Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1I.C1(C)C=CC=CC=1.[C:22]([Si:24]([CH3:27])([CH3:26])[CH3:25])#[CH:23]>CCOC(C)=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.[Cu]I>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[C:23]#[C:22][Si:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: N#Cc1ccc(F)c(I)c1C(F)(F)F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1C(F)(F)F
Temperature: 60 °C
Yield: 81 %

Procedure:
A 20 mL vial was charged with 4-fluoro-3-iodo-2-(trifluoromethyl)benzonitrile, (0.315 g, 1.00 mmol), Pd(PPh3)2Cl2 (0.014 g, 0.020 mmol) and CuI (0.0076 g, 0.040 mmol), and sealed with a rubber septum. Anhyd PhMe (5 mL) and DIPA (0.210 mL, 1.500 mmol) were added via syringe and the mixture was degassed 10 min by sparging with N2 while immersed in an ultrasonic bath. Ethynyltrimethylsilane (0.155 mL, 1.100 mmol) was added dropwise via syringe and the septum was replaced by a PTFE-faced crimp top. The mixture was stirred in a heating block at 60° C. Upon cooling the mixture was diluted with EtOAc and filtered through Celite. The filtrate was washed (satd NH4Cl, water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording 4-fluoro-2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzonitrile (0.231 g, 81% yield) as a light orange oil: 1H NMR (400 MHz, CDCl3) δ 7.75 (ddd, J=8.7, 5.0, 0.6 Hz, 1H), 7.39 (ddd, J=8.6, 7.8, 0.5 Hz, 1H), 0.28 (s, 9H); MS (GCMS EI) m/z 285 ([M]+, 15%), 270 ([M-CH3]+, 100%).
Reaction SMILES: [C-:1]#[N:2].[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.Cl[CH2:31][C:32]1[CH:48]=[CH:47][C:35]([CH2:36][CH2:37][C:38]2[N:43]3[CH:44]=[N:45][CH:46]=[C:42]3[CH:41]=[CH:40][CH:39]=2)=[CH:34][CH:33]=1>C(#N)C>[C:1]([CH2:31][C:32]1[CH:48]=[CH:47][C:35]([CH2:36][CH2:37][C:38]2[N:43]3[CH:44]=[N:45][CH:46]=[C:42]3[CH:41]=[CH:40][CH:39]=2)=[CH:34][CH:33]=1)#[N:2]
Reactant: ClCc1ccc(CCc2cccc3cncn23)cc1
Reactant: [C-]#N
Agent: [K+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CC#N
Product: N#CCc1ccc(CCc2cccc3cncn23)cc1

Procedure:
Potassium cyanide (11.18 g) and dibenzo-18-crown-6(1.0 g) are added to a solution of 5-[p-(chloromethyl)phenethyl]imidazo[1,5-a]pyridine (9.5 g) in 300 ml of dry acetonitrile under nitrogen. The mixture is refluxed for 24 hours, the solvent is evaporated and the residue partitioned between methylene chloride and water. The organic phase is separated, dried and evaporated to yield 5-[p-(cyanomethyl)phenethyl]imidazo[1,5-a]pyridine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]([C:17]1[NH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25](I)=[CH:24][C:23]=2[F:29])=[CH:20][N:21]=1)[C@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:38][Si:39]([C:42]#[CH:43])([CH3:41])[CH3:40].C(OCC)(=O)C>CN(C)C=O.[Cu]I.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>[C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]([C:17]1[NH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:43]#[C:42][Si:39]([CH3:41])([CH3:40])[CH3:38])=[CH:24][C:23]=2[F:29])=[CH:20][N:21]=1)[C@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)c1ncc(-c2ccc(I)cc2F)[nH]1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)c1ncc(-c2ccc(C#C[Si](C)(C)C)cc2F)[nH]1
Reaction time: 0.08 h
Yield: 96.1 %

