Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:7][C:8]1[CH:32]=[CH:31][C:11]([C:12]([NH:14][CH2:15][C@H:16]([N:21]2[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[C:17]([O:19]C)=[O:18])=[O:13])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6]>O1CCCC1.O>[CH2:3]([O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:14][CH2:15][C@H:16]([N:21]2[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[C:17]([OH:19])=[O:18])=[O:13])=[CH:31][CH:32]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCOc1ccc(C(=O)NC[C@@H](C(=O)OC)N2CCN(S(C)(=O)=O)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC#CCOc1ccc(C(=O)NC[C@@H](C(=O)O)N2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.8 %

Procedure:
2.1 ml (2.1 mmol) of an aqueous solution of lithium hydroxide having a concentration of 1N are added to a solution of 610 mg (1.4 mmol) of methyl (S)-3-(4-but-2-ynyloxybenzoylamino)-2-(4-methanesulphonylpiperazin-1-yl)propanoate in 12 ml of tetrahydrofuran and 2 ml of water. The reaction medium is stirred at ambient temperature for 18 h then the solvents are concentrated under vacuum. The mixture is brought to pH=6 by addition of 2.5 ml of an aqueous solution of hydrochloric acid having a concentration of 1N. The solid which precipitates is filtered, rinsed with water then with diethyl ether, and dried under vacuum. 420 mg (72%) of (S)-3-(4-but-2-ynyloxybenzoylamino)-2-(4-methanesulphonylpiperazin-1-yl)propanoic acid are obtained in the form of a white solid.
Reaction SMILES: I[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:3]=1[CH3:23].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[C:35]([Sn](CCCC)(CCCC)CCCC)=[CH:34][CH:33]=[N:32]2)=[CH:27][CH:26]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]2[C:35]([C:2]3[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5](=[O:12])[N:4]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=4)[C:3]=3[CH3:23])=[CH:34][CH:33]=[N:32]2)=[CH:29][CH:30]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1-c1ccc(Cl)cc1
Reactant: COC(=O)c1nc(I)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1nc(-c2ccnn2-c2ccc(Cl)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Yield: 61.6 %

Procedure:
Methyl 6-iodo-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (SM1, 0.133 g, 0.304 mmol), 1-(4-chlorophenyl)-5-tributylstannyl-1H-pyrazole (0.16 g, 0.33 mmol), bis(triphenylphosphine)palladium(II) chloride (0.011 g, 0.015 mmol) and anhydrous THF (1.5 mL) in a vial were heated three consecutive times (for 55 minutes in total) in a microwave reactor (Biotage) at 130° C. until most of the iodo SM was consumed. The dark solution was concentrated to dryness with silica and applied to a silica column. Flash chromatography with ethyl acetate/n-heptane (1:4 through 2:1) gave methyl 6-[2-(4-chlorophenyl)pyrazol-3-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (0.0915 g, 62%) as an off-white solid.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[OH:6][CH2:7][CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:18])[NH:13]2.O>O1CCCC1.CN(C)C=O>[O:18]=[C:12]1[CH2:11][C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7][O:6][C:4](=[O:5])[NH:3][CH2:1][CH3:2])[NH:13]1
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: CCN=C=O
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCNC(=O)OCCc1cccc2c1CC(=O)N2
Temperature: 80 °C
Yield: 15.9 %

Procedure:
Ethyl isocyanate (0.633 mL, 8 mmol) was added dropwise to a stirred mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (709 mg, 4 mmol) in tetrahydrofuran (8 mL) and dimethylforamide (2 mL) under nitrogen atmosphere. The mixture was heated at 80° C. for 48 hours. The reaction was cooled, poured into water (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on silica gel eluting with ethyl acetate/hexane to give 158 mg (16%) of ethyl-carbamic acid 2-(2-oxo-2,3-dihydro-1H-indol-4-yl)-ethyl ester as a white powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:28])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([C:26]#[N:27])([CH3:25])[CH3:24])[CH:18]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.O>N1C=CC=CC=1>[C:26]([C:23]([C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([NH:1][S:36]([C:33]3[CH:34]=[CH:35][C:30]([CH3:29])=[CH:31][CH:32]=3)(=[O:38])=[O:37])=[CH:3][CH:4]=2)[CH:10]=1)=[O:28])([CH3:24])[CH3:25])#[N:27]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc(N)nc3)c2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)cn2)cc1
Temperature: 80 °C
Yield: 98.5 %

Procedure:
To a solution of N-{3-[(6-aminopyridin-3-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (2.5 g, 6.71 mmol) in pyridine (60 mL) was added 4-methylbenzenesulfonyl chloride (1.34 g, 7.05 mmol) under ice-cooling, and the mixture was 5 stirred with heating at 80° C. for 2 days. After the reaction mixture was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine (300 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (3.48 g, 99%) as a colorless powder. The powder was used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([CH3:9])=[C:6](Cl)[N:7]=1.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[O:27][CH3:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(COC)OC.C(Cl)(Cl)Cl>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[N:4][C:5]=2[CH3:9])=[CH:20][C:19]=1[O:27][CH3:28])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1cc(B(O)O)ccc1OCc1ccccc1
Reactant: Cc1nnc(Cl)nc1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2nc(Cl)nnc2C)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
A degassed solution of 3,5-dichloro-6-methyl-1,2,4-triazine (151 mg, 0.9 mmol), 4-(benzyloxy)-3-methoxybenzene boronic acid (236 g, 0.9 mmol), tetralis(triphenylphosphine)palladium(0) (55 mg, 0.05 mmol) and tripotassium phosphate (249 mg, 1.2 mmol) in dimethoxyethane (5 mL) was heated at reflux for 24 h. Upon cooling to room temperature the solution was diluted with CHCl3 and filtered through Celite®. The filtrate was concentrated in vacuo and the product purified by column chromatography using ethyl acetate-hexane (25:75) as eluent to furnish (75 mg, 22%).
Reaction SMILES: Br[C:2]1[C:7]([CH:8]2[O:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][O:9]2)=[C:6]([O:16][CH2:17][O:18][CH3:19])[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1.[NH2:22][CH2:23][C@@H:24]([OH:35])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1[CH3:34].C(O)CO.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC(O)C.[Cu]I>[CH3:14][C:11]1([CH3:15])[CH2:12][O:13][CH:8]([C:7]2[C:6]([O:16][CH2:17][O:18][CH3:19])=[C:5]([O:20][CH3:21])[CH:4]=[CH:3][C:2]=2[NH:22][CH2:23][C@@H:24]([OH:35])[CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=2[CH3:34])[O:9][CH2:10]1
Reactant: Cc1ccc(OC[C@H](O)CN)c(C)c1
Reactant: COCOc1c(OC)ccc(Br)c1C1OCC(C)(C)CO1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: COCOc1c(OC)ccc(NC[C@@H](O)COc2ccc(C)cc2C)c1C1OCC(C)(C)CO1
Temperature: 90 °C
Yield: 641.3 %

Procedure:
A mixture of 2-(6-bromo-3-methoxy-2-methoxymethoxy-phenyl)-5,5-dimethyl-[1,3]dioxane (36 mg, 0.1 mmol), (R)-1-amino-3-(2,4-dimethyl-phenoxy)-propan-2-ol (30 mg, 0.15 mmol), CuI (51.4 mg, 0.27 mmol), ethylene glycol (168 mg, 2.7 mmol), and K3PO4 (573 mg, 2.7 mmol) in 2-propanol (8 mL) was heated at 90° C. in a sealed vial for 14 h and evaporated. Chromatography of the residue with hexanes and EtOAc afforded the title compound (305 mg, 71%). 1H NMR (CDCl3) δ 0.79 (s, 3H, CH3), 1.29 (s, 3H, CH3), 2.21 (s, 3H, CH3), 2.25 (s, 3H, CH3), 2.95 (br s, 1H, OH), 3.30 (m, 1H), 3.49 (s, 3H, OCH3), 3.51 (m, 1H), 3.65 (m, 2H), 3.75 (s, 3H, OCH3), 3.77 (m, 2H), 4.00 (m, 2H), 4.25 (m, 1H), 5.09 (s, 2H), 6.05 (s, 1H), 6.48 (d, J=8 Hz, 1H), 6.69 (d, J=8 Hz, H), 6.82 (d, J=8 Hz, 1H), 6.92 (d, J=8 Hz, 1H), 6.95 (s, 1H). ESI-MS m/z 476.8 (MH+).
