Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[F:19][C:20]([F:30])([F:29])[C:21]1[C:22]([CH:27]=O)=[N:23][CH:24]=[CH:25][CH:26]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7]/[C:8](=[CH:27]\[C:22]3[C:21]([C:20]([F:29])([F:19])[F:30])=[CH:26][CH:25]=[CH:24][N:23]=3)/[C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Reactant: O=Cc1ncccc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1ncccc1C(F)(F)F)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (250 mg, 1.010 mmol) in toluene 10 mL was added 3-(trifluoromethyl) picolinaldehyde (177.0 mg, 1.010 mmol). PTSA (384.5 mg, 2.021 mmol) was added to the reaction mixture and stirred at 120° C. for 6 h. The reaction mass was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound (E)-6-methoxy-5-morpholino-2-((3-(trifluoromethyl)pyridin-2-yl)methylene)-2,3-dihydro-1H-inden-1-one 67. The compound 67 was purified through flash chromatography by using 100-200 mesh silica gel. The compound was eluted at 34% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.[O:17]1[C:21]2([CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[O:20][CH2:19][CH2:18]1>C1COCC1>[F:14][C:13]([F:16])([F:15])[C:9]1[CH:8]=[C:7]([C:24]2([OH:27])[CH2:25][CH2:26][C:21]3([O:20][CH2:19][CH2:18][O:17]3)[CH2:22][CH2:23]2)[CH:12]=[CH:11][CH:10]=1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2cccc(C(F)(F)F)c2)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
To a round bottom flask was added n-BuLi (3.84 mL, 9.60 mmol) at −78° C. under argon. THF (10 mL) was added followed by addition of 1-bromo-3-(trifluoromethyl)benzene (0.884 mL, 6.40 mmol) in THF (1 mL). The reaction mixture was stirred for 30 minutes at −78° C. A solution of 1,4-dioxaspiro[4.5]decan-8-one (1.00 g, 6.40 mmol) in THF (5 mL) was then added dropwise to the reaction mixture at −70° C. The reaction was stirred for 1 h at −70° C., and then quenched by the addition of 1 N HCl. The reaction mixture was extracted with EtOAc and the organic portions were separated and combined. The organic layer was dried over Na2SO4, filtered, and concentrated to give Intermediate 3A (1.87 g, 6.19 mmol, 97.0% yield). LCMS=325 [M+Na], RT=1.89 minutes (Method B).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:6]([C:10]2[CH:11]=[C:12]([NH:20]C(=O)C3C=CC(C)=C(C#C)C=3)[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=2)[CH:7]=[CH:8][N:9]=1)[CH3:3].CN(CC1N(C2C=C(NC(=O)C3C=CC(C)=C(C#C[Si](C)(C)C)C=3)C=C(C(F)(F)F)C=2)C=CN=1)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:3][N:2]([CH2:4][C:5]1[N:6]([C:10]2[CH:11]=[C:12]([CH:13]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:15]=2)[NH2:20])[CH:7]=[CH:8][N:9]=1)[CH3:1]
Reactant: C#Cc1cc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)ccc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1C#C[Si](C)(C)C
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C)Cc1nccn1-c1cc(N)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potential synthesis of N-[3-{2-[(dimethylamino)methyl]-1H-imidazol-1-yl}-5-(trifluoromethyl)phenyl]-3-ethynyl-4-methylbenzamide: To a solution of N-[3-{2-[(dimethylamino)methyl]-1H-imidazol-1-yl}-5-(trifluoromethyl)phenyl]-4-methyl-3-[(trimethylsilyl)ethynyl]benzamide (4.1 mmol) in THF (15 mL) is added 5 mL of TBAF in THF (1.0M). After stirring at rt for 1 h, the mixture is partitioned between H2O and EtOAc. The combined organic layers are dried over Na2SO4, filtered, and then concentrated on a rotavap and the residue is purified on a silica gel column (eluent: 10% MeOH in CH2Cl2, MeOH was pre-saturated with ammonia gas) to give the desired product.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[S:13][C:12]([CH3:18])([CH3:17])[CH2:11][C:10]2=[O:19])(=O)=O.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24]>CCN(CC)CC.CN(C=O)C.O.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>[CH3:17][C:12]1([CH3:18])[CH2:11][C:10](=[O:19])[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])[CH:8]=2)[S:13]1
Reactant: CC1(C)CC(=O)c2cc(OS(=O)(=O)C(F)(F)F)ccc2S1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)c2cc(C#C[Si](C)(C)C)ccc2S1
Temperature: 95 °C
Yield: 90.9 %