Procedure:
A solution of {(1S,2S)-1-[5-(2-fluoro-4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-carbamic acid tert-butyl ester (286 mg, 0.55 mmol) (prepared in step 30-E), copper (I) iodide (10.50 mg, 0.055 mmol) and dichlorobis(triphenylphosphine)palladium(II) (39 mg, 0.055 mmol) in N,N-dimethylformamide (5 mL) was degassed with dry nitrogen with stirring for 5 minutes. Triethylamine (229 μL, 1.65 mmol) and trimethylsilylacetylene (233 μL, 1.65 mmol) were added and the resulting solution was stirred for 24 hours at room temperature. The reaction was poured into ethyl acetate (25 mL) and washed with water (2×10 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography over silica gel gradient eluted between 10 and 50% v/v ethyl acetate in hexanes to give {(1S,2S)-1-[5-(2-fluoro-4-trimethylsilanylethynyl-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-carbamic acid tert-butyl ester (260 mg, 96%). HR-MS: calcd for C28H34FN3O2Si [M+H+] 492.2477. Found 492.2475.
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[NH2:17][C:18](N)=[O:19]>>[C:18](=[O:19])([O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:15][CH:14]=1)[NH2:17]
Reactant: CCCCCCCCCc1ccc(O)cc1
Reactant: NC(N)=O
Product: CCCCCCCCCc1ccc(OC(N)=O)cc1
Yield: 85 %

Procedure:
The same method as step (6-1) of Example 6 was carried out with the exception of using 11003 g of 4-nonyl phenol (Tokyo Chemical Industry Co., Ltd., Japan) instead of 4-phenyl phenol, using 499 g of urea and carrying out the reaction for 15 hours. When a portion of the reaction liquid was removed and analyzed by liquid chromatography, the formation of (4-nonylphenyl) carbamate was confirmed. The yield was about 85% based on the charged amount of urea.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([CH2:6][CH2:7][OH:8])[CH2:2]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1COCC1.C(OCC)(=O)C>[CH3:16][S:17]([O:8][CH2:7][CH2:6][C@H:3]1[CH2:4][CH2:5][O:1][CH2:2]1)(=[O:19])=[O:18]
Reactant: OCC[C@H]1CCOC1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCC[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of 1.00 g (0.861 mmol) of 2-[(3S)-oxolan-3-yl]ethan-1-ol in anhydrous THF (1.5 mL) are added triethyl amine (0.13 mL, 0.947 mmol) and methanesulfonyl chloride (0.07 mL, 0.947 mmol) slowly at 0° C. The reaction is stirred at room temperature for 2 h. The mixture is diluted with ethyl acetate (20 mL) and washed with saturated aqueous NaHCO3 solution (2×5 mL) and 1M aqueous HCl solution (2×5 mL). The organic layer is dried (MgSO4), filtered and the filtrate is concentrated under reduced pressure to afford 167 mg of 2-[(3R)-oxolan-3-yl]ethyl methanesulfonate. Yield: 100%, 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.40-1.60 (1H, m), 1.70-1.87 (1H, m), 1.95-2.12 (1H, m), 2.16-2.37 (1H, m), 2.96 (3H, s), 3.32 (1H, dd, J=8.22, 7.16 Hz), 3.62-3.91 (3H, m), 4.13-4.24 (2H, m).
Reaction SMILES: B(Br)(Br)Br.C(Cl)Cl.C[O:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[C:17]([CH3:20])[N:16]([CH3:21])[C:15]2=[O:22].[OH-].[Na+].Cl>>[OH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[C:17]([CH3:20])[N:16]([CH3:21])[C:15]2=[O:22]
Reactant: COc1cccc2c(=O)n(C)c(C)nc12
Agent: BrB(Br)Br
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc2c(O)cccc2c(=O)n1C
Yield: 57.1 %

