-3-(1H-imidazol-2-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]acetic acid (96 mg, 1 equiv), HATU (98 mg, 1.3 equiv) and N,N-diisopropylethylamine (0.276 mL, 8 equiv) in DMF (0.5 mL) was stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, and purified by TLC to give 2-[4-amino-3-(1H-imidazol-2-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-1-[4-(4-chloro-3-trifluoromethoxyphenyl)piperazin-1-yl]ethanone. 1H NMR (400 MHz, CD3OD) δ 8.18 (s, 1H), 7.39 (s, 1H,), 7.18 (d, 2H, J=8.8 Hz), 6.95 (s, 2H), 5.40 (s, 2H), 3.85 (m, 4H), 3.25 (m, 4H). The three remaining protons (from the amino group and the imidazole ring) were not observed due to the use of CD3OD as solvent. MS (ES) m/z 522.1 (M+H+).