Procedure:
A solution of 2,2-dimethyl-4-oxo-thiochroman-6-yl trifluoromethanesulfonate (Compound 220, 2.88 g, 8.50 mmol) in 10 mL Et3N and 20.0 mL DMF was sparged with argon for 10 minutes. To this solution was added trimethylsilylacetylene (4.15 g, 42.0 mmol) and bis(triphenylphosphine)-palladium(II) chloride (298.0 mg, 0.425 mmol). The solution was heated to 95° C. for 5 hours, cooled to room temperature, and diluted with H2O. Extraction with EtOAc was followed by washing the combined organic layers with H2O and saturated aqueous NaCl and drying over MgSO4. Concentration of the dry solution under reduced pressure and isolation of the product by column chromatography (3% EtOAc/hexanes) afforded 2.23 g (91%) of the title compound as an orange oil. 1H NMR (300 MHz, CDCl3) δ: 8.18 (1H, d, J=1.9 Hz), 7.34 (1H, dd, J=1.9, 8.1 Hz), 7.15 (1H, d, J=8.1 Hz), 2.85 (2H, s), 1.45 (6H, s), 0.23 (9H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH:11]([OH:13])[CH3:12])=[CH:9][CH:10]=1)=[O:5])[CH3:2].[C:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([CH3:30])=[CH:28][C:27](O)=[CH:26][C:25]=2[CH3:32])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CO>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH:11]([O:13][C:27]2[CH:28]=[C:29]([CH3:30])[C:24]([C:21]3[CH:22]=[CH:23][C:18]([C:14]([CH3:16])([CH3:15])[CH3:17])=[CH:19][CH:20]=3)=[C:25]([CH3:32])[CH:26]=2)[CH3:12])=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(C(C)O)s1
Reactant: Cc1cc(O)cc(C)c1-c1ccc(C(C)(C)C)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(C(C)Oc2cc(C)c(-c3ccc(C(C)(C)C)cc3)c(C)c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
A mixture of (±)-5-(1-hydroxy-ethyl)-thiophene-2-carboxylic acid ethyl ester (0.416 g, 2.08 mmol), 4′-tert-butyl-2,6-dimethyl-biphenyl-4-ol (0.561 g, 2.20 mmol), and PPh3 (0.787 g, 3.00 mmol) is dissolved in toluene (19 mL) and treated with 1,1′-(azodicarbonyl)dipiperidine (ADDP, 0.760 g, 3.01 mmol) and stirred overnight at rt. The mixture is diluted with MeOH until homogeneous and conc. The residue is loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 40% giving (±)-5-[1-(4′-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-ethyl]-thiophene-2-carboxylic acid ethyl ester (0.604 g, 671%) as a clear syrup.
Reaction SMILES: O=P(Cl)(Cl)Cl.C1(N(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]1([N:31]([C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN([CH:51]=[O:52])C>>[CH:51]([C:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:38]([N:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:39][CH:40]=1)=[O:52]
Reactant: c1ccc(N(c2ccccc2)c2cccc3ccccc23)cc1
Reactant: CN(C)C=O
Agent: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(N(c2ccccc2)c2ccccc2)c2ccccc12
Yield: 39.7 %

Procedure:
The method of Example 4, Stage 1, was followed except that there was used 4.7 g of POCl3, 13.6 g of DMF, and in place of triphenylamine there was used N,N-diphenyl-1-naphthylamine (MW 295, 0.031M, 9.2 g) to give 4 g (40% yield) of 1-formyl-4-(N,N-diphenylamino) naphthalene as a yellow solid, m.p. 107°-110° C.
Reaction SMILES: [Cl-:1].[Li+].[F:3][C:4]([F:14])([F:13])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12]>CN(C=O)C.O.O.[Cu](Cl)Cl>[Cl:1][C:10]1[CH:9]=[CH:8][C:7]([OH:12])=[C:6]([O:5][C:4]([F:13])([F:14])[F:3])[CH:11]=1
Reactant: Oc1ccccc1OC(F)(F)F
Reactant: [Cl-]
Agent: Cl[Cu]Cl
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc(Cl)cc1OC(F)(F)F
Temperature: 100 °C
Reaction time: 72 h