Procedure:
A 1.0 M solution of BBr3 in DCM (2.9 ml, 2.9 mmol) was added to 8-methoxy-3-N-methyl-2-methylquinazolin-4-[3 H]-one (0.2 g, 0.98 mmol) to form a yellow suspension, which was gently refluxed for 48 hours. The solvent was directly distilled from the reaction vessel to leave a yellow/green solid, which was hydrolysed with 10% aq. NaOH solution to give a cream suspension. The suspension was neutralised with 1.0 M aqueous HCl and then extracted into EtOAc. The organic layers were combined, dried (MgSO4) and filtered. The solvent was removed under vacuum to leave a pale brown solid (0.18 g, 0.94 mmol, 96% crude yield). The product (0.16 g) was purified by column chromatography, using DCM:MeOH (98:2) as eluent to give a white solid (0.12 g, 0.56 mmol, 57%).
Reaction SMILES: II.Br[CH2:4][CH:5]1[CH2:7][CH2:6]1.[OH:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:17]2[CH2:18][C@H:19]3[CH2:31][C@H:20]3[C:21]=2[N:22]([C:24]2[CH:29]=[N:28][C:27](Br)=[CH:26][N:25]=2)[N:23]=1)=[O:15])([CH3:12])[CH3:11]>CC(N(C)C)=O.C1COCC1.[Zn].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:17]2[CH2:18][C@H:19]3[CH2:31][C@H:20]3[C:21]=2[N:22]([C:24]2[CH:29]=[N:28][C:27]([CH2:4][CH:5]3[CH2:7][CH2:6]3)=[CH:26][N:25]=2)[N:23]=1)=[O:15])([CH3:12])[CH3:11]
Reactant: BrCC1CC1
Reactant: CC(C)(CO)NC(=O)c1nn(-c2cnc(Br)cn2)c2c1C[C@H]1C[C@@H]21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: II
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CC(C)(CO)NC(=O)c1nn(-c2cnc(CC3CC3)cn2)c2c1C[C@H]1C[C@@H]21
Temperature: 70 °C
Yield: 7.6 %

Procedure:
Under nitrogen protection, zinc suspension (1.76 mL, 1.338 mmol) was added to a solution of diiodine (4.5 mg, 0.018 mmol) in DMA at room temperature. After several minutes, (bromomethyl)cyclopropane (120 mg, 0.892 mmol) was added. The reaction mixture was heated at 70° C. for 3 h, cooled down to room temperature, then transferred to a flask containing (1aR,5aR)-2-(5-bromo-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (70 mg, 0.178 mmol) and bis(tri-t-butylphosphine)palladium (0) (9.1 mg, 0.018 mmol) in THF (1 mL). The whole reaction mixture was heated at reflux overnight, cooled down and quenched with saturated sodium bicarbonate. The solid was filtered, and the filtrate was extracted with ethyl acetate. The combined organics were dried and concentrated. The residue was purified by silica gel column chromatography to give the title compound (5 mg) as white solid. LCMS m/z=368.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.46 (td, J=4.7 and 3.3 Hz, 1H), 1.22-1.28 (m, 1H), 1.40 (s, 3H), 1.41 (s, 3H), 1.95-2.04 (m, 1H), 2.09-2.16 (m 1H), 2.26-2.32 (m, 1H), 2.37-2.41 (m, 4H), 2.68-2.74 (m, 1H), 2.91 (d, J=16.8 Hz, 1H), 3.00 (dd, J=16.5 and 6.2 Hz, 1H), 3.69 (d, J=6.3 Hz, 2H), 3.72-3.77 (m, 1H), 4.78 (br, 1H), 6.97 (s, 1H), 8.26 (d, J=1.3 Hz, 1H), 9.15 (d, J=1.3 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][N:11]3[CH:19]=2)=[CH:4][CH:3]=1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:20]([NH:24][C:16]([C:13]1[CH:14]=[CH:15][C:10]2[N:11]([CH:19]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=2)[CH:12]=1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(O)c1ccc2nc(-c3ccc(F)cc3)cn2c1
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1ccc2nc(-c3ccc(F)cc3)cn2c1
Yield: 100.9 %

