Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO>[CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2nc(C)cs2)=CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1csc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)n1
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[5,6-dihydro-5,5-dimethyl-8-(4-methylthiazol-2-yl)-2-naphthalenyl]ethynylbenzoate (Compound 16) (145.0 mg, 0.34 mmol) and 4 ml of EtOH at room temperature was added aqueous NaOH (1 ml, 1 M, 1 mmol). The resulting solution was warmed to 50° C. for 1 hour and concentrated in vacuo. The residue was suspended in a solution of CH2Cl2 and ether (5:1) and acidified to pH 5 with 1M aqueous HCl. The layers were separated and the organic layer was washed with brine, dried (Na2SO4), filtered and the solvents removed under reduced pressure to give the title compound as a white solid. 1H NMR (d6-DMSO): δ 7.94 (2H, d, J=8.1 Hz), 7.87 (1H, d, J=1.6 Hz), 7.63 (2H, d, J=8.3 Hz), 7.50 (1H, dd, J=1.6, 8.1 Hz), 7.45 (1H, d, J=8.1 Hz), 7.27 (1H, s), 6.58 (1H, t, J=4.8 Hz), 2.43 (3H, s), 2.37 (2H, d, J=4.8 Hz), 1.26 (6H, s).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[S:16](Cl)(=[O:18])=[O:17])([CH3:3])[CH3:2].CC(C)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>C(O)C.O>[CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[S:16]([N:24]=[N+:25]=[N-:26])(=[O:18])=[O:17])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCO
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2,4,6-triisopropylbenzenesulfonyl chloride (18.2 g, 60.0 mmol) in reagent acetone (70 mL) is added a solution of sodium azide (4.3 g, 60 μmol) in ethanol-H2O 1:1 (40 mL). The temperature of the mixture rises from 21° C. to 29° C. during the addition. After stirring at room temperature for 2 hours, the reaction mixture is partitioned between dichloromethane and half saturated brine. The aqueous solution is extracted with dichloromethane (3X), the combined organic solution is washed with half saturated brine, and dried (magnesium sulfate). Removal of solvent in vacuo gives a colorless oil which is purified by flash chromatography (silica gel, hexane-ethyl acetate/4:l) to yield the title compound as a white solid, 18.5 g; mp 44°-44.5° C. (Evans, D. , et al, Journal of the American Chemical Society 112:4011 (1990); mp 43°-44° C.).
Reaction SMILES: C1(O)C=CC=CC=1.B(F)(F)F.CCOCC.[CH2:17]1[CH:21]2[CH:22]3[CH:26]=[CH:25][CH:24]([CH:20]2[CH:19]=[CH:18]1)[CH2:23]3.C1CC=CC=1.C=CC(=C)C>>[CH2:17]1[CH:21]2[C@@H:22]3[CH:26]=[CH:25][C@H:24]([CH:20]2[CH:19]=[CH:18]1)[CH2:23]3
Reactant: C1=CC2C3C=CC(C3)C2C1
Agent: C1=CCC=C1
Agent: FB(F)F
Solvent: Oc1ccccc1
Solvent: CCOCC
Solvent: C=CC(=C)C
Product: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a reactor equipped with a stirrer, condenser, thermowell and heater add 1882 gms (20 moles) of phenol and 8 gms (0.4% based on total weight) of boron trifluoride etherate. Heat to 70° C. and add 132 gms (~1 mole) of a C10 diene stream containing mainly dicyclopentadiene and cyclopentadiene-isoprene codimers over a 20 minute (1200 s) period. Increase the temperature to 150° C. over a 3 hour (10,800 s) time period and hold for about 3 hours (10,800 s). Distill off unreacted phenol with a finishing temperature of 210° C. and less than 5 mm Hg. The recovered product is a dicyclopentadiene bisphenol with an average functionality of 2.07.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[C:7]=1C=O)#[N:2].[C:22](O)(=O)[CH2:23][C:24]([OH:26])=[O:25]>N1CCCCC1.N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[N:5][N:6]([C:10]2[C:11]([Cl:21])=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][C:15]=2[Cl:16])[C:7]=1[CH:22]=[CH:23][C:24]([OH:26])=[O:25])#[N:2]
Reactant: N#Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C=O
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: N#Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C=CC(=O)O
Yield: 56.7 %

