Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.O>O1CCCC1>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[OH:16])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
4-Chlorophenylmagnesium bromide (12.97 ml, 1M solution in diethyl ether) was added slowly to a solution of 4-bromobenzaldehyde (2.0 g, 10.81 mmol) in tetrahydrofuran (25 ml) at 0° C., under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature and was stirred for 17 hours. Water (3 ml) was then added and the solvent was removed under reduced pressure. The residue was then partitioned between ethyl acetate and 1N HCl solution. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The crude product was then purified by column chromatography (SiO2), eluting with ethyl acetate/petroleum ether (1:9), to yield the title compound (2.30 g). LC/MS: (PS-B3) Rt 3.49 [M−H]+ 297.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16](C(C)(C)C)=[CH:15][CH:14]=2)=[N:7][CH:6]=1)[CH3:2].[C:24](C1C=CC(C#C)=CC=1)([CH3:27])([CH3:26])[CH3:25]>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=2)=[N:7][CH:6]=1)[CH3:2]
Reactant: C#Cc1ccc(C(C)(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C(C)(C)C)cc2)nc1
Product: CCOC(=O)c1ccc(C#Cc2cccc(C(C)(C)C)c2)nc1

Procedure:
Using the same general procedure as described for Compound 3, but using instead 3-tert-butylphenylethyne (Compound 19), the title compound was synthesized as a white solid. PMR (CDCl3): & 1.34 (9H, s), 1.42 (3H, t, J~7.2 Hz), 4.43 (2H, q, J~7.2 Hz), 7.28-7.36 (1H, m), 7.40-7.46 (2H, m), 7.60 (1H, d, J~8.1 Hz), 7.67 (1H, s), 8.29 (1H, dd, J~8.1 Hz, 2.1 Hz), 9.21 (1H, d, J~2.1 Hz).
Reaction SMILES: CC(C)([O-])C.[K+].C[C:8]1(O)C=C[CH:11]=[N:10][CH2:9]1.CI.O.[CH2:18]1[CH2:22][O:21][CH2:20][CH2:19]1>>[CH3:20][O:21][C:22]1[CH:18]=[CH:19][C:9]([CH3:8])=[N:10][CH:11]=1
Reactant: C1CCOC1
Reactant: CC1(O)C=CC=NC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Potassium tert-butoxide (5.4 g, 48 mmol) was added to 3-methyl-pyridin-3-ol (5 g, 45.87 mmol) in THF (200 mL) at 0° C. The mixture was stirred at room temperature for 30 min. MeI (3.2 mL, 48 mmol) was added dropwise at 0° C. and stirring was continued at room temperature for 8 h. Water was added and the mixture was evaporated to half its volume and extracted with EtOAc. The organic layer was washed with brine and water, dried over anhydrous MgSO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography to give 5-methoxy-2-methyl-pyridine (4.8 g, 85%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[CH3:3].[CH3:14][N:15]([CH3:28])[C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27]CNC[CH2:23]2)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH3:23][N:22]([CH3:27])[C:19]1[CH:20]=[CH:21][C:16]([N:15]2[CH2:28][CH2:1][N:2]([CH2:4][C:5]3[C:13]4[C:8](=[N:9][CH:10]=[CH:11][CH:12]=4)[NH:7][CH:6]=3)[CH2:3][CH2:14]2)=[CH:17][CH:18]=1
Reactant: CN(C)c1ccc(N2CCNCC2)cc1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Solvent: Cc1ccccc1
Product: CN(C)c1ccc(N2CCN(Cc3c[nH]c4ncccc34)CC2)cc1
Yield: 44.8 %