Procedure:
2-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridine-6-carboxylic acid (example 45; 40 mg, 0.14 mmol), tert-butylamine (73.1 mg, 0.0.27 mmol), HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate; 57.2 mg, 0.15 mmol) and triethylamine (56.8 μl, 0.41 mmol) in 3 ml DMF were stirred at room temperature for 2 hours. The mixture was evaporated. ethyl acetate and water were added, the organic layer was separated, washed with water, dried and evaporated. The crude product was purified by preparative HPLC (RP18, acetonitrile/water 0.1% TFA) to yield 44 mg (99%) of the desired product. MS: M+H+=312.15.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[CH:3]=1.[C:9]([N:17]1[CH2:21][C:20](=O)[N:19]=[CH:18]1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:9]([N:17]1[CH2:21][CH2:20][N:19]=[C:18]1[NH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[CH:3]=1)(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CN(C(=O)c2ccccc2)C=N1
Reactant: Cc1cc(N)n(C)n1
Product: Cc1cc(NC2=NCCN2C(=O)c2ccccc2)n(C)n1

Procedure:
5-amino-1,3-dimethylpyrazole (20.0 g.) and 1-benzoyl-2-imidazolinone (British Pat. No. 1,392,849) (28.4 g.) were reacted as described in Example I to give 22.02 g. product. mp 147°-149°
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([CH3:18])[O:15][N:14]=2)[CH:10]=[CH:9][C:8]=1[CH2:19][NH:20][C:21](=[O:33])[C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([CH3:30])=[C:24]([O:31][CH3:32])[CH:23]=1.[Li+].[OH-].Cl>C1COCC1>[CH3:29][O:28][C:26]1[CH:27]=[C:22]([CH:23]=[C:24]([O:31][CH3:32])[C:25]=1[CH3:30])[C:21]([NH:20][CH2:19][C:8]1[CH:9]=[CH:10][C:11]([C:13]2[N:17]=[C:16]([CH3:18])[O:15][N:14]=2)=[CH:12][C:7]=1[NH:6][CH2:5][CH2:4][C:3]([OH:34])=[O:2])=[O:33]
Reactant: COC(=O)CCNc1cc(-c2noc(C)n2)ccc1CNC(=O)c1cc(OC)c(C)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCCC(=O)O)cc(OC)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of compound 15a (89 mg, 0.19 mmol) in THF (1 mL) was added 10% LiOH (1 mL). The reaction mixture was stirred for 1 h at rt, and then acidified with 1 N HCl. This mixture was extracted with dichloromethane. The combined organic phases were dried and concentrated to give compound 54a (80 mg, 93%) as a beige foam. ESI-MS m/e 455.3 (M+1).
Reaction SMILES: [Na+].[NH2:2][C:3]([O:5][CH2:6][CH:7]1[O:11][CH2:10][CH:9]([S:12][C:13]2[CH:19]([CH3:20])[CH:18]3[N:15]([C:16](=[O:24])[CH:17]3[CH:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O-:27])=[O:26])[CH2:8]1)=[O:4].[C:28]([O:34][CH2:35]Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].C(=O)(O)[O-].[Na+].[I-].[Na+]>>[CH3:30][C:29]([CH3:32])([CH3:31])[C:28](=[O:33])[O:34][CH2:35][O:26][C:25]([C:14]1[N:15]2[CH:18]([CH:19]([CH3:20])[C:13]=1[S:12][CH:9]1[CH2:8][CH:7]([CH2:6][O:5][C:3]([NH2:2])=[O:4])[O:11][CH2:10]1)[CH:17]([CH:21]([OH:23])[CH3:22])[C:16]2=[O:24])=[O:27]
Reactant: CC(O)C1C(=O)N2C(C(=O)[O-])=C(SC3COC(COC(N)=O)C3)C(C)C12
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Product: CC(O)C1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(SC3COC(COC(N)=O)C3)C(C)C12

Procedure:
The title compound is prepared by the procedure of Example 407 using 0.460 g of product from Example 18, 0.24 ml of chloromethyl pivalate, 0.189 of sodium bicarbonate and 0.252 g of sodium iodide to give after chromatography 0.3 g of the desired product.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][CH:3]=1.C[Si]([C:15]#[CH:16])(C)C>>[C:15]([C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][CH:3]=1)#[CH:16]
Reactant: C#C[Si](C)(C)C
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: C#Cc1ccc(S(N)(=O)=O)s1

