Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:4][S:3][CH2:2]1.O=S(Cl)Cl>ClCCl>[CH2:1]1[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:4][S:3][CH2:2]1
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(O)CCCCC1CCSS1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The synthesis of lipoic acid chloride (DL-thioctic acid) was carried out under argon at ambient temperature following a standard protocol: lipoic acid (5 g, 24 mmol) is solubilised in dichloromethane (40 ml) and SOCl2 (1.3 eq) is added dropwise. After 1 hour of stirring at ambient temperature, the lipoic acid chloride formed is poured onto a solution of resveratrol diacetate (1.2) (6 g, 19 mmol) in THF (100 ml), containing triethylamine (3 eq) and DMAP (0.45 eq). After 1 hour the reaction mixture is diluted with 100 ml CH2Cl2, then washed with two times 90 ml of HCl 5% v/v. The organic phase is dried over anhydrous MgSO4, filtered, then concentrated in a rotary evaporator. The crude product (11.4 g) is purified by chromatography on a column of silica with cyclohexane/ethyl acetate (4/1 v/v) as eluent. The fractions containing the pure product are evaporated to lead to 5.95 g of 3,5-resveratrol diacetate-4′-lipoate 1 (49% of yield) with a molar purity measured by NMR of the proton of 96%.
Reaction SMILES: [NH:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][C:2]1=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9]3.[CH3:20][C:21](C)([O-])C.[K+].BrCC>O1CCCC1>[CH2:20]([N:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][C:2]1=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH3:21]
Reactant: CC(C)(C)[O-]
Reactant: O=C1COc2cccc3nc4c(c(c23)N1)CCCC4
Agent: [K+]
Solvent: CCBr
Solvent: C1CCOC1
Product: CCN1C(=O)COc2cccc3nc4c(c1c23)CCCC4
Reaction time: 0.33 h
Yield: 81.6 %

Procedure:
To suspension of 1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (5.0 g) in dry tetrahydrofuran (110 ml) was added potassium tert-butoxide (2.65 g). The mixture was stirred for 20 mins, bromoethane (5.88 ml) was added, and the reaction mixture was refluxed for 6.5 hrs. The reaction mixture was concentrated, diluted with saturated potassium carbonate solution, and extracted with ethyl acetate. The organic extractions were dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was adhered to silica and flash chromatographed (20% ethyl acetate/hexane) to yield 4.53 g (82%) of 1-ethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([S:13](Cl)(=[O:15])=[O:14])[CH2:10]2)=[CH:5][CH:4]=1.[NH2:17][C:18]1[C:23]2[CH:24]=[C:25]([CH2:27][CH:28]([NH:38]S(C3C=CC(OC4CCOCC4)=CC=3)(=O)=O)[C:29]([N:31]3[CH2:36][CH2:35][CH:34]([CH3:37])[CH2:33][CH2:32]3)=[O:30])[S:26][C:22]=2[CH:21]=[CH:20][N:19]=1>>[NH2:17][C:18]1[C:23]2[CH:24]=[C:25]([CH2:27][CH:28]([NH:38][S:13]([N:9]3[CH2:8][CH2:7][C:6]4[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:10]3)(=[O:15])=[O:14])[C:29]([N:31]3[CH2:32][CH2:33][CH:34]([CH3:37])[CH2:35][CH2:36]3)=[O:30])[S:26][C:22]=2[CH:21]=[CH:20][N:19]=1
Reactant: CC1CCN(C(=O)C(Cc2cc3c(N)nccc3s2)NS(=O)(=O)c2ccc(OC3CCOCC3)cc2)CC1
Reactant: COc1ccc2c(c1)CN(S(=O)(=O)Cl)CC2
Product: COc1ccc2c(c1)CN(S(=O)(=O)NC(Cc1cc3c(N)nccc3s1)C(=O)N1CCC(C)CC1)CC2

Procedure:
This compound was prepared from 200 mg of 7-methoxy-3,4-dihydro-1H-isoquinoline-2-sulfonyl chloride and 210 mg of 30a using the procedure described for 58c. Yield: 110 mg; m.p. 175-176° C., (+)-FAB-MS: 544 (MH+).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:16])[CH:3]=1.B(O)(O)[C:18]1[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=1>>[F:16][C:4]1[CH:3]=[C:2]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=C1NCCn2c1cc1cc(F)cc(Br)c12
Product: Cc1ccc(-c2cc(F)cc3cc4n(c23)CCNC4=O)cc1

