Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1CC[N:4]([CH2:7][CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=CC=CC=3)[C:11]2=O)C1=O.O.NN.[CH2:25]1COCC1.CO>>[NH2:4][CH2:7][CH2:8][CH2:9][N:10]1[CH:11]([CH3:25])[CH2:12][CH2:17][C:18]1=[O:19]
Reactant: C1CCOC1
Reactant: CC1CCN(CCCN2C(=O)c3ccccc3C2=O)C1=O
Agent: NN
Solvent: CO
Solvent: O
Product: CC1CCC(=O)N1CCCN
Temperature: 50 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
2-[3-(3-Methyl-2-oxo-pyrrolidin-1-yl)-propyl]-isoindole-1,3-dione (0.5 g, 1.74 mmol) was taken in a mixture of THF/MeOH (3.0 mL/3.0 mL). Hydrazine hydrate (0.44 g, 8.7 mmol) was added to this and the reaction was stirred at 50° C. for 16 h. The precipitate was filtered and the filtrate was concentrated to give the product 1-(3-amino-propyl)-5-methyl-pyrrolidin-2-one (0.12 g, 45%).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:4]([NH2:6])=[S:5].O.[CH2:14](N)[C:15]#[CH:16]>C(O)C>[CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:4]([NH:6][CH2:16][C:15]#[CH:14])=[S:5]
Reactant: C#CCN
Reactant: COC(C(N)=S)c1ccccn1
Solvent: O
Solvent: CCO
Product: C#CCNC(=S)C(OC)c1ccccn1
Reaction time: 8 h

Procedure:
To 4.4 g. (0.026 mole) of 2-methoxy-2-(2-pyridyl)thioacetamide in 20 ml. of water at 0°C. is added 2.9 g. (0.053 mole) of propargylamine with stirring and the resulting suspension is allowed to stand overnight at 5°C. Ethanol (5 ml.) is added and the mixture is stirred for five hours, then extracted with dichloromethane. The extracts are dried and concentrated. The residue is chromatographed on a silica gel "dry-column," using 1:10 ethyl acetate/ether as the eluant. The product fraction is treated with charcoal, filtered, concentrated and the residue is recrystallized from benzene/ligroin to give 2-methoxy-N-propargyl-2-(2-pyridyl)thioacetamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:17](=O)[CH3:18])[C:5]2[N:9]=[CH:8][N:7](C3CCCCO3)[C:6]=2[CH:16]=1.CC([O-])=O.[Na+].Cl.[NH2:26][OH:27]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:17](=[N:26][OH:27])[CH3:18])[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:16]=1
Reactant: CC(=O)c1cc(F)cc2c1ncn2C1CCCCO1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(=NO)c1cc(F)cc2[nH]cnc12
Temperature: 80 °C
Yield: 89.6 %

Procedure:
A mixture of 1-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-4-yl)ethanone (676 mg, 3.8 mmol), NaOAc (3.12 g, 38 mmol), and hydroxylamine hydrochloride (792 mg, 11.4 mmol) in MeOH (60 mL) was heated at 80° C. for 1 h. The reaction mixture was concentrated in vacuo. To the residue was added water (200 mL) and the resulting mixture was extracted with EOAc (50 mL×3). The combined extracts were concentrated in vacuo to afford 1-(6-fluoro-1H-benzo[d]imidazol-4-yl)ethanone oxime as a yellow solid (658 mg, 89.8%). MS (ESI): m/z=194.3 [M+1]+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:21]([CH3:23])[CH3:22])[C:11]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[CH:7]=O)([CH3:3])[CH3:2].[Br:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2.N1CCCC1.Cl>C(O)C>[Br:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2=[CH:7][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:10]([CH:21]([CH3:23])[CH3:22])[CH:9]=1
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1OCCN1CCOCC1
Reactant: O=C1Cc2cc(Br)ccc2N1
Agent: Cl
Solvent: CCO
Solvent: C1CCNC1
Product: CC(C)c1cc(C=C2C(=O)Nc3ccc(Br)cc32)cc(C(C)C)c1OCCN1CCOCC1
Reaction time: 12 h
Yield: 12.4 %

Procedure:
A mixture of 3,5-diisopropyl-4-(2-morpholin-4-ylethoxy)-benzaldehyde (0.4 g), 5-bromo-2-oxindole (0.27 g) and pyrrolidine (0.5 ml) in ethanol (2 ml) was held in a sealed tube at 100° C. for 12 hours. The mixture was then added to 1N hydrochloric acid (100 ml) and the solids removed by filtration and washed with more water (50 ml). The solids were then dissolved in ethyl acetate (200 ml), the solution washed with 1N hydrochloric acid (75 ml) and brine (75 ml), dried with magnesium sulfate and concentrated. The crude solid was chromatographed (silica, 4:4:1 dichloromethane:hexanes:methanol) to give 80 mg (13%) of 5-bromo-3-[3,5-diisopropyl-4-(2-morpholin-4-ylethoxy)-benzylidene]-1,3-dihydroindol-2-one as a reddish-brown solid.
