Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].Br[CH2:40][CH2:41][O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([O:33][CH2:40][CH2:41][O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])=[CH:31][CH:32]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 36 h
Yield: 60.9 %

Procedure:
To a solution of (2R,3R,4R,5S,65)-2-(Acetoxymethyl)-6-(4-chloro-3-(4-hydroxybenzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (500 mg, 0.91 mmol) in dry DMF (10 mL), was added (2-bromoethoxy)(tert-butyl)dimethylsilane (436 mg, 1.82 mmol) and cesium carbonate (890 mg, 2.73 mmol). The reaction was stirred at r.t. for 36 h. After completion of reaction, as confirmed by TLC, the reaction mixture was diluted with ethyl acetate (150 mL) and washed with water (3×10 mL). The organic layer was dried over anhydrous Na2SO4 and volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 4:6 Acetone:Pet. Ether) to afford title compound (392 mg, 60.85%) as white solid.
Reaction SMILES: C(OC(N1CCC([CH2:14][NH:15][C:16]2[N:21]3[N:22]=[CH:23][C:24]([Br:25])=[C:20]3[N:19]=[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[CH:17]=2)CC1)=O)(C)(C)C.S(=O)(=O)(O)O.O1[CH2:43][CH2:42]OCC1>CO>[Br:25][C:24]1[CH:23]=[N:22][N:21]2[C:16]([N:15]([CH:43]3[CH2:42][CH2:14][NH:15][CH2:16][CH2:17]3)[CH3:14])=[CH:17][C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])=[N:19][C:20]=12
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(-c3ccccc3Cl)nc3c(Br)cnn23)CC1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CN(c1cc(-c2ccccc2Cl)nc2c(Br)cnn12)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
4-{[3-Bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester (441 mg, 0.847 mmoles) (prepared as described in Example 460, Step A above) was dissolved in methanol (4.5 mL) and 10% (v/v) conc. sulfuric acid in 1,4-dioxane (11.46 mL) was added. The mixture was stirred at 25° C. for 0.5 h. The product was worked up as described in Preparative Example 241, step B and chromatographed on a silica gel column (15×5 cm) using 8% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give [3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]piperidin-4-yl methylamine (314.4 mg, 88%): FABMS: m/z 420.0 (MH+); HRFABMS: m/z 420.0585 (MH+). Calcd. for C18H20N5BrCl: m/z 420.0591; δH (CDCl3) 1.34 (2H, m, CH2), 1.86 (2H, m, CH2), 1.91 (1H, m, CH), 2.10 (1H, bm, piperidine-NH), 2.67 (2H, m, CH2), 3.18 (2H, m, CH2), 3.38 (2H, m, CH2), 6.37 (1H, s, H6), 6.53 (1H, m, NH), 7.42 (2H, m, Ar—H), 7.52 (1H, m, Ar—H), 7.76 (1H, m, Ar—H) and 8.06 ppm (1H, s Ar—H); δC (CDCl3) CH2: 31.2, 31.2, 46.2, 46.2, 48.4; CH: 36.4, 89.5, 127.1, 130.1, 130.5, 131.6, 143.8; C: 83.2, 132.1, 138.9, 145.6, 146.4, 158.1.