Procedure:
The title compound, light grey solid (70 mg, 95%), MS (ISP) m/z=295.2 [(M+H)+], mp 271.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 1) (70.8 mg, 0.25 mmol) and commercially available p-tolylboronic acid (44.2 mg, 0.325 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([C:10](=O)[NH:11][C:12]1[C:17]2[NH:18][CH2:19][CH2:20][O:21][C:16]=2[C:15]([F:22])=[CH:14][CH:13]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.FC1C=CC2=C3C=1OCCN3C(C(NC(=O)C)C)=N2>CC(O)=O>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([C:10]1[N:18]2[C:17]3[C:16]([O:21][CH2:20][CH2:19]2)=[C:15]([F:22])[CH:14]=[CH:13][C:12]=3[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)c2c1NCCO2
Agent: CC(=O)NC(C)c1nc2ccc(F)c3c2n1CCO3
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(NC(=O)OC(C)(C)C)c1nc2ccc(F)c3c2n1CCO3
Reaction time: 16 h

Procedure:
A solution of [(S)-1-(8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazin-5-ylcarbamoyl)ethyl]carbamic acid tert-butyl ester (440 mg, 1.297 mmol) in AcOH (15 mL) was stirred successively at 80° C. for 1 h, 100° C. for 5 h and then 85° C. for 16 h. Toluene was added and the reaction mixture concentrated in vacuo to give a mixture of the title compound and N-[1-(6-fluoro-3,4-dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-yl)ethyl]acetamide. LCMS (Method B): RT 1.72 min [M+H]+ 264 & 2.51 min [M+H]+ 322
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([C:15]1[CH:16]=[N:17][CH:18]=[C:19]([OH:21])[CH:20]=1)[CH2:8][CH2:7]2.[C:22]([O:26][C:27](=[O:30])[CH2:28]Br)([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C>[C:22]([O:26][C:27](=[O:30])[CH2:28][O:21][C:19]1[CH:18]=[N:17][CH:16]=[C:15]([N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][CH:13]=[C:4]([Cl:3])[CH:5]=3)[C:10]2=[O:14])[CH:20]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C1c2ccc(Cl)cc2CCN1c1cncc(O)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.3 %

Procedure:
NaH (38 mg, 1.5 mmol) was added to a solution of 6-chloro-2-(5-hydroxy-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (288 mg, 1.0 mmol, example 252) in dry DMF (5 mL) at 0° C. After stirred at RT for 10 minutes, bromo-acetic acid tert-butyl ester (234 mg, 1.2 mmol) was added and the reaction mixture was stirred at RT for 1 hour before it was poured into ice-water and extracted with EtOAc (2×10 mL). The combined organic layers were dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product (320 mg, 82%) as a solid MS: 389.8 (M+H+).
Reaction SMILES: C(O[C:4](=[O:9])[C:5]([F:8])([F:7])[F:6])C.[CH2:10]([NH2:13])[CH2:11][NH2:12].C(N(CC)CC)C>CO>[C:5]([C:4]([NH:12][CH2:11][CH2:10][NH2:13])=[O:9])([F:6])([F:7])[F:8]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCCN
Solvent: CO
Solvent: CCN(CC)CC
Product: NCCNC(=O)C(F)(F)F
Reaction time: 8 h

Procedure:
N-1-trifluoroacetylethyldiamine (CF3CONH(CH2)2NH2 is prepared by adding ethyltrifluoroacetate (1.2 ml, 10 mmol) dropwise over one hour to a stirred mixture of ethylenediamine (0.6 g; 10 mmol) and triethylamine (1 ml; 7 mmol) in 20 ml methanol. The solution is stirred overnight. After removal of solvents, the reaction mixture is flash chromatographed on silica using 0-25% methanol in dichloromethane. The fractions containing the desired product are pooled and concentrated to give a colorless product.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[Br:12][CH2:13][CH2:14][C:15](OC)=[O:16]>>[Br:12][CH2:13][CH2:14][C:15]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=1)=[O:16]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CCBr
Product: O=C(CCBr)Nc1ccc(C(F)(F)F)cc1

Procedure:
22.3 ml of 4-(trifluoromethyl)aniline (29 g, 179.6 mmol, 1 equivalent) were reacted with 19.6 ml (30 g, 179.6 mmol, 1 equivalent) of methyl 3-bromopropanoate and worked up analogously to Example 152A. The crude product obtained was then purified on a silica gel column (mobile phase: dichloromethane). This gave 20.3 g (37% of theory) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18](=[O:26])[C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[C:6]=2[C:5](=[O:27])[NH:4][C:3]1=[O:28].[H-].[Na+].[F:31][CH2:32]Br>CN(C=O)C.O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][N:7]3[C:6]4[C:5](=[O:27])[N:4]([CH2:32][F:31])[C:3](=[O:28])[N:2]([CH3:1])[C:10]=4[N:9]=[CH:8]3)=[CH:17][CH:16]=2)=[O:26])=[CH:20][CH:21]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: FCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CF)c(=O)c2c1ncn2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Yield: 26.5 %

