Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]3[C:15]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([O:19]C)=[O:18])=[C:14]([CH3:24])[N:13]=[C:12]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:11]=3)[CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+]>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]3[C:15]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([OH:19])=[O:18])=[C:14]([CH3:24])[N:13]=[C:12]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:11]=3)[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2cc[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccc2cc[nH]c2c1
Yield: 52.8 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-(1H-indol-6-yl)-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.108 g; 0.270 mmol), sodium hydroxide 10N (0.270 mL; 2.7 mmol) in methanol (2.7 mL). Purification by flash-chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane furnished 0.055 g (52%) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].[I:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O.C(OCC)(=O)C>[I:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:2]([CH3:6])([C:3]#[CH:4])[CH3:5])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cc(O)ccc1I
Reactant: C#CC(C)(C)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: C#CC(C)(C)Oc1ccc(I)c([N+](=O)[O-])c1
Temperature: 65 °C
Yield: 90.9 %

Procedure:
3-Chloro-3-methyl-1-butyne (640 μL, 5.7 mmol, 3.0 equiv) was added to a stirred solution of 4-iodo-3-nitrophenol (500 mg, 1.89 mmol, 1 equiv), tetrabutylammonium iodide (2.10 g, 5.7 mmol, 3.0 equiv), and potassium carbonate (522 mg, 3.8 mmol, 2.0 equiv) in acetone (5.2 mL) at 23° C. The reaction mixture was warmed to 65° C. and was heated at this temperature for 18 h. The product solution was allowed to cool to 23° C., then was diluted with ethyl acetate (50 mL). The diluted product solution was washed with saturated aqueous sodium bicarbonate solution (5 mL) and saturated aqueous sodium chloride solution (5 mL). After washing, the organic layer was dried over sodium sulfate and the solids were filtered. The filtrate was concentrated. The residue obtained was dissolved in ethyl acetate (10 mL) and the resulting solution was filtered through a pad of Celite, eluting with ethyl acetate (50 mL). The eluent was concentrated and the residue obtained was purified by flash-column chromatography (4% acetone-hexanes) to furnish 1-iodo-4-(2-methyl-3-butyn-2-yloxy)-2-nitrobenzene as a pale yellow oil (569 mg, 91%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[CH3:14])[N:10]=[C:9]1[NH:15][C:16]3[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][C:21]=3[C:8]1=[N:7]2.Cl.[CH3:24][N:25]([CH2:27][CH2:28]Cl)[CH3:26]>CS(C)=O>[CH3:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[CH3:14])[N:10]=[C:9]1[N:15]([CH2:28][CH2:27][N:25]([CH3:26])[CH3:24])[C:16]3[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][C:21]=3[C:8]1=[N:7]2
Reactant: Cc1cc2nc3[nH]c4ccc(Br)cc4c3nc2cc1C
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc2nc3c4cc(Br)ccc4n(CCN(C)C)c3nc2cc1C
Temperature: 35 °C
Reaction time: 4 h

Procedure:
To a suspension of 5.38 g sodium hydride (0.22 mole) in 600 ml dry dimethylsulphoxide maintained at 35° C. 32.6 g 2,3-dimethyl-9-bromo-6H-indolo(2,3-b)quinoxaline (0.10 mol) is added under nitrogen and with good stirring. 30 minutes after completed addition 15.9 g N,N-dimethylamino-2-chloroethane-HCl (0.11 mole) are added at 35° C. The mixture is stirred at 35° C. for four hours and then the solvent is distilled off in vacuum at room temperature. The residue is dissolved after soaking out with water in methylacetate and slowly cooled to -30° C. whereby the base crystallizes out. Yield 22 g, 55%, mp. 146°-147° C.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:13]([O:17][CH3:18])(=[O:16])[CH2:14][SH:15].[F:19][C:20]1[CH:34]=[CH:33][C:23]([CH:24](O)[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH:24]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[S:15][CH2:14][C:13]([O:17][CH3:18])=[O:16])=[CH:33][CH:34]=1
Reactant: COC(=O)CS
Reactant: OC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)CSC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 50 %