Procedure:
A mixture of 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (0.4450 g, 2.54 mmol) and 1-(4-dimethylaminophenyl)piperazine (0.55 g, 2.68 mmol) in toluene (20 ml) was heated at reflux under nitrogen for 7 h. The mixture was allowed to cool and the solid formed was collected. Recrystallisation from methanol gave the title compound (0.382 g, 45%) as colourless needles, m.p. 199°-201° C.; (Found: C, 71.32; H, 7.37; N, 20.71. C20H25N5 requires C, 71.61; H, 7.51; N, 20.88%); δH (DMSO-d6) 2.52 (4H, m, 2×piperazinyl CH2), 2.76 (6H, s, N(CH3)2), 2.95 (4H, m, 2×piperazinyl CH2), 3.67 (2H, s, CH2N), 6.66 (2H, m, ArH), 6.80 (2H, m, ArH), 7.03 (1H, dd, J 7.8, 4.7 Hz), 7.35 (1H, d, J 2.0 Hz, 2-H), 8.04 (1H, dd, J 7.8, 1.5 Hz, 4-H), 8.19 (1H, dd, J 4.7, 1.5 Hz, 6-H), and 11.41 (1H, br s, NH); m/z (CI+, NH3) 336 (M+1)+.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12]CCCCCCBr.BrCCBr.C([O-])(O)=O.[Na+]>CO.CC1C=CC(S(O)(=O)=O)=CC=1>[O:4]1[CH:5]=[CH:1][CH:2]=[C:3]1[C:7]([C:8]1[O:6][CH:11]=[CH:10][CH:9]=1)=[O:12]
Reactant: BrCCCCCCOC1CCCCO1
Reactant: C1CCOC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: BrCCBr
Solvent: CO
Product: O=C(c1ccco1)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
Preparation of 1-(2-Furyl)-7-hydroxy-1-heptanone (R=n-C6H12OH)—Magnesium turnings (8.20 g, 0.342 mol, 4.5 eq/halide) were covered with anhydrous THF (40 mL) and a solution of 1-(tetrahydropyran-2-yloxy)-6-hexyl bromide (20.1 g, 76.0 mmol in anhydrous 100 mL THF) was added dropwise once the reaction was initiated with 1,2-dibromoethane. The remaining halide solution was added dropwise and the mixture was allowed to stir at rt overnight. The resulting mixture was then added to a cooled solution of the Weinreb amide (10.3 g, 66.1 mmol in 100 mL anhydrous THF, 0° C.) via cannula. The resulting slurry was stirred (3 h) and then quenched with equal amounts of 1 N HCl and H2O. After warming to rt the mixture was separated and the aqueous layer was extracted with Et2O (2×). The combined organics were washed with sat'd. NaHCO3, brine, dried (Na2SO4), filtered, and evaporated to yield crude residue, which was then dissolved in MeOH (200 mL) with a small amount of TsOH and allowed to stir overnight. The reaction mixture was stirred with NaHCO3, evaporated, and the residue taken up in hexane. The hexane portion was washed with H2O (2×), brine, dried (Na2SO4), and concentrated to yield crude furyl ketone, which was distilled under vacuum (b.p. 164–167° C., 0.2 mm Hg) to give pure furyl ketone (6.95 g, 35.4 mmol, Yld. 53.6%). 1H NMR: δ 7.57 (dd, 1H, 3JH,H=1.7 Hz, 4JH,H=0.74 Hz, H-2), 7.17 (dd, 1H, 3JH,H=3.6 Hz, 4JH,H=0.76 Hz, H-4), 6.52 (dd, 1H, 3JH,H=3.6 Hz, 3JH,H=1.7 Hz, H-3), 3.63 (t, 2H, 3JH,H=6.6 Hz, H-12), 2.81 (t, 2H, 3JH,H=7.6 Hz, H-7), 2.13 (bs, 1H, OH), 1.72 (quintet, 2H, 3JH,H=7.4 Hz, H-8), 1.57 (quintet, 2H, 3JH,H=6.7 Hz, H-11), 1.39 (m, 4H, H-9 and 10). 13C NMR: δ 189.8, 152.7, 146.3, 117.0, 112.2, 62.8, 38.3, 32.5, 29.0, 25.5, 24.2.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O>[NH2:14][C:9]1[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]2[O:4][C:3]([CH2:2][N:29]3[CH2:30][CH2:31][CH:26]([NH:25][CH:24]([C:21]4[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=4)[C:32]4[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=4)[CH2:27][CH2:28]3)([CH3:16])[CH2:7][C:6]=2[C:8]=1[CH3:15]
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Reactant: Fc1ccc(C(NC2CCNCC2)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(NC(c3ccc(F)cc3)c3ccc(F)cc3)CC1)O2
Temperature: 172 °C
Reaction time: 4.5 h
Yield: 38.9 %