Procedure:
A solution of 3-methyl-7-[4-(4-chlorobenzoyl)-benzyl]xanthine (975 mg), sodium hydride (61 mg) and fluoromethyl bromide (121 mg) in DMF (10 ml) was stirred at 10° C. for 1 hour. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate =1:2) and recrystallized from ethyl acetate to provide the title compound as colorless solid (121 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][C@H:8]([CH:22]([CH3:24])[CH3:23])[CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@@H:11]2[CH2:13][O:12]2)=[CH:5][C:4]=1[O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32].[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>C(O)(C)C>[OH:12][C@H:11]([C@@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9][C@H:8]([CH2:7][C:6]1[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[C:4]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:5]=1)[CH:22]([CH3:24])[CH3:23])[CH2:13][N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: C1CCNCC1
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H]2CO2)C(C)C)ccc1OC
Solvent: CC(C)O
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN2CCCCC2)C(C)C)ccc1OC

Procedure:
A solution of 0.25 g of tert-butyl {3(S)-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methyl-1(S)-(R)-oxiranylpentyl}carbamate in 4 ml of isopropanol and 0.99 ml of piperidine is stirred at 70° C. over 1 hour. The reaction mixture is concentrated by evaporation, and the residue is admixed with water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a colourless oil. Rf=0.24 (9:1 dichloromethane-methanol); Rt=17.40 (gradient II).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.[CH2:31]([OH:35])[CH2:32][C:33]#[CH:34]>C(NCC)C.[Pd](Cl)Cl.[Cu]I>[OH:35][CH2:31][CH2:32][C:33]#[C:34][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: C#CCCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: COC(=O)c1ccc(C#CCCO)cc1
Yield: 75.8 %

Procedure:
To a mixture of 0.082 g (0.005 eq) of palladium chloride, and 0.244 g (0.01 eq) of triphenylphosphine, and 20.00 g (1.0 eq) of methyl 4-bromobenzoate in diethylamine which is stirred under nitrogen is added 0.178 g (0.01 eq) of copper (I) iodide and 6.52 g (1.0 eq) of 3-butyn-1-ol. The reaction mixture is stirred under nitrogen at room temperature (about 25° C.) for eighteen hours. Diethylamine is then removed under reduced pressure, water is added, and the mixture extracted with benzene. The benzene extracts are filtered through silica to remove the metal residue and the filtrate concentrated under reduced pressure to yield methyl 4-(4-hydroxybut-1-yn-1-yl)benzoate. Recrystallization from a mixture of benzene and hexane yields pure material in 75.8% yield, m.p. 95.5°-96.0° C.; IR (KBr) ν max 3310, 2955, 1718, 1604, 1433, 1275, 1177, 1108, 1040, 955, 852, and 769 cm-1 ; 1H NMR (CDCl3) delta 7.98 (d, J=8.3 Hz, 2H, Ar), 7.49 (d, J=8.3 Hz, 2H, Ar), 3.93 (s, 3H, --CH3), 3.87 (m, 2H, --CH2OH), 2.74 (t, J=6.2 Hz, 2H, --yl--CH2 --), 1.88 (m, 1H, --OH).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:14][N:15](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[OH:13][CH2:12][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1)[C:14]#[N:15]
Reactant: CN(C)C=O
Reactant: OCc1cc(Br)cc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(CO)cc(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
(3-Bromo-5-trifluoromethyl-phenyl)-methanol (33.9 g) is dissolved in N,N-dimethylformamide (400 mL) and thereto are added zinc(II) cyanide (16.39 g) and tetrakis(triphenylphosphine)palladium (7.68 g) and the mixture is heated under nitrogen atmosphere at 120° C. for 2 hours. The reaction solution is allowed to cool to room temperature, and filtered through Celite™, and the filtrate is concentrated under reduced pressure. Thereto is added water and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 3-hydroxymethyl-5-trifluoromethyl-benzonitrile (23.4 g). NMR (CDCl3): 2.09 (1H, t), 4.85 (2H, d), 7.83 (1H, s), 7.87 (2H, s)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH3:11][O:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=1>C1COCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:11][O:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: c1cocn1
Reactant: COC(=O)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ncco2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
To a solution of oxazole (0.285 mL, 4 mmol) in THF (40 mL) at −78° C. was added n-butyllithium (1.83 mL of a 2.4M solution in hexanes, 4.4 mmol) and the reaction stirred for 30 min at −78° C. then zinc chloride (12 mL of 1M solution in THF, 12 mmol) was added. The mixture was then allowed to slowly warm to 0° C. and was stirred for 45 min. A solution of methyl-4-bromobenzoate (0.860 g, 4 mmol) in THF (10 mL) was added followed by a solution of bis-(triphenylphosphine)-palladium (II) chloride (140 mg, 0.2 mmol) and n-butyllithium (0.17 mL of a 2.4M solution in hexanes, 0.4 mmol) in THF (4 mL). The resultant dark brown mixture was warmed to reflux and stirred for 1 h. After cooling, the reaction mixture was diluted with ethyl acetate (30 mL), then washed with water (1×20 mL) and brine (1×20 mL). The organic layer was dried (Na2SO4), filtered, concentrated and purified by chromatography on silica gel (98:2 CH2Cl2/MeOH) to give the desired methyl-4-(oxazol-2-yl)-benzoate (340 mg, 42%) as a yellow oil. 1H NMR (CDCl3) δ 3.94 (s, 3H), 7.28 (s, 1H), 7.76 (m, 1H), 8.09 (m, 4H).
Reaction SMILES: C1C=CC=CC=1.[CH3:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[H-].[Na+].[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(#N)C>[CH3:7][N:8]([Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11]
Reactant: CNC(=O)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CC#N
Product: CN(C(=O)C(F)(F)F)[Si](C)(C)C(C)(C)C

