Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Br[C:39]1[CH:47]=[C:46]2[C:42]([CH2:43][N:44]([CH3:49])[C:45]2=[O:48])=[CH:41][CH:40]=1.C([O-])(=O)C.[K+]>C(#N)C.O>[NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:39]2[CH:47]=[C:46]3[C:42](=[CH:41][CH:40]=2)[CH2:43][N:44]([CH3:49])[C:45]3=[O:48])=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(N)=O)CCOCC1
Reactant: CN1Cc2ccc(Br)cc2C1=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN1Cc2ccc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)cc2C1=O
Temperature: 25 °C
Yield: 64.3 %

Procedure:
(S)-tert-Butyl 4-(1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 16, step (i), 300 mg), 6-bromo-2-methylisoindolin-1-one (Example 30, step (i), 131 mg) and potassium acetate (171 mg) in a mixture of acetonitrile (15 mL) and water (5 mL) was stirred under nitrogen at 90° C. with 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (378 mg). After 4 h the reaction mixture was cooled to room temperature and diluted with water (50 mL). The products were extracted with ethyl acetate (3×50 mL) and the combined extracts dried over magnesium sulfate and concentrated to afford the sub-titled compound (200 mg).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=2[O:19][CH3:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][Li].O>C1COCC1.C(OCC)C>[C:1]1([S:7]([NH:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]([OH:16])[CH3:21])=[CH:13][C:12]=2[O:19][CH3:20])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [Li]C
Reactant: COc1cc(C=O)ccc1NS(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COc1cc(C(C)O)ccc1NS(=O)(=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of 4-phenylsulfonylamino-3-methoxybenzaldehyde (400 mg; prepared in Reference Example 44.) in THF (10 ml) was cooled to at −78° C. mg; prepared in Reference Example 44.) in THF (10 ml) was cooled to at −78° C. in a stream of argon. A solution of methyl lithium (1.0M) in diethyl ether (3.4 ml) was added dropwise thereto. The mixture was stirred for 20 minutes. After the termination of reaction, a mixture of H2O+1N HCl was added thereto to stop the reaction. The mixture was extracted with ethyl acetate three times. The organic layer was washed, dried over and purified on silica gel column chromatography (AcOEt:hexane=1:1) to give the title compound (421 mg) having the following physical data.
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[O:19])[CH:13]=2)[CH2:6]1)C.C(=O)(O)O.[NH2:35][C:36]([NH2:38])=[NH:37].O.O.O.C([O-])(=O)C.[Na+]>CCO>[NH2:37][C:36]1[N:38]=[CH:4][C:5]2[CH2:6][N:7]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=4)=[O:19])[CH:13]=3)[CH2:8][CH2:9][C:10]=2[N:35]=1
Reactant: N=C(N)N
Reactant: CN(C)C=C1CN(c2ccnc(C(=O)Nc3cccc(C(F)(F)F)c3)c2)CCC1=O
Agent: CC(=O)[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ncc2c(n1)CCN(c1ccnc(C(=O)Nc3cccc(C(F)(F)F)c3)c1)C2
Temperature: 80 °C
Reaction time: 23 h
Yield: 14.3 %

Procedure:
A solution of 4-[3-(dimethylamino)methylidene-4-oxopiperidin-1-yl]-N-[3-(trifluoromethyl)phenyl]pyridine-2-carboxamide (417 mg, 0.997 mmol) in EtOH (10 ml) was treated with guanidine carbonate (719 mg, 3.99 mmol), followed by adding sodium acetate trihydrate (1.09 g, 7.98 mmol). The reaction mixture was stirred at 80° C. for 23 hours and concentrated. The residue was partitioned between EtOAc and water resulting in the formation of a yellow, amorphous solid. The solid was collected, washed with water, EtOAc, MeOH, and dried to give the title compound (59 mg, 14%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.[Li].Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([N:8]1[C:7](=[O:12])[CH:6]2[CH2:13][O:14][CH2:15][CH2:16][N:5]2[C:4]2[N:3]=[C:2]([Cl:1])[N:11]=[CH:10][C:9]1=2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C1Nc2cnc(Cl)nc2N2CCOCC12
Agent: [Li]
Solvent: CN(C)C=O
Product: O=C1C2COCCN2c2nc(Cl)ncc2N1Cc1ccccc1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x38 using 2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (PREPARATION x1, 500 mg, 2.078 mmol), 1M lithium bis(trimethylsiylyamide) in hexanes (2.493 mL, 2.493 mmol) and (bromomethyl)benzene (0.271 mL, 2.286 mmol) in DMF (10 mL) at 0° C. for 18 hours. 1H NMR (400 MHz, DMSO-d6) δ 2.94-3.06 (m, 1H), 3.50-3.61 (m, 1H), 3.62-3.72 (m, 1H), 3.90-3.99 (m, 1H), 4.17-4.32 (m, 2H), 4.56-4.67 (m, 1H), 5.02-5.22 (m, 2H), 7.29 (s, 5H), 7.72 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C16H15ClN4O2, 331.09. found 331.2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[Li]CCCC.[B:14](OC(C)C)([O:19]C(C)C)[O:15]C(C)C.Cl>>[B:14]([OH:19])([OH:15])[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ccc(Br)cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Product: OB(O)c1ccc(Cl)nc1
Yield: 60 %

Procedure:
5-Bromo-2-chloropyridine was treated with n-BuLi (1.6 M in hexanes, 12.0 mL, 19.1 mmol), triisopropyl borate (4.8 mL, 20.9 mmol) and HCl(aq) (2.7 N, 16.8 mL) as for 1 to give the title compound 4 (1.7 g, 60% yield) as a pink solid: 1H NMR (CD3OD) δ 8.58 (br s, 1H), 7.95 (br d, J=6.7 Hz, 1H), 7.95 (d, J=8 Hz, 1H). This material was used directly in Suzuki cross coupling reactions.
Reaction SMILES: Cl.C(O)C.C(OC([NH:12][C@H:13]1[CH2:18][C@H:17]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:16][CH2:15][C@H:14]1[NH:23][C:24]([C:26]1[NH:27][C:28]2[C:33]([CH:34]=1)=[CH:32][C:31]([Cl:35])=[CH:30][CH:29]=2)=[O:25])=O)(C)(C)C>O1CCOCC1>[ClH:35].[Cl:35][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:24]([NH:23][C@@H:14]1[CH2:15][CH2:16][C@@H:17]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:18][C@@H:13]1[NH2:12])=[O:25])=[CH:34]2
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](C(C)(C)O)CC[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)(O)[C@@H]1CC[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@@H](N)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 4N hydrogen chloride solution in dioxane (10 ml) was added to an ethanol solution (5 ml) of (1R*,2S*,4R*)-N2-tert-butoxycarbonyl-N1-[(5-Chloroindol-2-yl)carbonyl]-4-(1-hydroxy-1-methylethyl)-1,2-cyclohexanediamine, and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure to obtain the title compound (100 mg) as a colorless oil.