Procedure:
Prepared from 5-bromo-thiophene-2-sulfonic acid amide (1.94 g, 8 mmol) and trimethylsilylacetylene (2.2 mL, 12 mmol) by applying in analogous manner the procedures described in example D.1 (method 1, steps 1-2). Obtained after chromatographic purification of the crude product (SiO2, 0-75% AcOEt/heptane) as a light brown solid (0.49 g, 33%). MS (ISP) 186.1 [(M−H)−]; mp 114-116° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:14]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCCc1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(O)c1ccc(NCCc2ccccc2)cc1
Temperature: -20 °C

Procedure:
A mixture of 16.5 g. of ethyl p-aminobenzoate, 10.3 g. of (2-bromoethyl)benzene and 50 ml. of hexamethylphosphoramide is heated in an oil bath at 115°-120° C. for 17 hours. The mixture is put into ice and water and extracted with ether. The ether extracts are washed with water, dried over magnesium sulfate and concentrated in vacuo to an oil. The oil is combined with 200 ml. of ethanol-water (9:1) and 20 g. of potassium hydroxide and the mixture is refluxed for 3.5 hours. After chilling the mixture is made acidic with concentrated hydrochloric acid, diluted with 150 ml. of water, chilled, diluted with water and extracted with chloroform. The chloroform extracts are washed with water, dried over magnesium sulfate and concentrated in vacuo to a gum. Ethanol is added, the mixture is chilled and filtered to give yellow crystals. The mother liquors are chilled at -20° C. to give a second crop of crystals. Recrystallization of the combined crops of crystals from hexane-ethanol gives yellow crystals, m.p. 123°- 125° C. Recrystallization from ethanol gives pale yellow crystals, m.p. 124°-126° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([CH3:9])[C:4]=1[CH3:10].[C:11]([N:14]1[CH2:18][C:17](=O)[N:16]=[CH:15]1)(=[O:13])[CH3:12]>>[C:11]([N:14]1[CH2:18][CH2:17][N:16]=[C:15]1[NH:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([CH3:9])[C:4]=1[CH3:10])(=[O:13])[CH3:12]
Reactant: Cc1nn(C)c(N)c1C
Reactant: CC(=O)N1C=NC(=O)C1
Agent: Cl
Product: CC(=O)N1CCN=C1Nc1c(C)c(C)nn1C

Procedure:
5-Amino-1,3,4-trimethyl pyrazole hydrochloride (8.00 g.) and 1-acetyl-2-imidazolinone (7.05 g.) were reacted as described in Example I to give 7.90 g. mp 212°-215° (crystallized from CH3CN)
Reaction SMILES: [C:1]([O:10]C1C=CC=CC=1)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH:17]([C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22])([CH3:19])[CH3:18]>>[CH:17]([C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:1](=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])([CH3:19])[CH3:18]
Reactant: CC(C)c1ccccc1N
Reactant: O=C(Oc1ccccc1)c1ccccc1O
Product: CC(C)c1ccccc1NC(=O)c1ccccc1O

Procedure:
The 2′-isopropyl-salicylanilide was prepared by condensing phenyl salicylate with 2-isopropylaniline then purified as described in Example 2a. The ligand mixture was then prepared from 2′-isopropyl-salicylanilide and binaphthol using the procedure described in Example 2a. 31P NMR (121.77 MHz): several peaks between 117.1-120.9 ppm.
Reaction SMILES: [Cl:1][C:2]1[C:40]([Cl:41])=[CH:39][C:5]2[NH:6][C:7]([O:9][CH:10]([C:19]3([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=5)=[CH:27][CH:26]=4)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[N:8][C:4]=2[CH:3]=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44].CCN(C(C)C)C(C)C>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[C:40]([Cl:41])=[CH:39][C:5]2[NH:6][C:7]([O:9][CH:10]([C:19]3([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=5)=[CH:27][CH:26]=4)[CH2:24][CH2:23][N:22]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:21][CH2:20]3)[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[N:8][C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)CCOCC(Oc1nc2cc(Cl)c(Cl)cc2[nH]1)C1(c2ccc(-c3cccc(C#N)c3)cc2)CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCC(Oc1nc2cc(Cl)c(Cl)cc2[nH]1)C1(c2ccc(-c3cccc(C#N)c3)cc2)CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 128.3 %