Procedure:
A solution of copper(II)chloride dihydrate (37.2 mmol, 6.34 g) and lithium chloride (18.6 mmol, 788 mg) in DMF (60 mL) was heated to 80° C. before the addition of 2-(trifluoromethoxy)phenol (18.6 mmol, 4 g) dropwise. The reaction was stirred at 100° C. for 72 hours. After cooling, the reaction mixture was partitioned between EtOAc (60 mL) and water (120 mL), extracted with EtOAc (60 mL). The organic layer was washed with water (60 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography, eluting product with a gradient of 0-100% DCM in heptane to yield the title compound as a waxy solid (637 mg, 10%). This was used in the next step with no further purification.
Reaction SMILES: CO[C:3](=[O:32])[C@H:4]([CH2:28][CH2:29][S:30][CH3:31])[NH:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][C:8]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH3:33]>CO>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][NH:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([NH2:33])=[O:32])[CH2:28][CH2:29][S:30][CH3:31])=[O:27])=[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:9]=2)[CH:16]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NCc2cccnc2)cc1-c1ccccc1
Reactant: N
Solvent: CO
Product: CSCC[C@H](NC(=O)c1ccc(NCc2cccnc2)cc1-c1ccccc1)C(N)=O
Temperature: 0 °C

Procedure:
[4-(3-pyridylmethylamino)-2-phenylbenzoyl]methionine methyl ester (80 mg, 0.18 mmol), prepared as in Example 192C, was dissolved in methanol (5 mL), cooled to 0° C., and the solution was saturated with anhydrous ammonia. The reaction was sealed for 72 hours at ambient temperature. Evaporation to dryness afforded [4-(3-pyridylmethylamino)-2-phenylbenzoyl]methionineamide (78 mg). MS m/e 435 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.59 (m, 2H), 1.83 (m, 2H), 2.02 (s, 3H), 4.43 (s, 2H), 4.51 (m, 1H), 5.16 (s, 1H), 5.64 (m, 1H), 6.14 (m, 1H), 6.50 (d, J=3 Hz, 1H), 6.63 (m, 1H), 7.38 (m, 7H), 7.66 (m, 2H), 8.55 (m, 1H), 8.62 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([CH3:19])=[N:7][C:6]=1[OH:20])([O:3][CH3:4])=[O:2].I[CH2:22][CH3:23]>CN(C)C=O.C(=O)([O-])[O-].[Ag+2]>[C:1]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([CH3:19])=[N:7][C:6]=1[O:20][CH2:22][CH3:23])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1c(O)nc(C)c2cc(OC)c(OC)cc12
Reactant: CCI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOc1nc(C)c2cc(OC)c(OC)cc2c1C(=O)OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A slurry of 4-carbomethoxy-3-hydroxy-6,7-dimethoxy-1-methylisoquinoline (0.500 g, 1.81 mmol) and silver carbonate (0.498 g, 1.81 mmol) in dimethylformamide (15 mL) was stirred for 20 minutes and then iodoethane (0.326 g, 2.09 mmol) was added and the slurry was stirred at room temperature for two days. The silver iodide precipitate was filtered off and the filtrate was diluted with water (75 mL) and extracted with ether (3×40 mL). The ether was successively washed with water and saturated sodium chloride solution and dried (Na2SO4). The ether was evaporated in vacuo and the solid residue was triturated with ether/hexane to give the title compound (310 mg, 56% as a pale yellow solid, mp 147°-149° C. IR (KBr): 1709, 1629, 1572 cm-1. NMR (CDCl3): δ 1.40 (t, 3H, 4-OCH2CH3), 2.80 (s, 3H, 1-CH3), 3.98 (s, 9H, 6,7-Ar-OCH3 and 4-COOCH3); 4.50 (q, 2H, 4-OCH2CH3); MS: 305 (M+).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH3:15][C@H:16]1[CH2:44][O:43][C@@:19]2([O:23][C@H:22]3[CH2:24][C@H:25]4[C@@H:30]5[CH2:31][CH2:32][C@@H:33]6[CH2:38][C@H:37]([OH:39])[CH2:36][CH2:35][C@:34]6([CH3:40])[C@H:29]5[CH2:28][CH2:27][C@:26]4([CH3:41])[C@H:21]3[C@@H:20]2[CH3:42])[CH2:18][CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:64](O)(=[O:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>C1COCC1>[CH3:15][CH:16]1[CH2:44][O:43][C:19]2([O:23][CH:22]3[CH2:24][CH:25]4[CH:30]5[CH2:31][CH2:32][CH:33]6[CH2:38][CH:37]([O:39][C:64]([C:65]7[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=7)=[O:71])[CH2:36][CH2:35][C:34]6([CH3:40])[CH:29]5[CH2:28][CH2:27][C:26]4([CH3:41])[CH:21]3[CH:20]2[CH3:42])[CH2:18][CH2:17]1
Reactant: O=C(O)c1ccccc1
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@H]5C[C@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1CCC2(OC1)OC1CC3C4CCC5CC(OC(=O)c6ccccc6)CCC5(C)C4CCC3(C)C1C2C
Temperature: 25 °C