Reaction SMILES: N1C=CC=CC=1C(O)=O.[NH2:10][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:15][CH:14]=[CH:13][N:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[C:35]([CH3:40])[CH:34]=1>[Cu]I.CS(C)=O>[F:39][C:36]1[CH:37]=[CH:38][C:33]([O:23][C:20]2[CH:21]=[CH:22][C:17]([C:16]3[C:11]([NH2:10])=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:18][CH:19]=2)=[CH:34][C:35]=1[CH3:40]
Reactant: Nc1ncccc1-c1ccc(O)cc1
Reactant: Cc1cc(Br)ccc1F
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: Cc1cc(Oc2ccc(-c3cccnc3N)cc2)ccc1F
Temperature: 130 °C
Reaction time: 5 h
Yield: 45.8 %

Procedure:
Copper(I) iodide (102 mg) was added to a mixture of picolinic acid (66.1 mg), 4-(2-aminopyridin-3-yl)phenol (500 mg), tripotassium phosphate (1710 mg), 4-bromo-1-fluoro-2-methylbenzene (609 mg) and DMSO (8 mL). The mixture was stirred at 130° C. under nitrogen for 5 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). Water was added and the extracted organic layer was washed with brine. Silica-gel was added to the organic layer and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH-silica gel, eluted with EtOAc in hexane) to give the title compound (362.3 mg) as a pale-yellow solid.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].Cl[CH2:14][CH2:15][NH:16][C:17](=[O:21])[O:18][CH2:19][CH3:20].CCOCC>CCCCCC.CN(C=O)C>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:14][CH2:15][NH:16][C:17](=[O:21])[O:18][CH2:19][CH3:20])=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCOC(=O)NCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)NCCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To sodium hydride (1.35 g, 56.2 mmol), prewashed in hexane, in 30 ml of DMF is added 4-nitrophenol in 5 ml of DMF at 15°. After anion formation is complete, ethyl N-chloroethylcarbamate (7.12 g, 47.0 mmol) is slowly added. The slurry is heated to 85° and stirred for 17 hours, after which the reaction is cooled to RT, poured into ice water and ether, and extracted with ether. The combined organic layers are washed with 10% sodium hydroxide, with water and with brine, dried and filtered and the solvent is removed by rotoevaporation to give ethyl N-[2-(4-nitrophenoxy)-ethyl]carbamate.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([Li])CCC.CN(C)[C:24](=[O:26])[CH3:25].Cl>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][C:9]([C:24](=[O:26])[CH3:25])=[CH:8][C:6]=2[N:7]=1
Reactant: CC(=O)N(C)C
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine 4, Example 2) (1.0 eq) dissolved in THF (0.1M) at −78° C. was added a solution of n-butyllithium (1.3 eq, 1.6M in hexanes) following General Procedure D. The reaction mixture was stirred at −40° C. for 30 minutes. N,N-dimethylacetamide (4.0 eq) was added and reaction mixture was allowed to slowly warm up to 0° C. and stirred for 2 hours. Reaction mixture was poured in a cold solution of 0.25M HCl, and extracted with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated. The crude reaction mixture was purified by flash chromatography to yield 1-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)ethanone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[CH2:35]([N:38]1[CH2:43][CH2:42][CH:41]([CH2:44][OH:45])[CH2:40][CH2:39]1)[C:36]#[CH:37]>>[F:1][C:2]1[CH:3]=[C:4]([N:19]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:37]#[C:36][CH2:35][N:38]3[CH2:43][CH2:42][CH:41]([CH2:44][OH:45])[CH2:40][CH2:39]3)[S:17][C:10]=12