Procedure:
Under argon gas, a suspension of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine (1.4 g), N-[bis(4-fluorophenyl)methyl]-4-piperidinamine (4.5 g), and potassium carbonate (1.4 g) in N,N-dimethylacetamide (20 mL) was stirred at 172° C. for 4.5 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatograph (silica gel/ethyl acetate and basic silica gel/hexane:ethyl acetate=9:1-85:15) and recrystallized from ethyl acetate-hexane to provide the title compound (0.97 g, yield 39%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][OH:12].[C:13]([NH:20][CH2:21][C:22](O)=[O:23])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][CH2:10][CH2:11][OH:12])=[C:2]([NH:1][C:22](=[O:23])[CH2:21][NH:20][C:13](=[O:14])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1cc(Br)ccc1NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cc(Br)ccc1NCCO
Yield: 107.1 %

Procedure:
2-(2-Amino-4-bromophenylamino)ethanol (700 mg, 3.03 mmol), N-Boc-glycine (639 mg, 3.65 mmol), HATU (1.39 g, 3.66 mmol) and i-Pr2NEt (785 mg, 1.0 mL, 6.09 mmol) were stirred in methylene chloride (20 mL) for 20 min. The mixture was purified by column chromatography eluting with methylene chloride and a 9:1 methanol/ammonium hydroxide mixture; gradient 100% methylene chloride to 85% methylene chloride, to provide the title compound (1.26 g, quant) as a yellow oil: ESI MS m/z 388 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[C@@H:20]([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[CH2:9][O:10][C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[C@@H:20]([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1
Reactant: OCc1ccc(F)c(F)c1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Product: C[C@H]1Cn2c(cc(OCc3ccc(F)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,4-difluorophenyl)methanol and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [F:1][C:2]([F:9])=[C:3]([F:8])[Si](C)(C)C.[Si:10]([O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]2[C@@:24]3([CH:44]=[CH2:45])[C@H:33]([C@@H:34]([CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=[O:41])[CH2:35][C@:19]12[CH3:20])[C:32]1[CH:31]=[CH:30][C:29]([O:42][CH3:43])=[CH:28][C:27]=1[CH2:26][CH2:25]3)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>>[Si:10]([O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]2[C@@:24]3([CH:44]=[CH2:45])[C@H:33]([C@@H:34]([CH2:36][CH2:37][CH2:38][CH2:39][CH:40]([O:41][Si:10]([CH3:13])([CH3:12])[CH3:11])[C:3]([F:8])=[C:2]([F:9])[F:1])[CH2:35][C@:19]12[CH3:20])[C:32]1[CH:31]=[CH:30][C:29]([O:42][CH3:43])=[CH:28][C:27]=1[CH2:26][CH2:25]3)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:12]
Reactant: C[Si](C)(C)C(F)=C(F)F
Reactant: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCC=O)C[C@]1(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]12
Product: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCC(O[Si](C)(C)C)C(F)=C(F)F)C[C@]1(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]12

Procedure:
In the reaction with 1,1,2-trifluoro-2-trimethylsilyl ethylene analogously to instructions 1.1, 60 mg of aldehyde 9a yields 77 mg of trimethylsilyl ether 23a as a colorless foam (GC-MS: m/z theor.: 664, pract.: 664) and a mixture of its diastereomers. The latter is used without further purification in the next stage.
Reaction SMILES: C[O-].[Na+].[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9](=O)[CH2:10][CH2:11][C:12]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)=O.[CH:20]1[CH2:24][CH:23]=[CH:22][CH:21]=1>CO.CS(C)=O>[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1[CH:10]=[CH:11][C:12]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)=[C:20]2[C:21]=1[CH:22]=[CH:23][CH2:24]2
Reactant: C1=CCC=C1
Reactant: O=C(CCC(=O)c1ccco1)c1ccco1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: C1=Cc2c(-c3ccco3)ccc(-c3ccco3)c2C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 28.6 %