Procedure:
A solution of diisopropylazodicarboxylate (0.81 g, 4.0 mmol) in dry THF (2 ml) was added to a stirred solution of epismilagenin (0.83 g, 2.0 mmol), triphenylphosphine (1.05 g, 4.0 mmol) and benzoic acid (0.49 g, 4.0 mmol) in dry THF (20 ml). The mixture was stirred at room temperature and monitored by TLC. After 2 h all the starting material had been consumed. The solvent was removed in vacuo, the residual syrup dissolved in ether (30 ml) and the solution washed with aqueous saturated sodium hydrogen carbonate (25 ml). The organic layer was dried over MgSO4 and passed down a short silica pad, the pad being washed with ether. The combined washings and filtrate were concentrated in vacuo to afford smilagenin benzoate as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][C:15](=O)N(CCC2C=CC=CC=2)C1=O.[CH2:28]1[CH:35](N2C(=O)C3C(=CC=CC=3)C2=O)C(=O)O[C:30](=O)[CH2:29]1.C(N)CC1C=CC=CC=1>>[CH2:12]([N:3]1[C:4](=[O:11])[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2]1=[O:1])[CH2:17][C:16]1[CH:15]=[CH:30][CH:29]=[CH:28][CH:35]=1
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)O1
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CCc1ccccc1
Agent: NCCc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCc1ccccc1
Temperature: 177 °C
Reaction time: 2 h

Procedure:
1,3-Dioxo-2-(1-phenethyl-2,6-dioxopiperidin-3-yl)isoindoline (8) was specifically prepared and isolated as follows. A mixture of N-phthaloyl-DL-glutamic anhydride (300 mg, 1.13 mmol) and phenethylamine (139 mg, 1.13 mmol) was stirred in a 177° C. oil bath for two hours. The reaction mixture was cooled down and purified by column chromatography, first using petroleum ether/dichloromethane (1:5) as an eluent to afford N-phenethyl phthalimide as a pale yellow solid [1H NMR (CDCl3) δ 7.78-7.77 (m, 2 H), 7.65-7.62 (m 2H), 7.22-7.16 (m, 5 H), 3.83 (t, 2 H), 2.92 (t, 2H)], and then using dichloromethane as an eluent to afford N-phenethyl thalidomide as a syrup that was then recrystallized from ether to provide white crystals [(139 mg, 34%): mp 122-123° C.; 1H NMR (CDCl3) δ 7.84-7.81 (dd, J=3.1 Hz, J=5.4 Hz, 2H), 7.72-7.69 (dd, J=3.1 Hz, J=5.4 Hz, 2 H), 7.20-7.14 (m, 5 H), 4.89 (dd, J=5.4 Hz, J=12.5 Hz, 1 H), 4.01-3.92 (m, 2 H), 2.90-2.63 (m, 5 H), 2.06-2.02 (m, 1 H); Anal. Calcd for C21H18N2O4: C, 69.60; H, 5.01; N, 7.73. Found: C, 69.40; H, 5.13; N, 7.74].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:9]=[CH:10][C:5]2=[CH:4][N:3]=1.[F:17][C:18]1[C:23]([O:24][CH3:25])=[CH:22][C:21]([O:26][CH3:27])=[C:20]([F:28])[C:19]=1B1OC(C)(C)C(C)(C)O1.C(N(C(C)C)CC)(C)C>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:17][C:18]1[C:23]([O:24][CH3:25])=[CH:22][C:21]([O:26][CH3:27])=[C:20]([F:28])[C:19]=1[C:2]1[N:7]=[C:6]2[N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:9]=[CH:10][C:5]2=[CH:4][N:3]=1
Reactant: COc1cc(OC)c(F)c(B2OC(C)(C)C(C)(C)O2)c1F
Reactant: Clc1ncc2cnn(C3CCCCO3)c2n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC)c(F)c(-c2ncc3cnn(C4CCCCO4)c3n2)c1F
Temperature: 125 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
A mixture of 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (477 mg, 2.00 mmol), 2-(2,6-difluoro-3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (600. mg, 2.00 mmol), bis(tri-t-butylphosphine)palladium (150.0 mg, 0.300 mmol) and diisopropylethylamine (0.700 mL, 4.02 mmol) in 1,4-dioxane (20 mL) was degassed and recharged with nitrogen for three times. The mixture was stirred at 125° C. overnight. The solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (gradient: 0-50%) to afford the desired product (0.30 g, 40%). LCMS (M+H)+=377.2.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[N:14]1([C:2]2[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(C(F)(F)F)cc1N1CCOCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
A 100 mL round-bottom flask was charged with 2-fluoro-4-(trifluoromethyl)benzaldehyde (1.90 g, 9.89 mmol, 1.00 equiv), morpholine (1.30 g, 14.9 mmol, 1.51 equiv), potassium carbonate (3.45 g, 25.0 mmol, 2.52 equiv), and dimethyl sulfoxide (20 mL). The resulting solution was stirred overnight at 100° C. in an oil bath and diluted with H2O (30 mL). The resulting solution was extracted with dichloromethane (2×20 mL) and the organic layers were combined, washed with H2O (3×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/5) to yield 1.06 g (41% yield) of 2-(morpholin-4-yl)-4-(trifluoromethyl)benzaldehyde as yellow oil. LCMS (ESI, m/z): 260 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:34]=2)[CH2:25][CH2:24]1>>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[CH:30]=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:34]=3)[CH2:27][CH2:28]2)=[O:11])=[CH:13][CH:14]=1
Reactant: Cc1ccc(C(C(=O)O)c2ccc(C)cc2)cc1
Reactant: CCCC(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Product: CCCC(=O)Nc1cc(C2CCN(CCCNC(=O)C(c3ccc(C)cc3)c3ccc(C)cc3)CC2)ccc1F