Procedure:
A slurry of ρ-toluenesulfonic acid monohydrate (108 mg, 0.57 mmol) and activated 3 Å molecular sieves (300-500 mg) in 4 mL of toluene is stirred for 15 minutes. Methyl thioglycolate (265 mg, 2.50 mmol ) is then added followed by 4,4'-difluoro-benzhydrol (Aldrich) (500 mg, 2.27 mmol). The reaction is stirred for 2.5 hours at room temperature followed by heating at 50°-60° C. for 45 minutes. The mixture is diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, brine and dried over magnesium sulfate. Chromatography on silica gel, eluting with a gradient of 10% ethyl acetate in hexane to 20% ethyl acetate in hexane, provides methyl [[bis-(4-fluorophenyl)methyl]thio]acetate as a yellow oil in 50% yield.
Reaction SMILES: Br[C:2]1[O:3][CH:4]=[CH:5][CH:6]=1.C(NC(C)C)(C)C.C1COCC1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>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.[Cu]I.O>[O:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19]
Reactant: C#C[Si](C)(C)C
Reactant: Brc1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)C#Cc1ccco1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.6 %

Procedure:
A mixture of 2-bromofuran (500 mg, 3.402 mmol), Pd(PPh3)2Cl2 (75.69 mg, 0.10784 mmol), CuI (40.17 mg, 0.2109 mmol) and diisopropylamine (0.89 ml, 6.395 mmol) in tetrahydrofuaran (THF) (4 ml) was degassed thoroughly with argon, and trimethylsilyl acetylene (0.648 ml, 4.694 mmol) was added at room temperature. After stirring the reaction mixture for 16 hours at room temperature, it was poured into water and extracted with dichloromethane. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate and the solvent was evaporated. The crude material was purified by column chromatography (100-200 mesh silica gel) using hexane as eluent to yield the desired (furan-2-ylethynyl)trimethylsilane (200 mg, 1.21 mmol, yield 35.84%).
Reaction SMILES: [CH2:1]([N:3]([CH3:6])[CH:4]=O)[CH3:2].[Cl:7][C:8]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:9]=1[O:10][C:11]1[N:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1.[OH-].[Na+]>ClCCl>[Cl:7][C:8]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:9]=1[O:10][C:11]1[N:16]=[CH:15][C:14]([N:17]=[CH:4][N:3]([CH2:1][CH3:2])[CH3:6])=[CH:13][CH:12]=1
Reactant: CCN(C)C=O
Reactant: Nc1ccc(Oc2ccc(Cl)cc2Cl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCN(C)C=Nc1ccc(Oc2ccc(Cl)cc2Cl)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
In a 25 ml single-necked round-bottomed flask, ethylmethylformamide (350 mg) is solubilized in dry dichloromethane (4 ml) at ambient temperature (colourless solution). Under stirring phosphorous oxide chloride (0.4 ml) is added dropwise by syringe. Stirring at ambient temperature is continued for 1 hour. To this solution, 6-(2,4-Dichloro-phenoxy)-pyridin-3-ylamine (0.5 g) dissolved in 1.0 ml of dry dichloromethane is added dropwise by syringe, giving a yellow solution. Stirring is continued at an ambient temperature for 1 hour. The mixture is then poured into ice/water (pH=2, water phase). 2 M aqueous NaOH is then added to get a pH of about 11 and stirring is continued for 10 minutes. The mixture is then extracted with dichloromethane (2×50 ml). The combined organic phases are then dried over sodium sulfate, filtered and the solvent is removed in vacuo. Purification by flash chromatography over silica gel with hexane/ethyl acetate 3:4 (v:v) gives 0.31 g of the compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14]([C:19]1[N:20]=[CH:21][N:22](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:23]=1)([OH:18])[CH:15]([CH3:17])[CH3:16])[CH:8]=[CH:7]2)[CH3:2]>C(O)(=O)C.[C].[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14]([C:19]1[N:20]=[CH:21][NH:22][CH:23]=1)([OH:18])[CH:15]([CH3:17])[CH3:16])[CH:8]=[CH:7]2)[CH3:2]
Reactant: CCOc1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 62.3 %

Procedure:
1-(6-Ethoxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (0.60 g) was dissolved in acetic acid (10 ml) and 10% palladium carbon (0.2 g) was added and the mixture was stirred at 50° C. for 2 h and at 60° C. for 3 h under a hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated to dryness. Recrystallization from THF-ethyl acetate gave the title compound (0.21 g) as a colorless crystalline powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1B(O)O>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4](=[O:19])[CH2:3][C:2]2([CH3:20])[CH3:1]
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: OB(O)c1cc(Cl)ccc1Cl
Product: CC1(C)CC(=O)c2ccc(-c3cc(Cl)ccc3Cl)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 2,5-dichlorophenyl boronic acid according to the procedure described in example 21. MS m/z 305; HRMS: calcd for C17H14Cl2O+H+, 305.04944; found (ESI, [M+H]+), 305.0502.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:20](=[O:32])[C@@H:19]([CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[O:18][C@H:10]1[O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:42][Li]>C(OCC)C>[CH2:1]([O:8][C@@H:9]1[C@@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C@:20]([CH3:42])([OH:32])[C@@H:19]([CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[O:18][C@H:10]1[O:11][CH2:12][CH2:13][Si:14]([CH3:16])([CH3:15])[CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]C
Reactant: COc1ccc(CO[C@H]2C(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H](OCC[Si](C)(C)C)[C@@H]2OCc2ccccc2)cc1
Solvent: CCOCC
Product: COc1ccc(CO[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCC[Si](C)(C)C)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@]2(C)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.3 %