Reactant: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)CC1
Reactant: C#CCN1CCC(CO)CC1
Product: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(C#CCN5CCC(CO)CC5)sc34)c(F)c2)CC1
Yield: 32.1 %

Procedure:
Prepared from N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Example 12, Step A, 20 mg, 0.0338 mmol) and (1-(prop-2-ynyl)piperidin-4-yl)methanol (10.4 mg, 0.0676 mmol) using the procedure described for Example 6, Step B. The crude was purified by preparative TLC (1 mm thickness, Rf=0.72) eluting with 20% MeOH/DCM. The product was obtained as a beige powder (6.7 mg, 32%). HPLC: 100% purity (220 nm); LRMS (APCI+): 100% purity, 220 nm, m/z 617 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 10.14 (s, 1H), 8.48 (d, J=5 Hz, 1H), 8.42 (s, 1H), 7.75 (m, 1H), 7.59 (s, 1H), 7.47 (m, 2H), 7.28 (m, 1H), 7.21 (m, 1H), 7.05 (t, J=9 Hz, 2H), 6.52 (d, J=5 Hz, 1H), 3.65 (s, 2H), 3.53 (d, J=6 Hz, 2H), 3.09 (m, 2H), 2.38 (m, 2H), 1.86 (m, 2H), 1.81 (m, 2H), 1.64 (m, 2H), 1.55 (m, 1H), 1.45 (m, 2H).
Reaction SMILES: Cl.[C:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:15])=[CH:11][C:12]=2N)[CH2:7][CH2:6]1)(=[O:4])[CH3:3].N([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].[C-:26]#[N:27].[Na+]>[Cu](C#N)C#N>[C:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:15])=[CH:11][C:12]=2[C:26]#[N:27])[CH2:7][CH2:6]1)(=[O:4])[CH3:3]
Reactant: CC(=O)N1CCc2cc(Br)cc(N)c21
Reactant: [C-]#N
Agent: N#C[Cu]C#N
Agent: Cl
Agent: O=C([O-])[O-]
Product: CC(=O)N1CCc2cc(Br)cc(C#N)c21
Temperature: -1 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
Into 6N hydrochloric acid (178.5 ml) was suspended N-acetyl-7-amino-5-bromoindoline (51.0 g), and aqueous solution (212 ml) of sodium nitrite (21.2 g) was dropwise added thereto under cooling with stirring over 30 minutes and at the inside temperature of not higher than -1° C. After stirred for 30 minutes at the temperature as such, sodium carbonate was added to the reaction mixture to neutralize it. This reaction mixture was poured into aqueous solution (200 ml) of copper cyanide (27.5 g) and sodium cyanide (30.7 g), and the mixture was allowed to stand for one night at room temperature. The reaction mixture was again subjected to stirring for 30 minutes at the inside temperature of 50° C. and was cooled to give a deposited crystal, which was then collected by filtration, washed with water and dried. The crude crystal was recrystallized from acetonitrile to give the intended compound 43.0 g (81.1%). M.P.: 170°-175° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[O:11][CH2:10][C:9]=2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1>[Pd].C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[O:11][CH2:10][C@H:9]2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)OCC(c1ccc(C(F)(F)F)cc1)=C2c1ccc(O)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1)OC[C@@H](c1ccc(C(F)(F)F)cc1)[C@H]2c1ccc(O)cc1
Reaction time: 24 h

Procedure:
Palladium on carbon (10%, 0.40 g, 0.4 mmol) was added to a stirred solution of 4-(4-hydroxyphenyl)-7-methoxy-3-(4-(trifluoromethyl)phenyl)chrom-3-ene (2.99 g, 7.51 mmol) in ethanol, (100 ml) and the mixture hydrogenated at room temperature for 24 h. The catalyst was removed by filtration, and the solvent evaporated to give an off-white solid which was purified by recrystallisation from 50 ml ethanol. This gave the first crop of product as colourless needles. The mother liquors were evaporated and the recrystallisation repeated from aqueous ethanol, to give a second crop of colourless needles. The solids were combined and vacuum dried.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][OH:24].O[C:27]1[CH:28]=[N:29][C:30]([C:33]2[CH:34]=[C:35]([CH:48]=[CH:49][CH:50]=2)[CH2:36][N:37]2[C:41]3=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=[C:40]3[O:39][C:38]2=[O:47])=[N:31][CH:32]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>CN(C=O)C>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][O:24][C:27]1[CH:32]=[N:31][C:30]([C:33]2[CH:34]=[C:35]([CH:48]=[CH:49][CH:50]=2)[CH2:36][N:37]2[C:41]3=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=[C:40]3[O:39][C:38]2=[O:47])=[N:29][CH:28]=1
Reactant: Cc1ccc2oc(=O)n(Cc3cccc(-c4ncc(O)cn4)c3)c2n1
Reactant: CN(C)CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc2oc(=O)n(Cc3cccc(-c4ncc(OCCN(C)C)cn4)c3)c2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
100 mg (0.3 mmol) of polymer-bound triphenylphosphine (3 mmol/g) and 30 μl (0.3 mmol) of 2-dimethylaminoethanol are added successively to a suspension of 67 mg (0.2 mmol) of 3-[3-(5-hydroxypyrimidin-2-yl)benzyl]-5-methyl-3H-oxazolo[4,5-b]pyridin-2-one in 3 ml of DMF. 69 mg (0.30 mmol) of di-tert-butyl azodicarboxylate are subsequently added. The reaction mixture is shaken at room temperature for 18 hours. A further 100 mg (0.3 mmol) of polymer-bound triphenylphosphine (3 mmol/g) and 69 mg (0.30 mmol) of di-tert-butyl azodicarboxylate are added, and the mixture is shaken at room temperature for 18 h. A further 100 mg (0.3 mmol) of polymer-bound triphenylphosphine (3 mmol/g), 69 mg (0.30 mmol) of di-tert-butyl azodicarboxylate and 30 μl (0.3 mmol) of 2-dimethylaminoethanol are subsequently added, and the mixture is shaken at room temperature for 18 h. The reaction mixture is filtered, the filtrate is evaporated in vacuo, and the residue is purified by column chromatography on silica gel, giving “A109”. The crude product is purified by preparative HPLC: ESI: 406; HPLC: Rt=2.31 min (method B);
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:13][CH:12]=[C:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1>O>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[N:8]1[CH2:9][CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]1
Reactant: Clc1ncccn1
Reactant: O=C(O)C1=CCNCC1
Solvent: O
Product: O=C(O)C1=CCN(c2ncccn2)CC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
2-Chloropyrimidine (0.570 g, 4.98 mmol) and 1,2,3,6-tetrahydro-4-pyridinecarboxylic acid (1.22 g) were combined in water (7 mL) and heated at 90° C. After 4 hours, the mixture was treated with additional 1,2,3,6-tetrahydro-4-pyridinecarboxylic acid (0.52 g) and stirred overnight. The mixture was diluted with water and extracted with CH2Cl2. The aqueous layer was acidified with concentrated HCl (pH˜3) and extracted with CHCl3. The organic layer was dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title.