Procedure:
To a solution of 0.030 g of 4′-{4-[5,6-dichloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yloxymethyl]-piperidin-4-yl}-biphenyl-3-carbonitrile (0.05 mmol) 55 in 1 mL of dichloromethane was added methanesulfonyl chloride (0.005 mL, 0.053 mmol, 1.1 eq) and DIEA (0.011 mL, 0.06 mmol, 1.2 eq). The resulting mixture was stirred at room temperature for 16 h, diluted with 5 mL of ethyl acetate, and washed with H2O and saturated brine. The organic extracts were combined and dried over Na2SO4, filtered and concentrated by rotary evaporation to give 0.044 g of 4′-{4-[5,6-dichloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yloxymethyl]-1-methanesulfonyl-piperidin-4-yl}-biphenyl-3-carbonitrile as a pale foam. MS (ESI): m/z 684.8/686.8 (M+1/M+3).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[CH:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29]>ClC1N=C(N2CCS(=O)CC2)C2N=CN=C(Cl)C=2N=1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][S:12][C:8]2[C:6]3[N:7]=[C:2]([N:33]4[CH2:34][CH2:35][N:30]([CH:28]=[O:29])[CH2:31][CH2:32]4)[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]4)[C:5]=3[N:11]=[CH:10][N:9]=2)=[CH:15][CH:16]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4ccc(F)cc4)ncnc23)CC1
Reactant: O=CN1CCNCC1
Agent: O=S1CCN(c2nc(Cl)nc3c(Cl)ncnc23)CC1
Product: O=CN1CCN(c2nc(N3CCS(=O)CC3)c3ncnc(SCc4ccc(F)cc4)c3n2)CC1

Procedure:
This compound was prepared analogous to Example 93 from 2-chloro-8-(4-fluorobenzyl-thio)-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 192°-194° C.) and N-formyl-piperazine in dioxane.
Reaction SMILES: C([O:4][CH2:5][C:6](Cl)=[O:7])(=O)C.[CH2:9]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].CCN(CC)CC.[OH-].[Na+]>C(Cl)(Cl)Cl.O.CO>[OH:4][CH2:5][C:6]([N:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:7]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
(Acetyloxy)acetyl chloride (3.8 g; 28.1 mmol) (commercial product) dissolved in CHCl3 (150 mL) was added dropwise to a solution of dioctadecylamine (13.3 g; 25.5 mmol) and Et3N (3.9 mL; 28.1 mmol) in CHCl3 (350 mL) and the solution was stirred at room temperature overnight. MeOH (250 mL) and 2 N NaOH (50 mL) were added to the solution. H2O was added to the reaction mixture and a two phase system was obtained. The lower organic layer was separated and evaporated. The solid residue was suspended in n-hexane and filtered to give the desired compound (12.1 g;20.9 mmol). Yield 82%. HPLC: 96% (area %). K.F.: <0.1%. The 13C-NMR, MS and IR spectra were consistent with the structure.
Reaction SMILES: [C:1]([N:4]([C:33]1[CH:38]=[CH:37][C:36](Cl)=[CH:35][CH:34]=1)[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:31]=[CH:30][C:20]([O:21][CH2:22][CH2:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)=[O:16])[CH:7]([CH3:32])[CH2:6]1)(=[O:3])[CH3:2]>C(O)C.[Pd]>[C:1]([N:4]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:31]=[CH:30][C:20]([O:21][CH2:22][CH2:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:32])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(c1ccc(Cl)cc1)C1CC(C)N(C(=O)c2ccc(OCCC(C)(C)C(=O)O)cc2)c2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCC(C)(C)C(=O)O)cc2)c2ccccc21
Reaction time: 3 h

Procedure:
4-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-2,2-dimethyl-butyric acid (300 mg, 0.545 mmol) was dissolved in ethanol. Pd/C (10% Palladium) was added, followed by H2 gas (1 atm-balloon). After 3 hours, the reaction mixture was filtered and concentrated. The crude residue was purified by silica gel chromatography (100% ethyl acetate to 5% methanol/ethyl acetate gradient) to afford the product.