Procedure:
A stirred solution of 5.07 (9.2 g, 15 mmol) in ethyl ether (250 mL) was chilled to −78° C. then methyl lithium (48 mL of 1.6 M solution in diethyl ether, 76 mmol) was added dropwise over 20 minutes. The reaction was kept at −78° C. for an additional 4 h then warmed to room temperature and carefully quenched with saturated NH4Cl and transferred to a separatory funnel containing diethyl ether. The organic phase collected then washed with H2O and brine, dried over over Na2SO4, decanted, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography (8-12% EtOAc/petroleum ether) to give the desired glucopyranoside product 5.08 (7.2 g, 11.6 mmol, 76%) and its galactopyranoside diastereomer (2.1 g, 3.4 mmol, 22%). Desired glucopyranoside product 5.08: 1H NMR (500 MHz, CDCl3): δ ppm 7.38-7.27 (m, 7H, ArH), 6.86 (d, J=8.8 Hz, 2H, PMPH), 4.89, 4,71 (ABq, J=10.7 Hz, 1H each, OCH2Ar), 4.84, 4.79 (ABq, J=11.0 Hz, 1H each, OCH2Ar), 4.44 (d, J=7.8 Hz, 1H, H-1), 4.04-3.97 (m, 1H, OCHHCH2SiMe3), 3.92-3.81 (m, 2H, H-6), 3.80 (s, 3H, OMe), 3.57-3.65 (m, 1H, OCHHCH2SiMe3), 3.49 (d, J=9.8 Hz, 1H, H-3), 3.42 (t, J=6.8 Hz, 1H, H-5), 3.27 (dd, J=9.8, 7.8 Hz, 1H, H-2), 1.30 (s, 3H, Me2), 1.05 (t, J=8.3 Hz, 2H, OCH2CH2SiMe3), 0.93 (s, 9H, SiCMe3), 0.13, 0.12 (s, 3H each, SiMe), 0.04 (s, 9H, SiMe3); 13C NMR (125 MHz, CDCl3): δ ppm 159.21, 138.96, 131.46, 129.60, 128.41, 128.14, 127.66, 113.85, 103.85, 86.30, 81.41, 75.78, 75.32, 75.16, 75.10, 67.85, 62.73, 55.36, 25.99, 18.71, 18.31, 16.37, −1.29, −5.32, −5.48; HRMS calcd for C33H58NO7Si2 [M+NH4]+: 636.3752. found 636.3726.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:3]=1[NH:4][C:5]([O:7][CH3:8])=[O:6].[CH2:14](Br)[C:15]#[CH:16].CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:1][C:2]1[C:3](=[CH:9][C:10](=[N:13][CH2:16][C:15]#[CH:14])[CH2:11][CH:12]=1)[NH:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)Nc1cc(N)ccc1F
Reactant: C#CCBr
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CCN=C1C=C(NC(=O)OC)C(F)=CC1
Temperature: 60 °C
Reaction time: 6 h
Yield: 80.9 %

Procedure:
under an atmosphere of nitrogen, compound methyl 2-fluoro-5-aminoaniline formate (72.5 mg, 0.39 mmol) was dissolved in dried DMF (5 mL), then propargyl bromide (44 μL, 0.59 mmol) and DIPEA (140 μL, 0.78 mmol) were added. The resulting solution was stirred for 6 h at 60° C., and diluted with water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic phases were washed with saturated saline solution (15 mL×3), dried with anhydrous Na2SO4, concentrated and then loaded on chromatography column (PE/EtOAc=6:1-4:1) to produce a product of methyl 2-fluoro-5-(N-propargyl-imino)-aniline formate (70.1 mg, 81%);
Reaction SMILES: Br[C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([CH:12]=[O:13])[CH:3]=1.[CH3:14]N(C=O)C>[F-].[K+]>[CH3:14][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([CH:12]=[O:13])[CH:3]=1
Reactant: O=Cc1cc(Br)c2c(c1)OCCO2
Reactant: CN(C)C=O
Agent: [F-]
Agent: [K+]
Product: Cc1cc(C=O)cc2c1OCCO2
Temperature: 70 °C
Yield: 83 %