Reaction SMILES: [CH2:1]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)[C:10](N(OC)C)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][Mg]Br.CCOCC>C1COCC1>[CH2:27]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1)[C:10](=[O:11])[CH3:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CON(C)C(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
To a 250 mL round bottom flask containing (S)-2-(dibenzylamino)-N-methoxy-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide (10.49 g, 23.0 mmol) was added THF (200 mL), and the flask was cooled to 0° C. Methylmagnesium bromide (3.16 M in ether, 12.7 mL, 40.2 mmol) was added dropwise over 10 minutes. After 2 hours, additional methylmagnesium bromide, 3.16 in ether (12.7 mL, 40.2 mmol) was added dropwise over 10 minutes. After 1 hour, the mixture was poured into ammonium chloride—ice (200 mL), washed with brine (100 mL), dried over sodium sulfate, and stored at −20° C. for 15 hours. Plate-like crystals formed the next morning. The mixture was decanted from sodium sulfate and evaporated to provide a yellow oil that crystallized in the freezer over the weekend. The solid was triturated with hexane and chilled at −20° C. before filtration. The product was obtained as a white crystalline solid. The yellow filtrate was adsorbed onto silica gel and purified by chromatography through a Redi-Sep® pre-packed silica gel column (330 g), eluting with a gradient of 0% to 70% EtOAc in hexane to provide additional product as an oil that crystallized under hi vacuum. The two lots were combined to provide (S)-3-(dibenzylamino)-4-(4-(trifluoromethyl)phenyl)butan-2-one (8.09 g, 85.6% yield) as a white solid. LCMS (ES+) m/z=412.3 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 2.13 (s, 3H) 2.93 (dd, J=13.30, 3.52 Hz, 2H) 3.21 (dd, J=13.30, 9.39 Hz, 1H) 3.50-3.60 (m, 3H) 3.82 (d, J=13.69 Hz, 2H) 7.19-7.30 (m, 4H) 7.30-7.35 (m, 8H) 7.46 (d, J=8.02 Hz, 2H).
Reaction SMILES: [CH:1]1[CH:6]=[C:5](F)[C:4]([C:8]([NH:10][C:11]([NH:13]C2C=C(Cl)C(OC3N=CC(C(F)(F)F)=CC=3Cl)=C(Cl)C=2)=[O:12])=[O:9])=[C:3](F)[CH:2]=1.C1C=C(F)C(C(NC(NC2C=CC(Cl)=CC=2)=O)=O)=C(F)C=1.C1C=C(F)C(C(NC(NC2C=CC(Cl)=C(OC3N=CC(C(F)(F)F)=CC=3Cl)C=2)=O)=O)=C(F)C=1.C1C=C(F)C(C(NC(NC2C=CC(CO/N=C(\C3CC3)/C3C=CC(Cl)=CC=3)=CC=2)=O)=O)=C(F)C=1.C1C=C(F)C(C(NC(NC2C=CC(OC3C=CC(C(F)(F)F)=CC=3Cl)=CC=2F)=O)=O)=C(F)C=1.C1C=C(F)C(C(NC(NC2C=C(Cl)C(OC(F)(F)C(F)F)=C(Cl)C=2)=O)=O)=C(F)C=1.C1C=C(F)C(C(NC(NC2C(Cl)=CC(OC(F)(F)C(F)C(F)(F)F)=C(Cl)C=2)=O)=O)=C(F)C=1.C1C=C(F)C(C(NC(NC2C=CC(OC(F)(F)C(F)OC(F)(F)F)=C(Cl)C=2)=O)=O)=C(F)C=1.C1C=C(F)C(C(NC(NC2C=C(Cl)C(OC(F)(F)C(F)C(F)(F)F)=C(Cl)C=2F)=O)=O)=C(F)C=1.C1C=C(F)C(C(NC(NC2C=C(Cl)C(F)=C(Cl)C=2F)=O)=O)=C(F)C=1.C1C=CC(Cl)=C(C(NC(NC2C=CC(OC(F)(F)F)=CC=2)=O)=O)C=1>>[C:8]([NH:10][C:11]([NH2:13])=[O:12])(=[O:9])[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Agent: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(F)c(Cl)c1F
Agent: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(OC(F)(F)C(F)C(F)(F)F)c(Cl)c1F
Agent: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(OC(F)(F)C(F)C(F)(F)F)cc1Cl
Product: NC(=O)NC(=O)c1ccccc1

Procedure:
chlorfluazuron, bistrifluoron, diflubenzuron, fluazuron, flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, novaluron, noviflumuron, teflubenzuron, triflumuron;