Procedure:
To 800 ml of dry benzene:acetonitrile (v/v, 1:1) was added 127 g (1.0 mole) of N-methyl-trifluoroacetamide. To this solution, while stirring and maintaining the temperature at 0 degress C., was slowly added 23.5 g (0.98 mole) of sodium hydride. The solution was then stirred for 4 hours at 4 degrees C. At this time, 173.34 g (1.15 mole) of t-butyldimethylsilyl chloride was added in four equal aliquots over a period of 80 minutes. After the last addition the solution was stirred for 2 hours at 4 degrees C. The precipitate of sodium chloride was then removed from the reaction mixture by filtration under dry nitrogen and the resulting filter cake washed twice with 100 ml each of dry benzene. Washings and filtrate were combined and concentrated. The remaining yellow solution was fractionally distilled with the distillate at 158-172 degrees C. being collected. Redistillation of this fraction gave the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH2:19][C:20]2[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]3[CH:30]=[N:29][N:28]([CH2:31][CH3:32])[C:23]3=[N:24][C:25]=2[CH2:26][CH3:27])[C:11]([C:13]2([C:16]([NH2:18])=[O:17])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:40][N:41]1[CH2:46][CH2:45][CH:44]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[C:50](B3OC(C)(C)C(C)(C)O3)[CH:49]=2)[CH2:43][CH2:42]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:31]([N:28]1[C:23]2=[N:24][C:25]([CH2:26][CH3:27])=[C:20]([CH2:19][N:10]([CH2:9][C:4]3[CH:3]=[C:2]([C:52]4[CH:51]=[CH:50][CH:49]=[C:48]([CH2:47][CH:44]5[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]5)[CH:53]=4)[C:7]([CH3:8])=[CH:6][CH:5]=3)[C:11]([C:13]3([C:16]([NH2:18])=[O:17])[CH2:15][CH2:14]3)=[O:12])[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]2[CH:30]=[N:29]1)[CH3:32]
Reactant: CN1CCC(Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(Br)c1)C(=O)C1(C(N)=O)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(-c2cccc(CC3CCN(C)CC3)c2)c1)C(=O)C1(C(N)=O)CC1
Temperature: 100 °C
Yield: 32.4 %

Procedure:
A mixture of N1-[(3-bromo-4-methylphenyl)methyl]-N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,1-cyclopropanedicarboxamide (35 mg, 0.059 mmol), 1-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}piperidine (23.51 mg, 0.059 mmol), Na2CO3 (18.62 mg, 0.176 mmol) and PdCl2(dppf) (4.29 mg, 5.86 μmol) was diluted in a mixture of 1,4-dioxane (3 mL) and water (1 mL) in a 2-5 mL Biotage microwave reaction tube. The mixture was degassed by bubbling argon through it for 5 minutes and was then heated in a Biotage microwave at normal absorption for 10 min at 100° C. The crude mixture was filtered through a PL-Thiol MP SPE+ and was then washed with ethyl acetate and water. The organic layer was concentrated under vacuum to obtain the crude residue. It was purified by reverse phase hplc with a Gilson HPLC (acidic conditions: 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined and washed with saturated NaHCO3 and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-({6-methyl-3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)-1,1-cyclopropanedicarboxamide as a solid (13.5 mg, 32.6%). LC-MS m/z 707 (M+H)+, 0.76 min (ret time).
Reaction SMILES: Br[CH2:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[C:17]1(=[O:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[N:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.C(OCC)(=O)C>[C:7]([C:6]1[CH:15]=[CH:16][C:3]([CH2:2][N:18]2[CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]2=[O:26])=[CH:4][CH:5]=1)(=[O:8])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1N=Cc2ccccc21
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)c1ccc(CN2Cc3ccccc3C2=O)cc1
Yield: 91 %