Procedure:
By the method of Example 5, Step H, 1.5 g (0.0045 mole) of 4-cyano-5-formyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole and 1.0 g (0.0096 mole) of malonic acid were reacted in the presence of 5 mL of pyridine and 10 drops of piperidine, yielding 0.96 g of 3-[4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazol-5-yl]acrylic acid. The nmr spectrum of this solid was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[O:6][CH:5]=[C:4]([C:7]([NH:9][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[O:8])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:47]2[N:51]([CH3:52])[N:50]=[CH:49][CH:48]=2)OC1>O1CCOCC1.O.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>[O:22]=[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:21])[N:12]1[CH2:11][C@@H:10]([NH:9][C:7]([C:4]1[CH:3]=[C:2]([C:47]2[N:51]([CH3:52])[N:50]=[CH:49][CH:48]=2)[O:6][CH:5]=1)=[O:8])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: O=C(N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O)c1coc(Br)c1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
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
Product: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)co1
Temperature: 75 °C
Reaction time: 5 h
Yield: 49.7 %

Procedure:
To a solution of 5-bromo-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-3-furancarboxamide (400 mg, 0.77 mmol) in dioxane/H2O (5:1, 50 mL) was added K2CO3 (0.32 g, 2.3 mmol), tetrakistriphenylphosphine Pd(0) (20 mg, 40 μmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (0.19 g, 0.92 mmol). The reaction mixture was heated to 75° C. in a sealed tube. After 5 h, additional tetrakistriphenylphosphine Pd(0) (20 mg, 40 μmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (0.19 g, 0.92 mmol) were added. After 8 h, the reaction solution was then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organics were dried (Na2SO4), concentrated under vacuum and purified on silica gel (hexanes/EtOAc, 1:2) to give the title compound (200 mg, 50%) as white solid: LCMS (ES) m/z=523.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:14](Cl)(=[O:16])[CH3:15].[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](C1C=CC=CC=1)([O-])=O>[C:14]([C:4]1[CH:3]=[C:2]([F:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=1)(=[O:16])[CH3:15]
Reactant: COc1ccc2cccc(F)c2c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc2cc(C(C)=O)cc(F)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
A solution of 1-fluoro-7-methoxynaphthalene (13 g, 0.074 mol) and acetyl chloride (8.01 g, 0.10 mol) in nitrobenzene (120 ml) was treated at 0° C. with powdered anhydrous aluminium chloride (15.59 g, 0.11 mol) over a period of 30 minutes. After stirring at room temperature overnight, the reaction mixture was treated with a mixture of ice (50 g) and concentrated hydrochloric acid (20 ml). The mixture was steam distilled until removal of nitrobenzene was complete. The residue was cooled and the product extracted into ether. The ether layers were washed, dried and concentrated to give a brown solid which was purified by column chromatography on silica gel using petroleum ether/ether mixture as eluant. The product was recrystallised from ether to give a coloured solid 5.33 g. m.p. 96°-7° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15](Br)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.O.[C:31]([O:34][CH2:35]C)(=[O:33])C>CO.[Cl-].[Na+].O>[CH3:35][O:34][C:31]([C:15]1[N:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C@H:10]1[N:18]2[C@H:19]([CH3:21])[CH2:20][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)=[O:33]
Reactant: CCOC(C)=O
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.4 %

Procedure:
To a solution of 6.0 g (16.3 mmol) (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 5, intermediate b) in 60 ml methanol were added 0.57 g (0.8 mmol) and 3.4 ml (2.5 g, 24.4 mmol) triethylamine and the reaction mixture was stirred at 80 deg C. for 24 h under a carbon monoxide atmosphere of 40 bar. The suspension was cooled to room temperature, poured into a mixture of water, ethyl acetate and brine and was extracted with further portions of ethyl acetate. The combined organic layers were separated, dried over magnesium sulfate and filtered. The residue was purified by chromatography on silica gel (0.032–0.063 mm) to afford the product as a light yellow foam (74.4%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([N+:16]([O-])=O)=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][CH2:3]1>CCOC(C)=O.[Pd]>[NH2:16][C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[CH:13][C:12]=1[C:14]#[N:15]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(C#N)c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(N)c(C#N)c2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-(4-Methylpiperazinyl)-2-nitrobenzenecarbonitrile (1.0 eq) was dissolved in EtOAc. The flask was purged with nitrogen, and 10% Pd/C (0.1 eq) was added. The flask was evacuated and purged with H2 three times. The resulting mixture was stirred for three days at room temperature. The mixture was filtered through Celite and the filter pad was washed with EtOAc. The solvent was removed in vacuo to give a yellow solid which was purified by silica gel chromatography (5:1:95 MeOH:Et3N:EtOAc) to give the desired product as a yellow solid. LC/MS m/z 217.3 (MH+), Rf 0.95 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:56]([CH3:58])[CH3:57])[C:7]([N:9]1[CH2:13][C@@H:12]([S:14][CH3:15])[CH2:11][C@H:10]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4[NH:37][C:36]([C@@H:38]5[CH2:42][C@H:41]([CH2:43][O:44][CH3:45])[CH2:40][N:39]5C(OCC5C=CC=CC=5)=O)=[N:35][CH:34]=4)=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:8])=[O:4].Br.[C:60]([O:64][C:65]([NH:67][C@H:68]([C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)[C:69]([OH:71])=O)=[O:66])([CH3:63])([CH3:62])[CH3:61].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O.CN(C=O)C.CO>[C:60]([O:64][C:65]([NH:67][C@H:68]([C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)[C:69]([N:39]1[CH2:40][C@@H:41]([CH2:43][O:44][CH3:45])[CH2:42][C@H:38]1[C:36]1[NH:37][C:33]([C:30]2[CH:29]=[CH:28][C:27]([C:24]3[CH:25]=[CH:26][C:21]([C:18]4[NH:17][C:16]([C@@H:10]5[CH2:11][C@H:12]([S:14][CH3:15])[CH2:13][N:9]5[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:56]([CH3:58])[CH3:57])=[N:20][CH:19]=4)=[CH:22][CH:23]=3)=[CH:32][CH:31]=2)=[CH:34][N:35]=1)=[O:71])=[O:66])([CH3:61])([CH3:62])[CH3:63]
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc(-c4ccc(-c5cnc([C@@H]6C[C@H](SC)CN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]5)cc4)cc3)[nH]2)N(C(=O)OCc2ccccc2)C1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: Br
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc(-c4ccc(-c5cnc([C@@H]6C[C@H](SC)CN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]5)cc4)cc3)[nH]2)N(C(=O)[C@H](NC(=O)OC(C)(C)C)c2ccccc2)C1
Reaction time: 1 h
Yield: 73.2 %