Procedure:
To a solution of 8-bromo-2,3-dihydro-1,4-benzodioxin-6-carbaldehyde (240 mg, 0.987 mmol) in DMF (5 mL) were added LiCL (126 mg, 2.96 mmol), Me Sn (0.137 mL, 0.987 mmol) and PdCL2(PPh)2 (35 mg, 0.049 mmol). After heated at 70° C. for 12 hr, the mixture was cooled down to room temperature and diluted with aqueous KF solution. The resulting solution was extracted several times with DCM. The organic parts were combined, concentrated and purified with column chromatography (silica, 10-40% Ethyl acetate in hexane) affording the title compound as an off-white solid (145 mg, 83%): MS (ES) m/z 179 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:13]=2)=[C:4]([Cl:23])[CH:3]=1.C(=O)([O-])[O-].[Ca+2].[C:29](Cl)(Cl)=[S:30].Cl>ClCCl.O>[Cl:23][C:4]1[CH:3]=[C:2]([N:1]=[C:29]=[S:30])[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:13]=1
Reactant: S=C(Cl)Cl
Reactant: CS(=O)(=O)Nc1cccc(-c2c(Cl)cc(N)cc2C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(-c2c(Cl)cc(N=C=S)cc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
To a cold (0° C.) suspension of N-(4′-amino-2′-chloro-6′-(trifluoromethyl)biphenyl-3-yl)methanesulfonamide (570 mg, 1.56 mmol, Eq: 1.00) and calcium carbonate (313 mg, 3.13 mmol, Eq: 2) in dichloromethane (3.38 ml) and water (3.38 ml) was added thiophosgene (198 mg, 131 μl, 1.72 mmol, Eq: 1.1). The reaction mixture was allowed to warm up to room temperature and was vigorously stirred for 16 h. 1N HCl was added to adjust the pH to ca. 2. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and washed with water then brine and purified on silica gel (column 24 g, dichloromethane/ethyl acetate 1:0 to 85:15) to give 565 mg (89%) of the desired product as a colorless oil.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:34][CH:35]1[CH2:38][CH2:37][CH2:36]1>CN(C)C=O>[CH:35]1([CH2:34][N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]2)=[O:9])[CH2:38][CH2:37][CH2:36]1
Reactant: BrCC1CCC1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3CC2CCC2)CC1
Yield: 69 %

Procedure:
The title compound was synthesized in analogy to example 51, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), sodium hydride and (bromomethyl)cyclobutane in N,N-dimethylformamide, to give the desired product as a colorless foam (69%).
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=1[CH2:23][OH:24].[B:25](OC)(OC)[O:26]C>C1COCC1>[F:20][C:19]([F:22])([F:21])[C:15]1[C:14]2[CH2:23][O:24][B:25]([OH:26])[C:13]=2[CH:18]=[CH:17][CH:16]=1
Reactant: OCc1c(Br)cccc1C(F)(F)F
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB1OCc2c1cccc2C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
To a 2.5 M solution of n-BuLi in hexane (27.81 mL, 69.53 mmol) in dry THF (30 mL), cooled to −78° C. and under an Argon atmosphere was added a solution of (2-bromo-6-(trifluoromethyl)phenyl)methanol (CXXIX) (5.49 g, 23.16 mmol) in dry THF (30 mL) dropwise very slowly. The reaction mixture was stirred at −78° C. for 2 h before adding trimethyl borate (3.88 mL, 34.76 mmol). The reaction mixture was stirred at −78° C. for an additional 30 min, and then allowed to warm up slowly to room temperature and stirred overnight. The reaction was then cooled to 0° C. and slowly quenched with 2 M HCl and stirred for 2.5 h at room temperature. The reaction mixture was extracted with EtOAc and the organic layer was dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography using (100:1 DCM/MeOH) to give 4-(trifluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol (CXXX) as an orange oil (1.17 g, 5.79 mmol, 25% yield). ESIMS found for C8H6BF3O2 m/z 201.4 (M−H).
Reaction SMILES: O=[C:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:16][C@H:17]([C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24])=[O:20])[CH3:18].C([BH3-])#N.[Na+]>C(O)C.O>[CH2:6]([O:5][C:3]([CH:2]([NH:16][C@H:17]([C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24])=[O:20])[CH3:18])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4])[CH3:7]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Yield: 65.1 %