Procedure:
18.9 ml of a 30 percent strength solution of sodium methanolate (105 mmol) in methanol was initially introduced into the reaction vessel at 0° C, and a solution of 9.2 g (42.2 mmol) of 1,4-bis(2-furyl)-1,4-butanedione and 3.8 ml (46.2 mmol) of cyclopentadiene in DMSO were added dropwise in the course of 1 hour. After the mixture had been stirred at room temperature for 45 minutes it was poured onto ice-water and extracted with diethyl ether. After drying and evaporation, the residue was chromatographed on silica gel. 3.0 g (29 %) of the indene 14 could be obtained with hexane/methylene chloride (2:1) as the mobile phase.
Reaction SMILES: [CH2:1](S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1>C(#N)C>[CH2:1]([C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cccnc1Cc1ccccc1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 90.2 %

Procedure:
39.1 g (0.315 mol) of benzylmercaptan are introduced into 200 ml of acetonitrile, 47.8 g (0.346 mol) of K2CO3 are added, and the mixture is stirred for 40 minutes at 60° C. 50.0 g (0.315 mol) of 2-chloro-3-nitropyridine, dissolved in 150 ml of acetonitrile, are subsequently added dropwise and the mixture is refluxed for 4 hours. The acetonitrile is distilled off under reduced pressure, the residue is taken up in dichloromethane, the organic phase is washed in each case once with saturated sodium hydrogen carbonate solution and with 1N hydrochloric acid, the organic phase is dried over magnesium sulfate and the drying agent is filtered off, and the dichloromethane is removed under reduced pressure. Recrystallization from methanol gives 60.9 g (79% of theory) of 2-benzyl3-nitropyridine of melting point 72° C.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([OH:34])=O)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][CH2:40][CH2:41][OH:42]>C(OCC)(=O)C.CO>[OH:42][CH2:41][CH2:40][NH:39][C:32](=[O:34])[C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=1[S:27]([CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:28])=[O:29]
Reactant: NCCO
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(NCCO)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 58 %

Procedure:
Using the method for Example 164, this compound was prepared from 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (159 mg, 0.30 mmol) and 2-aminoethanol (92 mg, 1.50 mmol). The reaction product was extracted into ethyl acetate and purified by a silica column (eluted with dichloromethane-MeOH 20:1) to give a pale yellow solid, 100 mg, 58% yield; mp 241-243° C. (from ethyl acetate-MeOH). NMR was consistent with the structure. Calcd. For C31H31N306S
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[C:25]3[C:20](=[C:21]([O:26]CC4C=CC=CC=4)[CH:22]=[CH:23][CH:24]=3)[CH:19]=[N:18]2)[CH:5]=[C:6]([F:16])[C:7]=1[O:8]CC1C=CC=CC=1>C(O)C.C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:17]2[C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:26])[C:20]=3[CH:19]=[N:18]2)[CH:5]=[C:6]([F:16])[C:7]=1[OH:8]
Reactant: Fc1cc(-n2ncc3c(OCc4ccccc4)cccc32)cc(F)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Oc1c(F)cc(-n2ncc3c(O)cccc32)cc1F
Yield: 82.8 %