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].Cl.[NH2:27][OH:28].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH:23]1([N:9]([CH:6]2[CH2:7][CH2:8][N:3]([C:1](=[NH:2])[NH:27][OH:28])[CH2:4][CH2:5]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: NO
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N=C(NO)N1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide (200 mg), hydroxylamine hydrochloride (70 mg), and potassium carbonate (82 mg) in ethanol (0.70 mL) and water (1.00 mL) is heated under reflux for 5 h. The reaction mixture is cooled to room temperature, stirred at this temperature for two days and concentrated in vacuo. The residue is mixed with water and ethyl acetate and the organic phase is separated, dried and concentrated in vacuo. The crude product is purified by HPLC (MeOH/H2O/TFA). LC (method 3): tR=1.35 min; Mass spectrum (ESI+): m/z=370 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:13]([NH:14][C:15]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)=[CH:21][CH:22]=3)=[O:16])[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[F:29][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:15]([NH:14][CH:13]3[CH2:12][CH2:11][NH:10][CH2:9][CH:8]3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:16])=[CH:18][N:19]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(-c3cccc(F)c3)nc2)C(c2ccc(F)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(NC1CCNCC1c1ccc(F)cc1)c1ccc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-(4-fluorophenyl)-4-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)piperidine-1-carboxylate (348 mg, 0.71 mmol) in CH2Cl2 (5 mL) at 0° C. was added TFA (1.2 mL). After stirring overnight at rt the the reaction was diluted with toluene (5 mL) and then the solvent removed and the residue purified by chromatography (silica, 10% MeOH/DCM) to give the desired product, 6-(3-fluorophenyl)-N-[3-(4-fluorophenyl)piperidin-4-yl]nicotinamide. (168 mg, 61% yield). 1H NMR (400 MHz, DMSO-d6) □ ppm 8.87 (1H, d, J=2.0 Hz), 8.52 (1H, s), 8.04-8.15 (2H, m), 8.00 (2H, d, J=7.9 Hz), 7.58 (1H, d, J=6.1 Hz), 7.35 (4H, dd, J=9.0, 3.5 Hz), 7.08-7.22 (2H, m), 4.60-4.72 (1H, m), 3.81 (1H, t), 3.05-3.27 (4H, m), 1.91 (1H, s). LC/MS=(M+H)=394.1 observed, 394.17 expected.
Reaction SMILES: [OH:1][CH:2]([C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=1)[CH:3]([CH3:5])[CH3:4].[NH2:14][C@@H:15]([CH3:32])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[C:28]([F:30])[C:25]([C:26]#[N:27])=[C:24]([Cl:31])[CH:23]=2)=[N:18]1.CN(C=O)C>O.CCOC(C)=O>[Cl:31][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C@@H:15]([NH:14][C:11]([C:8]3[CH:7]=[C:6]([CH:2]([OH:1])[CH:3]([CH3:4])[CH3:5])[O:10][N:9]=3)=[O:13])[CH3:32])[N:18]=2)[CH:29]=[C:28]([F:30])[C:25]=1[C:26]#[N:27]
Reactant: CC(C)C(O)c1cc(C(=O)O)no1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)C(O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)no1
Yield: 1.8 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 5-(1-hydroxy-2-methylpropyl)isoxazole-3-carboxylic acid (2.160 mmol, 0.4 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzonitrile (1.800 mmol, 0.502 g) using DMF (10 ml) as the solvent. The reaction mixture was diluted with water and EtOAc, the phases were separated and the organic phase was washed with 2 M Na2CO3, water and brine. The organic phase was dried, filtered and evaporated. The crude product was purified by flash chromatography and preparative HPLC, respectively. 0.0146 g of the title compound was obtained. 1H-NMR (400 MHz, MeOH-d4): δ 0.89 (d, 3H), 0.92-0.98 (m, 3H), 1.26 (d, 3H), 2.01-2.13 (m, 1H), 4.28-4.45 (m, 2H), 4.51-4.64 (m, 2H), 6.53 (d, 1H), 6.79 (d, 1H), 7.68-7.77 (m, 2H), 7.91 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH2:11][CH3:12])[C:8]([N+:13]([O-])=O)=[CH:7][C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[NH2:13][C:8]1[C:9]([CH2:11][CH3:12])=[CH:10][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[C:6]([OH:16])[CH:7]=1