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[C:18]([Si:22]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)Cl)([CH3:21])([CH3:20])[CH3:19]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Si:22]([O:8][CH:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCC1CC=CCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](OC=C1C=CCCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 3-cyclohexene-1-methanol (Aldrich, 13.0 mL, 0.11 mol), N,N-diisopropylethylamine (43 mL, 0.244 mol) and 4-dimethylaminopyridine (2.70 g., 0.022 mol) in 375 mL of dry CH2Cl2 under N2 at 25° C. was added tert-butyldiphenylchlorosilane (32 mL, 0.123 mol). The mixture was stirred at 25° C. for 48 hours. The reaction mixture was washed sequentially with 150 mL portions of 1N HCl, water, brine and dried over anhydrous MgSO4. The solvent was evaporated. The residue was loaded onto a 4"×4" column of silica and slowly eluted using hexanes as eluant. 3-(tert-butyldiphenylsilyloxymethylene)-1-cyclohexene, 33.6 g (86%), was obtained as a colorless oil which was homogenous by TLC (Rf=0.4, hexanes).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].[C:25]1([Sn](CCCC)(CCCC)CCCC)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].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>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 82.2 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (200 mg, 0.51 mmol), PhSnBu3 (0.2 mL, 0.62 mmol), and PdCl2(PPh3)2 (72 mg, 0.10 mmol) in DMF (5 mL) was heated at 120° C. under nitrogen atmosphere for 2 h. After the mixture was cooled to r.t., brine (10 mL) and EtOAc (40 mL) were added. 1M HCl was added with stirring until pH was about 2. The aqueous layer was extracted with additional EtOAc and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (0-55% EtOAc/hexanes+2% AcOH) to give 162 mg of the title compound as a yellow solid. MS: (+) m/z 387.10 (M+1).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=2)=[N:6][N:7]2[CH2:12][CH:11]([CH:13]3[CH2:15][CH2:14]3)[N:10](C(OC(C)(C)C)=O)[CH2:9][C:8]=12)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:30][C:25]1[CH:24]=[C:23]([C:5]2[C:4]([C:1]([NH2:2])=[O:3])=[C:8]3[CH2:9][NH:10][CH:11]([CH:13]4[CH2:14][CH2:15]4)[CH2:12][N:7]3[N:6]=2)[CH:28]=[CH:27][C:26]=1[F:29]
Reactant: CC(C)(C)OC(=O)N1Cc2c(C(N)=O)c(-c3ccc(F)c(Cl)c3)nn2CC1C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1c(-c2ccc(F)c(Cl)c2)nn2c1CNC(C1CC1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To a stirred solution of Intermediate 348H (0.43 g, 0.989 mmol) in DCM (8.0 mL) was added TFA (4.0 mL, 51.9 mmol) and the resulting solution was stirred at RT for 2 h. The reaction mixture was concentrated and the residue was extracted with DCM (10 mL), and washed successively with water, a saturated aq. NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to afford Intermediate 3481 as an off-white solid (0.3 g, 67%). MS(ES): m/z=335 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.80-7.91 (m, 1H), 7.64-7.70 (m, 1H), 7.35-7.50 (m, 1H), 7.02-7.29 (m, 2H), 4.12-4.25 (m, 2H), 3.93 (d, J=16.56 Hz, 1H), 3.68-3.81 (m, 2H), 2.40 (br. s., 1H), 0.82-0.98 (m, 1H), 0.48 (d, J=8.03 Hz, 2H), 0.37 (d, J=5.02 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]=[C:7](O)[CH:6]=[CH:5]2.CN(C=O)C.C(Cl)(=O)C([Cl:22])=O.C(Cl)Cl>ClCCCl>[Cl:22][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=1
Reactant: Oc1ccc2cc(F)cc(F)c2n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Fc1cc(F)c2nc(Cl)ccc2c1
Temperature: 70 °C

Procedure:
6,8-Difluoro quinolin-2-ol (9.89 g, 54.6 mmol) was slurried in 1,2-dichloroethane (550 mL) and treated with DMF (1 mL), and then 2M oxalyl chloride in CH2Cl2 (81.9 mL, 164 mmol) was added dropwise. The reaction was heated to 70° C. for 1 hour and then cooled and concentrated in vacuo. The residue was dissolved in CHCl3 and washed with 50% saturated NaHCO3. The aqueous layer (pH 8) was washed twice with CHCl3 and the combined organics were dried over Na2SO4 and charcoal, filtered, and concentrated in vacuo to a brown solid. The solid was purified by recrystallization from hot hexanes and 1,2-dichloroethane (minimum volume). The solid was collected, washed with hexanes and air-dried to provide the desired product as an off-white solid (5.78 g).