Procedure:
A solution of 1-{3,5-difluoro-4-[(phenylmethyl)oxy]phenyl}-4-[(phenylmethyl)oxy]-1H-indazole (D35) (257 mg, 0.58 mmol) in ethanol (10 mL) and ethyl acetate (10 mL) was hydrogenated in an H-cube over a 10% palladium on charcoal catalyst. The resulting solution was concentrated and then the crude product purified by silica gel chromatography eluting with 5-100% ethyl acetate in hexane to yield the title compound (E19) (126 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[CH2:3][CH:4]([C:8]1[CH:9]=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=[C:12](C(F)(F)F)[CH:13]=1)[C:5]([OH:7])=[O:6].[F:25][C:26]([F:43])([F:42])[C:27]1[CH:28]=[C:29](/[CH:37]=[CH:38]/B(O)O)[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1>>[F:25][C:26]([F:43])([F:42])[C:27]1[CH:28]=[C:29]([CH:37]=[CH:38][C:12]2[CH:13]=[C:8]([CH:4]([CH2:3][CH:2]([CH3:1])[CH3:24])[C:5]([OH:7])=[O:6])[CH:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:26]([F:43])([F:42])[F:25])=[CH:20][CH:19]=3)[CH:11]=2)[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1
Reactant: OB(O)/C=C/c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)CC(C(=O)O)c1cc(-c2ccccc2)cc(C(F)(F)F)c1
Product: CC(C)CC(C(=O)O)c1cc(C=Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was prepared from a Nigishi coupling of 4-methyl-2-(5-trifluoromethyl-biphenyl-3-yl)pentanoic acid (intermediate compound 1g) with trans-2-(3,5-bis-trifluoromethylphenyl)-vinyl-boronic acid under the conditions described in Example 14; 1H NMR (400 MHz, MeOD) δ ppm 0.98 (dd, J=6.60, 3.18 Hz, 6 H), 1.56 (dt, J=13.39, 6.63 Hz, 1 H), 1.75 (ddd, J=13.69, 7.21, 6.97 Hz, 1 H), 2.05 (ddd, J=13.57, 7.70, 7.58 Hz, 1 H), 3.82 (t, J=7.70 Hz, 1 H), 7.52 (d, J=16.5 Hz, 1 H), 7.44 (d, J=16.5 Hz, 1 H), 7.60 (s, 1 H), 7.67 (s, 1 H), 7.74-7.84 (m, 6 H), 8.18 (s, 2 H); Calcd for C29H23F9O2 (M+H) 575.16, Found 575.1.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[C:4]([CH2:6][C:7]#[N:8])=[O:5].[C:14]([O:17][C:18](=O)C)(=O)C>>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[C:4]([C:6](=[CH:14][O:17][CH3:18])[C:7]#[N:8])=[O:5]
Reactant: N#CCC(=O)c1ccc(Cl)cc1Cl
Reactant: CC(=O)OC(C)=O
Product: COC=C(C#N)C(=O)c1ccc(Cl)cc1Cl
Temperature: 150 °C
Yield: 104.5 %