Reaction SMILES: [O:1]1CCC[CH2:2]1.Br[C:7]1[CH:21]=[CH:20][C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[CH:9][CH:8]=1.C([Li])CCC.CN(C)C=O>O>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:10]2[CH:20]=[CH:21][C:7]([CH:2]=[O:1])=[CH:8][CH:9]=2)=[N:14][CH:15]=1
Reactant: Cc1ccc(OCc2ccc(Br)cc2)nc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(OCc2ccc(C=O)cc2)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
To a tetrahydrofuran (150 mL) solution of 2-(4-bromo-benzyloxy)-5-methyl-pyridine (5.40 g, 19.4 mmol) described in Manufacturing Example 44-1-1 was added dropwise n-butyl lithium (2.67 M n-hexane solution, 8.73 mL, 23.3 mmol) on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere, which was stirred for 30 minutes at −78° C. N,N-dimethylformamide (2.99 mL, 38.8 mmol) was then added dropwise thereto, which was stirred for 10 minutes at −78° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated and washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:6→1:4) to obtain the title compound (2.93 g, 66.5%).
Reaction SMILES: [Mg].[C:2]1([SiH:8](Cl)Cl)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]1[CH2:15]O[CH2:13][CH2:12]1.C=CC=C>CCOCC.C(O)CO>[C:2]1([SiH:8]2[CH2:13][CH:12]=[CH:11][CH2:15]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[SiH](Cl)c1ccccc1
Reactant: C1CCOC1
Agent: C=CC=C
Agent: [Mg]
Solvent: OCCO
Solvent: CCOCC
Product: C1=CC[SiH](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 19 %

Procedure:
In a 500 mL two neck rb flask equipped with a reflux condenser, a Teflon covered magnetic stirring bar and a rubber septum was placed magnesium powder (9.6 g, 0.4 mol), phenyldichlorosilane (35.4 g, 0.2 mol) and THF (300 mL). The reflux condenser was connected to a refrigeration unit. Ethylene glycol cooled to -20° C. was circulated through the reflux condenser. 1,3-Butadiene (15.1 g, 0.28 mol) was condensed at -78° C. into a volumetric flask which was sealed with a rubber septum. The 1,3-butadiene was transferred into the reaction via a cannula. The reaction mixture was stirred at rt for 24 h. Ether (2×100 mL) was added. The organic solution was decanted from the magnesium chloride salts. There were transferred to a sintered glass funnel and were washed with ether (100 mL). The combined organic solution was washed with water (2×50 mL), dried over anhydrous magnesium sulfate, filtered and the volatile solvents removed by evaporation under reduced pressure. The residue was purified by distillation through a 10 cm vacuum jacketed Vigreux column. A fraction, bp 87° C./5 mm, 6.0 g, 19% yield, was collected.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]1=[O:15].Cl.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C@H:31]2[CH2:36][CH2:35][NH:34][CH2:33][C@@H:32]2[OH:37])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>O>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C@H:31]2[CH2:36][CH2:35][N:34]([CH:2]3[CH2:6][CH2:5][N:4]([CH2:7][C:8]4[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=4)[C:3]3=[O:15])[CH2:33][C@@H:32]2[OH:37])=[CH:27][CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccc(CN2CCC(Br)C2=O)cc1