Reaction SMILES: [CH3:1][N:2]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([OH:32])=O)=[CH:27][CH:28]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[CH2:6][CH2:5]2)[C:3]1=[O:33].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][N:2]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)=[O:32])=[CH:27][CH:28]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[CH2:6][CH2:5]2)[C:3]1=[O:33]
Reactant: CN1CCNCC1
Reactant: CN1C(=O)C2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2cc(C(=O)O)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc3c(c2)C2(CCN(C(=O)/C=C/c4ccccc4C(F)(F)F)CC2)C(=O)N3C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
To a solution of (E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylic acid (20 mg, 0.04 mmol) in anhydrous CH2Cl2 (5 mL) at 0° C. was added 1-methyl-piperazine (6.0 mg, 0.06 mmol), HOBt (12 mg, 0.09 mmol), EDCI (18 mg, 0.09 mmol) and DIEA (28 mg, 0.22 mol) and the mixture was stirred overnight at rt under N2. The reaction mixture was washed with 1 N aq HCl and water. The organic phase was dried over Na2SO4, filtered and concentrated to afford a residue, which was purified by prep TLC to give (E)-1-methyl-5-(4-methylpiperazine-1-carbonyl)-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidin]-2-one (12 mg, 57%). 1H NMR (CD3OD): 1.90 (m, 4H), 2.95 (s, 3H), 3.30 (m, 11H), 3.95 (m, 1H), 4.20 (m, 2H), 4.30 (m, 1H), 7.10 (m, 1H), 7.26 (m, 1H), 7.50 (m, 3H), 7.66 (m, 1H), 7.77 (m, 1H), 8.00 (m, 2H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=O)=[CH:21][CH:20]=2)[CH2:14][CH2:13]1.[NH2:29][C:30]1[N:34](C(OC(C)(C)C)=O)[N:33]=[C:32]([CH2:42][CH2:43][C:44]2[CH:49]=[C:48]([O:50][CH3:51])[CH:47]=[C:46]([O:52][CH3:53])[CH:45]=2)[CH:31]=1.[NH4+].[Cl-]>C1COCC1.CC(N(C)C)=O>[CH3:51][O:50][C:48]1[CH:49]=[C:44]([CH2:43][CH2:42][C:32]2[NH:33][N:34]=[C:30]([NH:29][C:23](=[O:25])[C:22]3[CH:21]=[CH:20][C:19]([CH2:18][N:15]4[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]4)=[CH:28][CH:27]=3)[CH:31]=2)[CH:45]=[C:46]([O:52][CH3:53])[CH:47]=1
Reactant: COC(=O)c1ccc(CN2CCN(C)CC2)cc1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: COc1cc(CCc2cc(NC(=O)c3ccc(CN4CCN(C)CC4)cc3)n[nH]2)cc(OC)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 5.2 %

Procedure:
A solution of NaHMDS (1M in THF) (2.83 mL, 2.83 mmol) was added dropwise to a stirred solution of methyl 4-((4-methylpiperazin-1-yl)methyl)benzoate (0.351 g, 1.41 mmol) and tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (0.589 g, 1.70 mmol) in THF (3 mL), over a period of 10 mins under nitrogen. DMA (3 mL) was added. The resulting solution was stirred at room temperature for 60 h. A further aliquot of NaHMDS (1.415 mL, 1.415 mmol) was added dropwise and the solution was stirred at room temperature for a further 90 mins. The reaction mixture was poured into saturated NH4Cl (25 mL), extracted with EtOAc (2×25 mL), washed with saturated brine and dried over MgSO4, filtered and evaporated to afford the crude product (0.8776 g) as an orange gum. The crude product was purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.034 g, 5.19%) as a white solid; 1H NMR (500.0 MHz, DMSO-d6) δ 2.18 (3H, s), 2.34-2.37 (2H, m), 3.54 (2H, s), 3.73 (3H, s), 6.32-6.33 (1H, t), 6.41-6.42 (2H, d), 7.38-7.39 (1H, d), 7.90-7.92 (1H, d), 10.02 (1H, s), 11.79 (1H, s)