Procedure:
A mixture of 8.8 g of 2,4-dichloro-benzoylacetonitrile, 69.2 g of methyl o-formate and 10.5 g of acetic anhydride is refluxed at a bath temperature of 150° C. for 3 hours. The volatile constituents are then distilled off in vacuo and finally under a fine vacuum at a bath temperature of 120° C. 11 g of 2-(2,4-dichloro-benzoyl)-3-methoxy-acrylonitrile are obtained as a viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:36](=[O:41])[C:37]([O:39][CH3:40])=[O:38].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:40][O:39][C:37](=[O:38])[C:36]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:41]
Reactant: COC(=O)C(=O)Cl
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (85 mg, 0.19 mmol) and methyl 2-chloro-2-oxoacetate (35 μL, 0.38 mmol) in CH2Cl2 (1 mL) was added Et3N (53 uL, 0.38 mmol), and catalytic amount of DMAP. The reaction mixture was stirred at RT for 3 h. The reaction was concentrated in vacuo and the residue was purified by flash chromatography on silica (10:1 CH2Cl2:MeOH). The product tert-butyl 5-(2-(3-(2-methoxy-2-oxoacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate was isolate. (18 mg, 18%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21](OCC)=[O:22])[O:18][N:17]=2)[N:3]=1.C[Al](C)C.[CH3:30][O:31][C:32]1[N:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]([NH:38][C:35]3[CH:36]=[N:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=3)=[O:22])[O:18][N:17]=2)[N:3]=1
Reactant: CCOC(=O)c1nc(-c2nc(N)nc(N(C)c3ccccc3)n2)no1
Reactant: COc1ccc(N)cn1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
To a solution of ethyl 3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazole-5-carboxylate (prepared in an analogous manner to Example 73, 0.2 g, 0.58 mmol) in toluene (10 mL) at 0 C was added trimethylaluminium (2M in toluene, 0.88 mL, 1.7 mmol) over a period of 5 min and the mixture was then stirred at room temperature for 2 h. 6-Methoxypyridin-3-amine (0.21 g, 1.7 mmol) was added and the mixture was heated to 60 C for 15 h. The mixture was cooled to room temperature and quenched with ice water. The mixture was extracted with EtOAc (3×20 mL) and the organic layers were concentrated under vacuum. The residue was slurried in acetonitrile for 30 min and the resultant precipitate was filtered off to afford the title compound (0.100 g, 43%).
Reaction SMILES: CCN=C=NCCCN(C)C.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20]1[O:24][C:23]([C:25]([NH:27][C:28]2[CH:29]=[N:30][C:31]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[CH:32][CH:33]=2)=[O:26])=[N:22][N:21]=1.[C:40](O)(=[O:43])[CH2:41][OH:42].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20]1[O:24][C:23]([C:25]([NH:27][C:28]2[CH:29]=[N:30][C:31]([N:34]3[CH2:39][CH2:38][N:37]([C:41](=[O:42])[CH2:40][OH:43])[CH2:36][CH2:35]3)=[CH:32][CH:33]=2)=[O:26])=[N:22][N:21]=1
Reactant: O=C(O)CO
Reactant: O=C(Nc1ccc(N2CCNCC2)nc1)c1nnc(Nc2ccccc2F)o1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(N2CCN(C(=O)CO)CC2)nc1)c1nnc(Nc2ccccc2F)o1
Reaction time: 16 h
Yield: 65 %

Procedure:
EDAC (60 mg, 0.31 mmol) was added to a stirred mixture of 5-[(2-fluorophenyl)amino]-N-(6-piperazin-1-ylpyridin-3-yl)-1,3,4-oxadiazole-2-carboxamide (Intermediate 41, 100 mg, 0.26 mmol), glycolic acid (20 mg (0.26 mmol) and HOBt (42 mg, 0.31 mmol) in 3 mL of DMF and stirring was continued for 16 h. Water (10 mL) was added and the resultant precipitate was collected by filtration, washed with water then ether and dried in vacuo to give the title compound (75 mg, 65%) as a solid; 1H NMR δ 10.94 (1H, s), 10.70 (1H, s), 8.50 (1H, s), 8.05 (1H, t), 7.90 (1H, d), 7.35-7.20 (2H, m), 7.20-7.10 (1H, m), 6.90 (1H, d), 4.60 (1H, t), 4.10 (2H, d), 3.60-3.4 (8H, m); MS m/e MH+ 442.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C[Si](C)(C)[N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16].I[CH2:20][CH:21]([CH3:23])[CH3:22]>C1COCC1>[CH3:20][CH:21]([CH3:23])[CH2:22][CH:13]1[CH2:14][CH2:15][NH:11][C:12]1=[O:16]
Reactant: C[Si](C)(C)N1CCCC1=O
Reactant: CC(C)CI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CC1CCNC1=O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 41 %

Procedure:
A solution of LDA (2.0M, 111 mL, 222 mmol) and THF (300 mL) is cooled to -78° C. and a solution of 1-trimethylsilyl-2-pyrrolidinone (29.4 g, 221 mmol) in THF (145 mL) is added. After stirring for 45 minutes at -78° C., the enolate solution is added via cannula over 1 hour to a solution of 1-iodo-2-methylpropane (42.7 g, 232 mmol) in THF (200 mL) at -78° C. The solution is allowed to warm slowly and stirred at room temperature overnight. The reaction is quenched by the addition of 50 mL of acetic acid. Aqueous workup (EtOAc, MgSO4) and purification by column chromatography (30→100% EtOAc/hexane) gives 12.8 g of the title compound as an oil.