Procedure:
Example 10 prepared from bis(4-methylphenyl)acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.30–8.13 (m, 1H), 8.08–7.92 (br, 1H), 7.43–6.89 (m, 9H), 6.76–6.61 (br, 1H), 4.98–4.79 (br, 1H), 4.70 (s, 1H), 3.39–3.16 (m, 4H), 2.83–2.63 (m, 2H), 2.63–2.47 (m, 1H), 2.45–2.12 (m, 4H), 2.27 (s, 6H), 2.02–1.64 (m, 8H), 1.02 (t, 3H, J=7.2 Hz); ESMS m/e: 544.4 (M+H)+.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:3].[CH2:13](I)[CH:14]([CH3:16])[CH3:15]>>[CH2:2]([O:4][C:5](=[O:12])[CH:6]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:3]
Reactant: CC(C)CI
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Product: CCOC(=O)C(CC(C)C)C(=O)OCC
Reaction time: 0.5 h

Procedure:
A solution of 23 g of sodium in 1500 ml of anhydrous alcohol was treated, with stirring, with 160.16 g of malonic acid diethyl ester. After stirring for 30 minutes, 184.03 g of isobutyl iodide were added dropwise to the solution. The mixture was then stirred for and additional further 15 hours at 20° and subsequently evaporated under reduced pressure. The residue was stirred with diethyl ether, filtered off from the solid material and evaporated under reduced pressure. The brown oil remaining as the residue was fractionated twice in a high vacuum. There was obtained 45.8 g of a main fraction of isobutylmalonic acid diethyl ester, boiling point 64°/0.6 mm Hg.
Reaction SMILES: [NH2:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.ClC([O:19][C:20](Cl)(Cl)Cl)=O.C.[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:20](=[O:19])[NH:1][O:2][CH:3]2[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]2)=[CH:28][CH:27]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(ON)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(ONC(=O)Nc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 67.4 %

Procedure:
A solution of tert-butyl 4-(aminooxy)piperidine-1-carboxylate (2.0 g, 9.2 mmol) in tetrahydrofuran (10 ml) was added over 30 minutes to a suspension of trichloromethyl chloroformate (2.74 g, 13.8 mmol) and activated charcoal (20 mg) in tetrahydrofuran (35 ml) at 0° C. over 30 minutes. After stirring at room temperature for 17 hours, the reaction mixture was filtered over silicagel and the filtrate was concentrated in vacuo. The residue was dissolved in tetrahydrofuran (15 ml), 4-fluoroaniline (2.0 g, 18.4 mmol) and N,N-diisopropylethylamine (3.58 g, 27.6 mmol) were added and the whole was stirred at room temperature for 17 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (50 ml), washed with H2O (20 ml×2), brine (20 ml×2), dried over Na2SO4 and concentrated in vacuo. The residual solid was recrystallized from diethyl ether to give tert-butyl 4-(3-(4-fluorophenyl)ureidooxy)piperidine-1-carboxylate (2.19 g, 67%) as a white solid: LCMS: 354 [M+1]+.