Reactant: CCc1cc(C(C)(C)C)c(O)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CCc1cc(C(C)(C)C)c(O)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
To a solution of 2-tert-butyl-4-ethyl-5-nitro-phenol (3.2 g, 14.3 mmol) in methanol (20 mL) was added Raney Nickel (200 mg, 3.4 mmol) under nitrogen atmosphere. The reaction mixture was then stirred overnight at room temperature under an atmosphere of hydrogen (1 atm). The catalyst was removed by filtration through a pad of celite and the filtrate was evaporated under vacuum to give 5-amino-2-tert-butyl-4-ethyl-phenol (1.2 g, 43%). 1H NMR (400 MHz, CDCl3) δ 6.92 (s, 1H), 6.06 (s, 1H), 2.45 (q, J=7.6 Hz, 2H), 1.37 (s, 9H), 1.21 (t, J=7.6 Hz, 3H). MS (ESI) m/e (M+H+) 194.2
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:13])=[C:7]([C:10]([OH:12])=O)[S:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[CH3:14][Li].[NH4+].[Cl-]>C(OCC)C>[CH2:1]([C:5]1[C:6]([CH3:13])=[C:7]([C:10](=[O:12])[CH3:14])[S:8][CH:9]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: [Li]C
Reactant: Cc1c(CC(C)C)csc1C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(=O)c1scc(CC(C)C)c1C
Reaction time: 0.5 h

Procedure:
To a solution of 4-isobutyl-3-methyl-thiophene-2-carboxylic acid (2.44 g, 12.3 mmol) in diethyl ether (50 mL), a solution of methyllithium (23.1 mL, 1.6 M solution in diethyl ether) is slowly added at 20-23° C. The resulting suspension is stirred at rt for 30 min before another portion of methyllithium (2.3 mL) is added. Stirring is continued for further 30 min before the mixture is poured into vigorously stirred 1 N. aq. NH4Cl (400 mL). The organic phase is separated and the aq. phase is extracted again with diethyl ether. The combined organic extracts are dried over Na2SO4, filtered and evaporated to leave 1-(4-isobutyl-3-methyl-thiophen-2-yl)ethanone (2.34 g) as pale yellow oil; LC-MS: tR=1.03 min, [M+1]=197.20; 1H NMR (CDCl3): δ7.08 (s, 1H), 2.52 (s, 3H), 2.46 (s, 3H), 2.42 (d, J=7.0 Hz, 2H), 1.82 (m, J=7.0 Hz, 1H), 0.92 (d, J=6.4 Hz, 6H).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:21].[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([C:32]([CH3:40])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:33])[CH:26]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:15]2[CH:14]=[C:13]([CH:18]=[C:17]([F:19])[CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:22])=[C:7]([CH3:21])[CH:8]=2)=[C:27]([C:32]([CH3:33])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:40])[CH:26]=1)[CH3:24]
Reactant: CCc1ccc(O)c(C(C)(C)c2ccccc2)c1
Reactant: COC(=O)CCc1ccc(Oc2cc(F)cc(Br)c2)cc1C
Product: CCc1ccc(Oc2cc(F)cc(Oc3ccc(CCC(=O)O)c(C)c3)c2)c(C(C)(C)c2ccccc2)c1