Procedure:
(2S,4S)-benzyl 2-(5-(4′-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methylthio)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (220 mg, 0.27 mmol) was dissolved in DCM (5 mL), MeOH (0.4 mL) and cooled to 0° C. HBr (33% in AcOH, 1 mL) was added dropwise. After stirring for 1 hr, the mixture was concentrated under reduced pressure, coevaporating with PhMe. The crude residue was treated with (R)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (68 mg, 0.27 mmol), COMU (129 mg, 0.27 mmol) and DMF (5 mL), then DIPEA (0.24 mL, 1.35 mmol) was added dropwise. After 1 h, the mixture was diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0% to 40% MeOH/EtOAc) to afford methyl (S)-1-((2S,4S)-2-(5-(4′-(2-((2S,4S)-1-((R)-(tert-butoxycarbonylamino)-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methylthio)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (179 mg, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH2:14])[NH:10][C:9]=2[CH:8]=[C:7]([C:15]#[N:16])[CH:6]=1)=[O:4].O.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28](O)=[O:29])[N:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH:14][C:28]([C:20]3[N:19]=[CH:18][C:27]4[C:22]([CH:21]=3)=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:29])[NH:10][C:9]=2[CH:8]=[C:7]([C:15]#[N:16])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(C#N)cc2[nH]c(N)nc12
Reactant: O=C(O)c1cc2ccccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C#N)cc2[nH]c(NC(=O)c3cc4ccccc4cn3)nc12

Procedure:
0.28 g (1.3 mmol) of 2-amino-6-cyano-1H-benzoimidazole-4-carboxylic acid methyl ester was added to a mixture of 0.22 g (1.3 mmol) of isoquinoline-3-carboxylic acid monohydrate, 0.49 g (1.3 mmol) of HBTU, 3 mL of DMF and 1 mL of DIEA to produce 6-cyano-2-[(isoquinoline-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid methyl ester, according to General Procedure A. LCMS: 373.0 (M+1)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[N:18]=[C:19](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:20][CH:21]=2)=[CH:11][CH:10]=1)(=O)=O.[NH:30]1[CH:34]=[CH:33][N:32]=[C:31]1[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[C:24]1(/[CH:23]=[CH:22]/[C:19]2[O:20][CH:21]=[C:17]([CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][N:30]4[CH:34]=[CH:33][N:32]=[C:31]4[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:14][CH:13]=3)[N:18]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CS(=O)(=O)OCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: CCOC(=O)c1ncc[nH]1
Product: CCOC(=O)c1nccn1CCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Yield: 68 %

Procedure:
In substantially the same manner as in Working Example 25, 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate was allowed to react with ethyl 2-imidazolecarboxylate to give ethyl 1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-2-imidazolecarboxylate. The yield was 68%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 123-124° C.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)([O-])=O.[OH-].[NH4+]>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)C(Cn1ccnc1)Oc1ccc([N+](=O)[O-])cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)C(Cn1ccnc1)Oc1ccc(N)cc1
Yield: 78.1 %