Procedure:
Ethyl 2-oxo-4-phenylbutyrate (1.03 g) and L-alanyl-L-proline (0.19 g) are dissolved in a 1:1 ethanol-water solvent. A solution of sodium cyanoborohydride (0.19 g) in ethanol-water is added dropwise at room temperature over the course of two hours. When reaction is complete, the product is absorbed on strong acid ion-exchange resin and eluted with 2% pyridine in water. The product-rich cuts are freeze dried to give 0.25 g of crude N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline. The mass spectrum shows a molecular ion at 448 m/e for the monosilylated species. Chromatography affords the desired isomer.
Reaction SMILES: C([CH:4]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[C:12]2[C:11](=[O:22])[CH2:10][CH2:9][CH2:8][C:7]=2[NH:6][C:5]1([C:24]([F:27])([F:26])[F:25])O)(O)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:27][C:24]([F:25])([F:26])[C:5]1[NH:6][C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:22])[C:12]=2[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[CH:4]=1
Reactant: N#Cc1cccc(C2C3=C(CCCC3=O)NC(O)(C(F)(F)F)C2C(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1cccc(C2C=C(C(F)(F)F)NC3=C2C(=O)CCC3)c1
Yield: 55.2 %

Procedure:
A suspension of 3-carboxy-2-trifluoromethyl-2-hydroxy-4-(3-cyanophenyl)- 4,6,7,8-tetrahydro-5(1H)-quinolone (2.25 g) in toluene (100 ml) was treated with p-toluene sulfonic acid monohydrate (0.33 g). The mixture was vigorously refluxed under Dean-Stark conditions for 1.5 hours and then partitioned between water and ethyl acetate. The organic portion was washed (water and brine) and evaporated. The residue was purified by chromatography (hexane/ethyl acetate, 1:1) to yield the title compound (1.04 g) as a white solid; m.p. 182°-183° C.; NMR: 1.80-2.00(m,2, CH2), 2.13-2.30(m,2,CH2), 2.50-2.67(m,2,CH2), 4.68(d,1, CH, J=5.2), 5.61(d,1, CH, J=5.3), 7.51(m,2, Ar), 7.60(s, 1, Ar), 7.64(m,1, Ar), 9.42(s, 1, NH); MS: m/z=318(M); Analysis for C17H13F3N2O: Calculated C, 64.15; H, 4.12; N, 8.80; Found: C, 64.15; H, 4.10; N, 8.63.
Reaction SMILES: O.C(=O)([O-])[O-].[K+].[K+].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([NH2:22])=[N:17][CH:18]=[C:19](Br)[CH:20]=2)=[CH:11][CH:10]=1.[CH3:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1>O1CCOCC1.C(Cl)(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([NH2:22])=[N:17][CH:18]=[C:19]([C:27]3[CH:26]=[N:25][N:24]([CH3:23])[CH:28]=3)[CH:20]=2)=[CH:11][CH:10]=1
Reactant: Nc1ccc(-c2cc(Br)cnc2N)cc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cn1cc(-c2cnc(N)c(-c3ccc(N)cc3)c2)cn1
Temperature: 100 °C
Reaction time: 5 h
Yield: 57.2 %

Procedure:
Water (5 ml), potassium carbonate (1742 mg) and tetrakis(triphenylphosphine)palladium (242 mg) were added to a solution of the compound obtained in Step 1 of Example 1 (1110 mg) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (874 mg) in 1,4-dioxane (50 ml), and the mixture was stirred at 100° C. for five hours. After leaving to cool, the reaction solution was diluted with chloroform. The organic layer was washed with water and brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=96:4 (v/v)] to give 638 mg of the title compound as a solid.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26][C:25]3=[O:34])=[CH:20][C:19]=2[F:35])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O.[Pd]>[F:35][C:19]1[CH:20]=[C:21]([N:24]2[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26][C:25]2=[O:34])[CH:22]=[CH:23][C:18]=1[NH:17][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(NC3CCN(C(=O)OCc4ccccc4)CC3)c(F)c2)C(=O)O1
Agent: [Pd]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC[C@H]1CN(c2ccc(NC3CCNCC3)c(F)c2)C(=O)O1
Reaction time: 4 h

Procedure:
A suspension of 480 mg (1 mmol) 4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenylamino}-piperidine-1-carboxylic acid benzyl ester and Pd/C in 2 ml of a methanol/acetic acid 1/1 mixture was stirred under H2 for 4 h. The Pd/C was filtered and the filtrate was evaporated to dryness.