Reactant: O[C@H]1CNCC[C@@H]1c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(CN2CCC(N3CC[C@H](c4ccc(OCc5ccccc5)cc4)[C@@H](O)C3)C2=O)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A mixture of 3-bromo-1-(4-methylbenzyl)pyrrolidin-2-one (Intermediate 2, 220 mg, 0.82 mmol), (3R,4R)-4-(4-(benzyloxy)phenyl)piperidin-3-ol hydrochloride (262 mg, 0.82 mmol, from step G) and triethylamine (11 mL, 8.2 mmol) was stirred at 60° C. for 1 h, 80° C. for 1 h, 100° C. for 1 h and 120° C. for 1 h. The reaction mixture was then allowed to cool, diluted with 40 mL of water and extracted four times with 50 mL of chloroform. The combined organic layers were washed with 60 mL brine, dried over anhydrous sodium sulfate, filtered, and evaporated to yield 382 mg of 3-((3R,4R)-4-(4-(benzyloxy)phenyl)-3-hydroxypiperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one which was used without further purification. LCMS (method J) (main component of a mixture) RT 2.23 min, m/z 471 (M+H+).
Reaction SMILES: O.[OH:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24]Br.O>CN(C=O)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][O:5][C:4](=[O:6])[CH:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:24][C:23]2[CH:26]=[CH:27][C:28]([Cl:29])=[C:21]([Cl:20])[CH:22]=2)=[CH:9][CH:8]=1)[OH:2]
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: O=C(O)C(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccc(Cl)c(Cl)c1)C(O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of hydroxy-(4-hydroxy-phenyl)-acetic acid monohydrate (10 g) in DMF (50 mL) was added K2CO3 (29.7 g,) followed by 3,4-dichlorobenzyl bromide (16.1 mL). The mixture was stirred at room temperature for 3 h. The mixture was poured into water (250 mL) and extracted with EtOAc. The organic layer was washed with water 1N HCl, brine, dried over Na2SO4, and concentrated. The resulting solid was triturated with diethyl ether and filtered to provide [4-(3,4-dichloro-benzyloxy)-phenyl]-hydroxy-acetic acid 3,4-dichloro-benzyl ester as a white solid (9.4 g). 1H NMR (400 MHz, DMSO d6): 7.69 (d, 1H), 7.63 (d, 1H), 7.55 (d, 1H), 7.41 (m, 1H), 7.37 (d, 1H), 7.31 (m, 2H), 7.20 (m, 1H), 6.97 (m, 2H), 6.06 (d, 1H), 5.16 (d, 1H), 5.1 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[C:38](Cl)=[O:39]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:38]([C:29]3[CH:30]=[CH:31][C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:28]=3)=[O:39])[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCNCC2)cc1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(NC2CCN(C(=O)c3ccc4ccccc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.5 %

Procedure:
Compound (49) (0.056 g, 0.2 mmol) and triethylamine (0.14 mL, 1 mmol) were added sequentially to a solution of 2-naphthoyl chloride (0.114 g, 0.6 mmol) in CH2Cl2 (5 mL) at 25° C. The mixture was stirred at 25° C. for 12 h, then was concentrated in vacuo to a residue. Purification of the residue by flash column chromatography (gradient elution 5 to 30% EtOAc in hexanes) provided the title compound (0.04 g, 50%): TLC (Rf =0.50; 50% EtOAc/hexanes); 1H NMR (CDCl3) δ 7.84 (m, 6H), 7.51 (m, 3H), 6.55 (d, 2H, J=8.8), 4.65 (br s, 1H), 4.01 (d, 2H, J=7.8), 3.66 (m, 1H), 3.18 (t, 2H, J=11.2), 2.05 (m, 2H), 1.56 (s, 9H), 1.46 (m, 2H); 13C NMR (CDCl3) δ 170.5, 166.0, 150.1, 133.8, 133.3, 132.9, 131.5, 128.4, 127.9, 127.8, 127.1, 126.8, 124.2, 121.1, 111.9, 79.9, 49.9, 32.6, 28.4; HRMS (FAB) m/z 430.2241 (M)+ (C27H30N2O3 requires 430.2256).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:15][CH2:16][O:17][CH2:18][C:19]#[CH:20])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1.I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)(O)[O-].[Na+]>>[CH3:1][C:2]1[N:3]([CH2:15][CH2:16][O:17][CH2:18][C:19]#[C:20][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1