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with 4-ethyl-2-(1-methyl-1-phenyl-ethyl)-phenol as in Example 18 to afford 0.027 g (10%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C33H33O4F 512, found 513 (M+1, 100%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12]C)[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:25])[N:7]2[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=1.ClC1C=CC=C(Cl)C=1N1C2C(=C([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][C:46]=3[F:52])C=C(O)C=2)CCC1=O>>[F:51][C:48]1[CH:47]=[C:46]([F:52])[CH:45]=[CH:50][C:49]=1[C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:25])[N:7]2[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=1
Reactant: COC(=O)c1ccc(C)c(N2C(=O)CCc3c(Br)cc(OC)cc32)c1
Reactant: O=C1CCc2c(-c3ccc(F)cc3F)cc(O)cc2N1c1c(Cl)cccc1Cl
Product: COC(=O)c1ccc(C)c(N2C(=O)CCc3c(-c4ccc(F)cc4F)cc(O)cc32)c1

Procedure:
5-(2,4-Difluorophenyl)-3,4-dihydro-7-hydroxy-1-(3-methoxycarbonyl-6-methylphenyl)-2(1H)-quinolinone was prepared from 5-bromo-3,4-dihydro-7-methoxy-1-(3-methoxycarbonyl-6-methylphenyl)-2(1H)-quinolinone (INTERMEDIATE 15) by a procedure analogous to that described in INTERMEDIATE 3. Mass spectrum (ESI) 424.1 (M+1). 1H NMR (500 MHz, DMSO-d6): δ 9.44 (s, 1H); 7.96 (d, J=8.0 Hz, 1H); 7.75 (s, 1H); 7.59 (d, J=8.0 Hz, 1H); 7.41 (m, 2H); 7.18 (t, J=6.0 Hz, 2H); 6.33 (s, 1H); 5.63 (s, 1H); 3.84 (s, 3H); 2.61 (m, 4H); 2.09 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:18][NH2:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:20][C:21]([F:36])([F:35])[C:22]1[O:26][N:25]=[C:24]([C:27]2[S:31][C:30]([C:32](O)=[O:33])=[CH:29][CH:28]=2)[N:23]=1>>[C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:18][NH:19][C:32]([C:30]4[S:31][C:27]([C:24]5[N:23]=[C:22]([C:21]([F:36])([F:20])[F:35])[O:26][N:25]=5)=[CH:28][CH:29]=4)=[O:33])[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(-c2noc(C(F)(F)F)n2)s1
Reactant: NCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Product: O=C(NCC1(c2nc(-c3ccccc3)cs2)CCOCC1)c1ccc(-c2noc(C(F)(F)F)n2)s1
Yield: 22 %

Procedure:
This compound was synthesized from (4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)thiophene-2-carboxylic acid as described in example 8 step 6 (25 mg, yield 22%): 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=7.3 Hz, 2H), 7.78 (m, J=4.0 Hz, 1H), 7.62 (br s, 1H), 7.53-7.48 (m, 4H), 7.42-7.38 (m, 1H), 3.97-3.91 (m, 2H), 3.86 (d, J=5.5 Hz, 2H), 3.78-3.73 (ddd, J=11.6 Hz, 7.5 Hz, 3.5 Hz, 2H), 2.33-2.27 (ddd, J=13.6 Hz, 7.0 Hz, 3.5 Hz, 2H), 2.06-1.99 (ddd, J=13.8 Hz, 7.3 Hz, 3.3 Hz, 2H). MS (ESI) m/z: Calculated for C23H19F3N4O3S2: 520.09. found: 521.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:16]=[N:17][NH:18][CH:19]=4)[C:11]=3[CH:20]=2)=[N:5][N:6]=1.[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br>>[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][N:18]1[CH:19]=[C:15]([C:12]2[C:11]3[CH:20]=[C:7]([C:4]4[O:3][C:2]([CH3:1])=[N:6][N:5]=4)[CH:8]=[CH:9][C:10]=3[O:14][CH:13]=2)[CH:16]=[N:17]1
Reactant: Cc1nnc(-c2ccc3occ(-c4cn[nH]c4)c3c2)o1
Reactant: Fc1ccccc1CBr
Product: Cc1nnc(-c2ccc3occ(-c4cnn(Cc5ccccc5F)c4)c3c2)o1
Yield: 88 %

Procedure:
In the same manner as in Example 1 and using 2-methyl-5-[3-(1H-pyrazol-4-yl)-1-benzofuran-5-yl]-1,3,4-oxadiazole instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and using 2-fluorobenzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 88%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([OH:26])=O)[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[C:36](=[O:40])[NH:35][CH2:34]2.CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:30][C:31]4[CH:32]=[C:33]5[C:37](=[CH:38][CH:39]=4)[C:36](=[O:40])[NH:35][CH2:34]5)=[O:26])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(N3CCCC(C(=O)O)C3)nc3scnc23)cc1OC