Procedure:
A mixture of 4-(bromomethyl)benzophenone (138 mg, 0.5 mmol), isoindolone (67 mg, 0.5 mmol), cesium carbonate (407 mg, 1.25 mmol), and 18-crown-6 (13 mg, 0.05 mmol) in acetone (10 mL) was stirred heating at reflux for 3 h. Workup and silica gel column chromatography using a gradient of hexanes to 50% ethyl acetate in hexanes afforded 2-(4-benzoylbenzyl)-2,3-dihydroisoindol-1-one (149 mg, 91%). GC/MS gave: m/z (rel.int.) 327 (M+, 97), 250 (5), 222 (42), 196 (20) 165 (31), 146 (31), 133 (53), 119 (94), 105 (71), 91 (100), and 77 (98). 1H NMR (300 MHz, CDCl3): δ 4.33 (s, 2H), 4.89 (s, 2H), 7.42 (d, 2H), 7.45-7.59 (m, 6H), 7.77 (dd, 4H), 7.91 (dd, 1H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35](=[O:47])(=[O:46])[NH:36][C:37](=[O:45])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:44])=[CH:25][CH:24]=2)[C:7](=[O:21])[N:8]([C:10]2[CH:15]=[C:14]([C:16](OC)=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:20])[N:9]=1)[CH2:2][CH2:3][CH3:4]>C(N)CCC>[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35](=[O:46])(=[O:47])[NH:36][C:37](=[O:45])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:44])=[CH:27][CH:28]=2)[C:7](=[O:21])[N:8]([C:10]2[CH:15]=[C:14]([C:16](=[O:17])[NH:6][CH2:5][CH2:1][CH2:2][CH3:3])[CH:13]=[CH:12][C:11]=2[Cl:20])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cc(C(=O)OC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Solvent: CCCCN
Product: CCCCNC(=O)c1ccc(Cl)c(-n2nc(CCCC)n(Cc3ccc(-c4ccccc4S(=O)(=O)NC(=O)c4ccccc4Cl)cc3)c2=O)c1
Yield: 186.7 %

Procedure:
A solution of 100 mg (0.14 mmole) of 5-n-butyl-2-[5-(carbomethoxy)-2-chlorophenyl]-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]biphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step D), in 1 mL of n-butylamine was stirred at 65° C. overnight. After removal of excess n-butylamine, the crude product was flash chromatographed over silica gel (gradient elution with 0.5-5.0% MeOH/CH2Cl2) to give 96 mg (91%) of the desired product as a white solid, mp >155° C. (gradual), homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 734 (M+1)+.
Reaction SMILES: [CH3:1][C:2](=[O:7])[C:3]([CH3:6])([CH3:5])[CH3:4].[CH:8]1[C:13]([CH:14]=O)=[CH:12][C:11]2[O:16][CH2:17][O:18][C:10]=2[CH:9]=1.[OH-].[Na+]>C(O)C.O>[O:18]1[C:10]2[CH:9]=[CH:8][C:13]([CH:14]=[CH:1][C:2](=[O:7])[C:3]([CH3:6])([CH3:5])[CH3:4])=[CH:12][C:11]=2[O:16][CH2:17]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(=O)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)C(=O)C=Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.1 %

Procedure:
To a mixture of pinacolone (55 g) and piperonal (75 g) in ethanol (200 ml) was added a sodium hydroxide (5.0 g) in water (115 ml) solution. The mixture solidified after stirring at room temperature for 2 days. Filtration collected 137 g of solid which was then dissolved in ethyl acetate (500 ml), washed with water (500 ml), and dried over anhydrous magnesium sulfate. Concentration and trituration in hexane yielded 104.5 g of colorless solid product, mp 94°-96° C. Using essentially the same procedures, additional alpha, beta-unsaturated ketones were prepared as intermediates and are listed in Table 5. [see Pace, E, Atti Acad Lincei, [6], 9, 778 (1929); Chemical Abstracts, 23, 4942, 1929].