Reactant: Ic1ccccc1
Reactant: C#CCOCCn1c(C)nc2cnc3ccccc3c21
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nc2cnc3ccccc3c2n1CCOCC#Cc1ccccc1
Reaction time: 20 h
Yield: 41.9 %

Procedure:
Using the general method of Example 12 Part A, 2-methyl-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline (3.6 g, 13.57 mmol) was reacted with iodobenzene (1.7 mL, 14.92 mmol) at ambient temperature. After 20 hours the reaction was judged complete. The solution was basified with 5% aqueous sodium bicarbonate and then extracted with dichloromethane (3×). The organics were combined, washed with water (3×), washed with brine, dried with anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. Purification was completed by chromatography over silica gel (95/5 dichloromethane/methanol) and recrystallization from acetonitrile to provide 1.94 g of 2-methyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10][C:11](=[O:22])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH3:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>COCCOC.O.[Pd]>[N:6]1[C:5]([C@H:8]([NH:10][C:11](=[O:22])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH3:9])=[CH:4][CH:3]=[C:2]([C:31]2[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=2)[CH:7]=1
Reactant: CC(C)c1ccc(CC(=O)N[C@H](C)c2ccc(Br)cn2)cc1
Reactant: OB(O)c1cccnc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)c1ccc(CC(=O)N[C@H](C)c2ccc(-c3cccnc3)cn2)cc1
Temperature: 100 °C

Procedure:
To a mixture of N-[(1R)-1-(5-bromopyridin-2-yl)ethyl]-2-(4-isopropylphenyl)acetamide (40 mg, 0.11 mmol), tetrakis(triphenyl)phosphine)palladium (0) (1.3 mg, 0.01 mmol), sodium carbonate (22 mg, 0.20 mmol) in DME/water (4:1, 3.0 ml) was added 3-pyridyl boronic acid (19 mg, 0.16 mmol). The reaction was heated for ten minutes in the Smith Personal microwave system at 100° C. and then washed with brine. Organics were extracted with EtOAc and dried over Na2SO4, filtered and concentrated in vacuo to give a red oily solid. Reverse phase prep HPLC chromatography afforded the mono-trifluoroacetate salt of N-[(1R)-1-(3,3′-bipyridin-6-yl)ethyl]-2-(4-isopropylphenyl)acetamide as an oil. 1H NMR (CD3OD, 400 MHz) δ 9.18 (s, 1H); 8.95 (s, 1H); 8.84 (d, J=4.80 Hz, 1H); 8.78 (dd, J=1.20 Hz and 6.40 Hz, 1H); 8.29 (dd, J=2.40 and 8.40 Hz, 1H); 8.06 (dd, J=5.20 and 8.20 Hz, 1H); 7.61 (d, J=8.40 Hz, 1H); 7.19 (m, 4H); 5.10 (q, J=6.80 Hz, 1H); 3.55 (s, 2H); 2.86 (m, 1H); 1.55 (d, J=7.20 Hz, 3H); 1.21 (d, J=6.80 Hz, 6H); HRMS (ES) exact mass calcd for C23, H25, N3O: 360.2071, Found: 360.2070.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][CH2:4][Si:5](OC)([O:8][CH3:9])[O:6][CH3:7].[CH2:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[Mg]Cl)[CH3:15].C(C1CCCCN1)C.C([Mg]Cl)(C)C>O1CCCC1>[F:1][C:2]([F:13])([F:12])[CH2:3][CH2:4][Si:5]([N:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[CH2:14][CH3:15])([O:8][CH3:9])[O:6][CH3:7]
Reactant: CO[Si](CCC(F)(F)F)(OC)OC
Reactant: CCC1CCCCN1[Mg]Cl
Agent: CC(C)[Mg]Cl
Agent: CCC1CCCCN1
Solvent: C1CCOC1
Product: CCC1CCCCN1[Si](CCC(F)(F)F)(OC)OC
Temperature: 70 °C
Yield: 87.8 %

Procedure:
Following the same general procedure described on Example 1, a flask was charged with one mol (218 gm) of 3,3,3-trifluoropropyltrimethoxysilane was added to one mol of 2-ethylpiperdinylmagnesium chloride, the salt having been prepared in situ by adding 2-ethylpiperidine (120 g, 1.05 mol) to isopropylmagnesium chloride (1 mol) in 500 ml of tetrahydrofuran. The reaction was mildly exothermic and the temperature rose to 45° C. at the end of the addition time of one hour. The reaction mixture was refluxed at the pot temperature of 70° C. for one hour and then cooled to room temperature. The 3,3,3-trifluoropropyl(2-ethylpiperidino)dimethoxysilane was filtered under nitrogen atmosphere from the magnesium methoxychloride. The filter cake was washed with ether (2×200 ml) to obtain the residual product. The solvent was removed by distillation to a pot temperature of 100° C. The residue was distilled under vacuum to yield 263 g of 3,3,3-trifluoropropyl(2-ethylpiperidino)dimethoxysilane as a colorless oil (purity>98%); bp 70° C./0.1 mm. The total yield was 88% of theoretical.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.Br[C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21].CO>[Pd](Cl)Cl.C1(C)C=CC=CC=1>[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:18]2[C:19]([C:20]#[N:21])=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:10][CH:9]=1
Reactant: N#Cc1ccccc1Br
Reactant: Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.25 h
Yield: 85.4 %

Procedure:
2M Sodium carbonate solution (200 ml) was added to a stirred mixture of 4-methylphenylboronic acid (30 g), 2-bromobenzonitrile (36.4 g), palladium (II) chloride (0.4 g), methanol (200 ml) and toluene (200 ml) at 5° C. The temperature rose to approximately 20° C. and a solid precipitated. The reaction mixture was then heated at reflux for 2 hours. The reaction mixture was allowed to cool and water (100 ml) was added, followed by diatomaceous earth (5 g). The mixture was stirred for 15 minutes, then filtered through diatomaceous earth. The organic phase of the filtrate was separated and washed with 2M sodium carbonate solution and then water. The organic phase was then filtered and the filtrate evaporated. The resultant solid was recrystallised from petroleum ether (b.p. 110°-120° C.) to give 4'-methylbiphenyl-2-carbonitrile (33 g) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.Cl[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(F)cc1OCc1ccccc1
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of 3 parts of 1-(4-fluoro-2-hydroxyphenyl)ethanone, 14.9 parts of (chloromethyl)benzene, 16.4 parts of potassium carbonate, 0.1 parts of potassium iodide and 120 parts of 2-propanone was stirred overnight at reflux temperature. The reaction mixture was evaporated. The reaction mixture was poured into water. The product was extracted three times with trichloromethane. The combined extracts were dried, filtered and evaporated. The residue was crystallized from a mixture of 2-propanol and water. The product was filtered off and dried, yielding 11 parts (58%) of 1-[4-fluoro-2-(phenylmethoxy)phenyl]ethanone (intermediate 76).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH:12]2[CH2:17][CH:16]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])[CH2:15][CH2:14][CH:13]2[NH:23][C:24](=[O:39])[CH2:25][C:26]2[NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([F:38])([F:37])[F:36])[C:28]=3[N:27]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:40]([O:42]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:41]>C1(C)C=CC=CC=1.