Reactant: Nc1ccc2c(c1)CNC2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1ccc(Nc2nc(N3CCCC(C(=O)Nc4ccc5c(c4)CNC5=O)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.7 %

Procedure:
To a solution of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylic acid (70 mg, 0.17 mmol) and 5-aminoisoindolin-1-one (25 mg, 0.17 mmol) in dichloromethane (15 mL) were added the solution of 1-methyl-1H-imidazole (55 mg, 0.68 mmol) and EDCI (129 mg, 0.68 mmol) in dichloromethane (5 mL), the reaction mixture was stirred at room temperature for 24 hours, the solvent was removed in vacuo, then methanol (5 mL) was added, the precipitate was collected by filtration and washed with methanol (3 mL) to afford 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(1-oxoisoindolin-5-yl)piperidine-3-carboxamide (48 mg, 51.8%) as a brown solid. 1H NMR (300 MHz, DMSO): δ 10.29 (s, 1H), 9.64 (s, 1H), 8.84 (s, 1H), 8.38 (s, 1H), 7.96 (s, 1H), 7.64-7.53 (m, 3H), 7.33 (dd, 1H, J1=8.4 Hz, J2=1.8 Hz), 6.80 (brs, 1H), 4.81-4.63 (m, 2H), 4.33 (s, 2H), 3.68 (s, 3H), 3.59 (s, 3H), 3.14-2.92 (m, 2H), 2.65-2.60 (m, 1H), 2.04-2.00 (m, 1H), 1.81-1.69 (m, 2H), 1.49-1.45 (m, 1H). LC-MS: 545.9 [M+H]+, tR=1.42 min. HPLC: 99.69% at 214 nm, 99.44% at 254 nm, tR=4.87 min.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:3]1.Cl[C:28]1[C:33]([Cl:34])=[N:32][CH:31]=[CH:30][N:29]=1.C([O-])([O-])=O.[K+].[K+].C(Cl)(Cl)Cl.CCO>CN(C=O)C.O>[Cl:34][C:33]1[C:28]([N:7]2[CH2:6][CH2:5][NH:4][CH2:3][C@H:2]2[CH3:1])=[N:29][CH:30]=[CH:31][N:32]=1
Reactant: C[C@@H]1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CNCCN1c1nccnc1Cl
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
A mixture of the product obtained in Step 1 above, 2,3-dichloropyrazine (154 g, 1.00 mol) and K2CO3 (160 g, 1.20 mol) in DMF (1 L) was heated at 110° C. for 20 h with vigorous stirring. (TLC monitoring system: CHCl3: EtOH (20:1); silica). The mixture was cooled and poured slowly into water (6 L) with stirring. The solid was collected, washed with water, dried, dissolved in CHCl3 (1 L), diluted with n-heptane (1 L), and filtered through SiO2. Solvents were evaporated off. The resulting oil was dried under vacuum (3 mm/50° C., 30 min) to remove the DMF. The oil was dissolved in hot ethanol (1 L), and HCl (10% aqueous solution, 300 mL) was added slowly. Trityl carbinol began to crystallize out after 10 min. After 30 min, the formed trityl carbinol was filtered off and the ethanol was evaporated. The aqueous solution was extracted by ether (2×200 mL) and made basic by addition of K2CO3 to pH 12. The alkaline layer was extracted with CHCl3 (3×200 mL). The combined organic layers were dried (K2CO3) and concentrated to give 140 g (66%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1
Reactant: COC(=O)c1ccc(F)cc1Br
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(F)cc1Oc1ccccc1

Procedure:
Methyl 2-bromo-4-fluorobenzoate (1 g), phenol (0.565 g), cesium carbonate (1.96 g), copper(I) triflate toluene complex (0.087 g), and ethyl acetate (0.034 mL) in toluene (12 mL) was stirred at 110° C. for 24 hours. The reaction was cooled and chromatographed on silica gel with 5% ethyl acetate/hexanes.