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][Si](C(C)C)(C(C)C)C(C)C)=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:32][CH3:33])[C:9]=3[C:8]2(O)[CH3:34])=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.C([SiH](CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([OH:21])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:32][CH3:33])[C:9]=3[CH:8]2[CH3:34])=[CH:36][CH:37]=1
Reactant: COc1c2c(c(O[Si](C(C)C)(C(C)C)C(C)C)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2(C)O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COc1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 16 (52 mg, 0.099 mmol) in 1.4 mL of dry CH2Cl2 under a N2 atmosphere, was added BF3.OEt2 (49 μL, 0.397 mmol) followed by triethylsilane (63 μL, 0.397 mmol). The solution was allowed to stir at ambient temperature for 1 day when LCMS indicated a clean conversion of starting materials to the desired product. The reaction was worked up by removing the solvent and dissolving the residue in EtOAc. The organic layer was washed with water and the solvent removed under reduced pressure. The residue was dissolved in 1 mL of EtOAc and triturated by addition of hexanes to provide the product 18. 1H NMR (300 MHz, CDCl3) δ 1.60 (d, 3H, J=7 Hz), 3.93 (s, 3H), 4.28 (d, 1H), J=15 Hz), 4.65 (q, 1H, J=7 Hz), 5.25 (d, 1H, J=15 Hz), 7.06 (t, 2H, J=8 Hz), 7.32 (dd, 2H, J=6, 8 Hz), 7.67 (dd, 1H, J=4, 8 Hz), 8.59 (br s, 1H), 8.61 (d, 1H, J=8 Hz), 9.11 (br s, 1H); 13C NMR (75 MHz, CDCl3) δ 16.9,42.8, 54.5, 61.9, 113.9, 115.7, 116.0, 122.7, 126.6, 129.8, 129.9, 130.8, 132.1, 133.1, 136.7, 142.4, 147.8, 148.3, 162.3 (d, J=245 Hz), 168.1; 19F NMR (282.6 MHz, CDCl3) δ 62.5; EI MS (m/z) 353.5 [MH+], 385.4 [M+Na].
Reaction SMILES: [Si:1]([O:8][CH:9]([C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)[CH2:10][CH2:11][CH:12]([CH:27]([NH:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[C:13](N1C(C2C=CC=CC=2)COC1=O)=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.O.O.O.[F-].C([NH+](CCCC)CCCC)CCC.C(O)(=O)C>COC(C)(C)C>[Si:1]([O:8][CH:9]([C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)[CH2:10][CH2:11][CH:12]1[CH:27]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[N:35]([C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)[C:13]1=[O:14])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC(CCC(C(=O)N1C(=O)OCC1c1ccccc1)C(Nc1ccc(F)cc1)c1ccc(O)cc1)c1ccc(F)cc1
Agent: CCCC[NH+](CCCC)CCCC
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: [F-]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OC(CCC1C(=O)N(c2ccc(F)cc2)C1c1ccc(O)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.63 g of 3-{5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-2-[(4-fluorophenyl-amino)-(4-hydroxyphenyl)methyl]pentanoyl}-4-phenyloxazolidin-2-one are suspended in 60 ml of tert-butyl methyl ether. 3.22 ml of bis(trimethylsilyl)acetamide and 122 mg of tributylammonium fluoride trihydrate are then added. The reaction mixture is stirred at room temperature for 3 h, and 0.6 ml of glacial acetic acid are then added. The reaction mixture is concentrated using a rotary evaporator and the residue is purified by column chromatography (SiO2; ethyl acetate/heptane 1:4). The product is obtained as clear crystals. C30H35F2NO3Si (523) MS (ESI): M+−131