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>[C:40]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C@@H:12]2[CH2:17][C@H:16]([N:18]([CH:20]([CH3:21])[CH3:22])[CH3:19])[CH2:15][CH2:14][C@@H:13]2[NH:23][C:24](=[O:39])[CH2:25][C:26]2[NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([F:36])([F:37])[F:38])[C:28]=3[N:27]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1)(=[O:42])[CH3:41]
Reactant: CC(C)N(C)C1CCC(NC(=O)Cc2nc3c(C(F)(F)F)cccc3[nH]2)C(CS(=O)(=O)c2ccc(Br)cc2)C1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(S(=O)(=O)C[C@@H]2C[C@H](N(C)C(C)C)CC[C@@H]2NC(=O)Cc2nc3c(C(F)(F)F)cccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(1S,2R,4R)-(N-[2-(4-Bromo-benzenesulfonylmethyl)-4-(isopropyl-methyl-amino)-cyclohexyl]-2-(4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetamide, Example 3, (50 mg) was dissolved in toluene (1 ml) prior to the addition of 1-ethoxyvinyltri-n-butyltin (0.5 ml), Pd(PPh3)4 (20 mg) and a few crystals of 2,6-tert-butyl-4-methyl phenol. The resulting solution was heated to reflux overnight. After cooling, the palladium catalyst was filtered off and the solution was concentrated. The residue was dissolved in dioxane (1 ml) prior to the addition of 1N HCl. The resulting solution was stirred at rt for 2 h. The solution was concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) of the resulting residue provided the title compound (8 mg). MS found: (M+H)+=593.5.
Reaction SMILES: C(C=O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:24][C:25]([C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1)=[O:26].N(C(C)C)C(C)C.[CH:41]#[C:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]>[Pd].CN(C)C=O>[C:41]([C:30]1[CH:31]=[CH:32][C:27]([C:25](=[O:26])[CH3:24])=[CH:28][CH:29]=1)#[C:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: C#CCCCCCCCC
Reactant: CC(=O)c1ccc(I)cc1
Agent: [Pd]
Agent: O=CC=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CCCCCCCCC#Cc1ccc(C(C)=O)cc1

Procedure:
Glyoxal synthesis step 1 is shown in FIG. 12. In a 100 mL Schlenk tube containing 46% Pd—C aerogel (110 mg, 0.47 mmol) were placed Cul (190 mg, 1 mmol), Ph3P (250 mg, 1 mmol), 4-iodoacetophenone (0.79 mmol), i-Pr2NH (0.17 mL, 1.2 mmol), deca-1-yne (8 mmol), and previously degassed dimethylformamide (DMF) (0.5 mL) under argon. This was magnetically stirred at 100° C. for a 16-h period. After cooling, the solution was removed and the catalyst was washed with DMF (3×3 mL) and recovered. The combined organic extracts were diluted in Et2O (100 mL), washed with brine (3×30 mL), dried (annh. MgSO4), and evaporated at reduced pressure. The residue (a yellow oil) was purified by preparative high pressure column chromatography (silica gel, n-hexane-EtOAc, 99.5:0.5) to give the product, 1-(4-(dec-1-ynyl)phenyl)ethanone as a yellow oil; yield: 96% 1H NMR (CDCl3): d=7.87 d,(2 H), 7.53 (d, 2 H), 2.55 (s, 3 H), 2.03 (2 H), 1.46 (2 H), 1.31 (m, 10 H), 0.86 (3 H) 13C NMR (CDCl3): d=CH3,14.0; CH2 22.6; CH2 31.5,; CH2 29.3; CH2 28.7; CH2 28.4; CH2 28.7; CH2 18.7; C (alkyne) 100.1; C (alkyne) 78.5; CH3 29.3; C (carbonyl) 199.8; C 136.4; CH 128.4; CH 132.2; C 127.1; CH 132.2; CH 128.4