Reaction SMILES: C([O-])(=O)C.[CH2:5]([N+:9]1[CH:13]=[CH:12][N:11]([CH3:14])[CH:10]=1)[CH2:6][CH2:7][CH3:8].[C:15]([O:21]C1C=CC([N+]([O-])=O)=CC=1CC(C1C=CC(OC)=CC=1)=O)(=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19]>>[C:15]([O-:21])(=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19].[CH2:5]([N+:9]1[CH:13]=[CH:12][N:11]([CH3:14])[CH:10]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCC(=O)Oc1ccc([N+](=O)[O-])cc1CC(=O)c1ccc(OC)cc1
Agent: CC(=O)[O-]
Agent: CCCC[n+]1ccn(C)c1
Product: CCCCC(=O)[O-]

Procedure:
The reaction was also carried out using 0.14 g (0.59 mmol) of the commercially available 1-butyl-3-methyl-imidazolium acetate with 0.11 g (0.29 mmol) of 2-(2-pentanoyloxy-5-nitrophenyl)-1-(4-methoxyphenyl)-ethanone (example 2) under the same reaction conditions as described in example 18. By comparing the LC-MS chromatogram of the crude reaction mixture with the chromatogram obtained from the reaction with 1-butyl-3-methyl-imidazolium valerate it was concluded that both methods delivered the targed compound in similar yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.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.[OH:40][C:41]([C:43]([F:46])([F:45])[F:44])=[O:42].[F:47][CH:48]([F:77])[CH2:49][NH:50][C:51]1[N:56]=[C:55]2[CH:57]([CH3:61])[NH:58][CH2:59][CH2:60][C:54]2=[N:53][C:52]=1[N:62]1[CH2:67][CH2:66][CH:65]([O:68][C:69]2[CH:74]=[CH:73][C:72]([F:75])=[CH:71][C:70]=2[F:76])[CH2:64][CH2:63]1>CN(C=O)C.C(Cl)Cl>[F:77][CH:48]([F:47])[CH2:49][NH:50][C:51]1[N:56]=[C:55]2[CH:57]([CH3:61])[N:58]([C:4](=[O:6])[CH2:3][O:2][CH3:1])[CH2:59][CH2:60][C:54]2=[N:53][C:52]=1[N:62]1[CH2:67][CH2:66][CH:65]([O:68][C:69]2[CH:74]=[CH:73][C:72]([F:75])=[CH:71][C:70]=2[F:76])[CH2:64][CH2:63]1.[C:41]([OH:42])([C:43]([F:46])([F:45])[F:44])=[O:40]
Reactant: COCC(=O)O
Reactant: CC1NCCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NCC(F)F)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NCC(F)F)nc2C1C

Procedure:
A solution of 2-methoxyacetic acid (2.4 mg, 0.027 mmol), HATU (10.3 mg, 0.027 mmol), and DIPEA (14.2 μL, 0.081 mmol) in DMF (271 μl) was stirred at room temperature for 10 min. To this was then added N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (15 mg, 0.027 mmol) in DCM (271 μL) and the reaction mixture was stirred overnight. Purification by HPLC Method A afforded the title compound as a TFA salt (7.4 mg) as an off-white film. 1H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm 1.47 (d, J=6.8 Hz, 2H), 1.58 (d, J=6.8 Hz, 1H), 1.93-2.03 (m, 2H), 2.10-2.18 (m, 2H), 2.63-3.06 (m, 4.1H), 3.12 (td, J=12.9, 3.9 Hz, 0.3H), 3.36-3.51 (m, 5.6H), 3.70-3.88 (m, 2H), 4.02 (dd, J=13.9, 5.6 Hz, 0.7H), 4.18-4.33 (m, 2H), 4.46 (dt, J=7.3, 3.7 Hz, 1H), 4.71 (dd, J=13.4, 5.6 Hz, 0.3H), 4.79-4.84 (m, 0.3H), 5.30 (q, J=6.8 Hz, 0.7H), 5.91-6.21 (m, 1H), 6.85-6.92 (m, 1H), 6.99 (ddd, J=11.3, 8.7, 2.9 Hz, 1H), 7.18 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 512.85.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[N:13]3[N:20]=[C:21]([CH2:23][CH2:24][OH:25])[CH:22]=[C:12]3[C:11]=2[CH:10]=1)C1C=CC=CC=1.C(O)C.Cl.[H][H]>[Pd]>[OH:8][C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[N:13]3[N:20]=[C:21]([CH2:23][CH2:24][OH:25])[CH:22]=[C:12]3[C:11]=2[CH:10]=1
Reactant: [H][H]
Reactant: O=c1[nH]c2ccc(OCc3ccccc3)cc2c2cc(CCO)nn12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2ccc(O)cc2c2cc(CCO)nn12
Temperature: 25 °C

Procedure:
29.2 g (0.1 mole) of 9-(benzyloxy)-2-(2-hydroxyethyl)pyrazolo[1,5-c]quinazolin-5(6H)-one and 0.5 g 10% palladium-on-carbon in 200 ml ethanol containing 0.2 moles of hydrogen chloride are hydrogenated on a Parr shaker, with cooling, at ambient temperature. The reaction is stopped after 0.3 moles of hydrogen are absorbed or when hydrogen uptake ceases, whichever comes first. The reaction is diluted with chloroform, filtered and the filtrate evaporated. The residue is suspended in methylene chloride and shaken with excess aqueous sodium bicarbonate. The organic phase is washed with water, dried and evaporated to give the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:28]4[C:23]([C:24]([NH2:29])=[N:25][CH:26]=[N:27]4)=[C:22]([C:30]4[CH:31]=[CH:32][C:33]5[C:37]([CH:38]=4)=[N:36][N:35]([CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH:34]=5)[CH:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:39]([N:35]1[CH:34]=[C:33]2[C:37]([CH:38]=[C:30]([C:22]3[CH:21]=[C:20]([C:16]4[CH:17]=[CH:18][CH:19]=[C:14]([N:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:15]=4)[N:28]4[C:23]=3[C:24]([NH2:29])=[N:25][CH:26]=[N:27]4)[CH:31]=[CH:32]2)=[N:36]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnn2c(-c3cccc(N4CCNCC4)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reaction time: 1 h
Yield: 30 %

Procedure:
The product from step 5 (55 mg, (0.09 mmol) was dissolved in 1 mL of CH2Cl2 and 1 mL of TFA was added dropwise. The mixture stirred for 1 hour and then concentrated to dryness. The residue was dissolved in acetonitrile and water was added and the pH was adjusted to 9 by the addition of aqueous K3PO4. The mixture was concentrated in vacuo and the solids obtained were extracted with MeOH, and then concentrated in vacuo again. The solid residue obtained was re-extracted with MeOH, filtered and the filtrate purified by preparative HPLC to provide 14 mg (30%) of the title compound. 1H-NMR (DMSO-d6) 8.35 (s, 1H), 7.61 (s, 1H), 7.58 (bs, 2H), 7.39-7.24 (m, 7H), 7.22 (s, 1H), 7.11-7.01, (m, 2H), 6.77 (d, 1H), 6.57 (d, 1H), 6.26 (d, 1H), 5.57 (s, 2H), 3.10 (m, 4H), 2.84 (m, 4H); LC-MS [M+H]+=501.2, RT=2.24 min.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11](OC(=O)C)(=[O:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(C#N)c(O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cc(C)ccc1C#N
Yield: 97.2 %

Procedure:
To a solution of 2-Hydroxy-4-methylbenzonitrile (0.563 g, 4.23 mmol) in CH2Cl2 (21 mL) was added acetic anhydride (0.60 mL, 6.36 mmol) followed by triethylamine (1.20 mL, 8.61 mmol) and the resultant solution was stirred at room temperature for 30 minutes. The mixture was diluted with CH2Cl2 (60 mL), washed with saturated aqueous NaHCO3 (20 mL) and brine (2×20 mL). The organic phase was dried (Na2SO4) and concentrated and provided 0.72 g (97%) of (2-cyano-5-methyl-phenyl) acetate as a white solid. 1H NMR (CDCl3) δ2.38 (s, 3H), 2.43 (s, 3H), 7.08 (s, 1H), 7.13 (d, 1H, J=9 Hz), 7.54 (d, 1H, J=9 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[OH:14].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[O:14][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]
Reactant: Oc1ccc(-c2ccccc2)cc1Br
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(COc1ccc(-c2ccccc2)cc1Br)c1ccccc1

Procedure:
A mixture of 137 g. (0.55 mole) of 2-bromo-4-phenylphenol, 109 g. (0.55 mole) of α-bromoacetophenone and 75 g. of sodium carbonate in 1.5 liters of acetone is heated at its reflux temperature for six days, filtered, then evaporated. The white residue is recrystallized from a benzene-hexane mixture to provide white needles of α-(2-bromo-4-phenylphenoxy)acetophenone, m.p. 93°-95° C.