Procedure:
The above nitro compound (2.00 g) was added to a stirred suspension of finely ground ferrous ammonium sulphate hexahydrate and the mixture heated to reflux. Concentrated ammonium hydroxide was added every two minutes in two ml aliquots until thin layer chromatography showed the reaction to be complete. Absolute ethanol (150 ml) was then added and the reaction mixture filtered through Celite. After evaporation of the solvent the residue was chromatographed on silica gel eluting with 5% methanol in methylene chloride to give 1-[2-(4-aminophenoxy)-3,3-dimethyl-n-butyl]imidazole (1.4 g) as an oil. This was converted to the bis hydrochloride salt as described in Example 16, the salt being recrystallized from ethyl acetate methanol with m.p. 265°-270° C. (dec.).
Reaction SMILES: [CH:1]([N:4]1[CH2:15][CH2:14][C:7]2([O:12][CH2:11][C:10](=O)[NH:9][CH2:8]2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[F-].[Na+].O>C1COCC1>[CH:1]([N:4]1[CH2:5][CH2:6][C:7]2([O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH2:14][CH2:15]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC2(CC1)CNC(=O)CO2
Agent: [F-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N1CCC2(CC1)CNCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9-Isopropyl-1-oxa-4,9-diaza-spiro[5.5]undecan-3-one was dissolved in THF and LiA1H4 (5 equivalents) was added. The reaction was heated at reflux for 4 hours and then cooled to room temperature. NaF (20 equivalents) and water (5 equivalents) were added and the reaction was stirred vigorously for 1 hour. The resulting precipitate was filtered away and the filtrate was concentrated to provide the title compound as a colorless oil. GC/MS (m/z) 198, Rt=12.57 minutes.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3[C:17]([CH3:24])=[C:18]([OH:23])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][C:13]2([CH3:26])[CH3:25])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].Cl.[Cl:28][CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1.O>CN(C)C=O>[ClH:28].[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3[C:17]([CH3:24])=[C:18]([O:23][CH2:29][C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]=4)[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][C:13]2([CH3:26])[CH3:25])=[CH:8][CH:7]=1)([CH3:5])[CH3:4]
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C)c2c(c(C)c1OCc1ccc3ccccc3n1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reaction time: 0.17 h
Yield: 71.1 %

Procedure:
Sodium hydride (60% liquid paraffin dispersion, 136 mg, 3.39 mmol) was added to a solution of 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol (1.0 g, 3.08 mmol) in N,N-dimethylformamide (30 mL) at 0° C., and the mixture was stirred for 10 minutes at the same temperature. To the reaction mixture was added 2-(chloromethyl)quinoline hydrochloride (730 mg. 3.39 mmol) and the mixture was stirred for 30 minutes at 80° C. The reaction mixture was poured into water (40 mL), and extracted twice with ethyl acetate. The organic layers were combined, washed with eater, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. To the residue was added 4 N HCl-ethanol, and the solvent was removed through distillation. The residue was crystallized from ethanol-hexane to obtain the title compound (1.1 g, yield 71%).
Reaction SMILES: [H-].[Na+].O([C:10]([NH:12][C@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])C1C=CC=CC=1.N[C@H](C(O)=O)C(C)C.[CH3:28][NH:29][CH2:30][C:31]1[N:32]=[C:33]([CH:36]([CH3:38])[CH3:37])[S:34][CH:35]=1>C1COCC1>[CH3:28][N:29]([C:10]([NH:12][C@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:15])[CH3:16])=[O:11])[CH2:30][C:31]1[N:32]=[C:33]([CH:36]([CH3:38])[CH3:37])[S:34][CH:35]=1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Reactant: CNCc1csc(C(C)C)n1
Agent: CC(C)[C@H](N)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred slurry of anhydrous 95% NaH (500 mg, 20.8 mmol) at -10° C. in 25 mL of THF was added N-phenoxycarbonyl-L-Valine (4.93 g, 20.8 mmol) followed by a 10 mL THF rinse keeping the temperature <0° C. using an ice-water bath. Following the addition of the N-protected Valine, N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amine (3.54 g, 20.8 mmol) was added at <0° C. The reaction was allowed to warm to ambient temperature. After 3 hours, 50 mL of THF was added followed by 25 mg (1 mmol) of NaH. After 16 hours at room temperature, the reaction was complete. The reaction was worked up by the procedures described in Example 1.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:17]([Si:21]([O:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([CH2:42]Br)[CH:36]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])([CH3:19])[CH3:18]>CCCCCC.CN(C=O)C>[Si:21]([O:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([CH:36]=1)[CH2:42][N:13]1[CH2:14][CH2:15][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:11][C:12]1=[O:16])([C:17]([CH3:19])([CH3:20])[CH3:18])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: CC(C)(C)[Si](Oc1ccc(Cl)c(CBr)c1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc2Cl)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% dispersion in mineral oil) (3.50 g, 0.0874 mmol) was washed with hexane, suspended in DMF (100 mL) at 0° C. with stirring under Ar, then treated with tert-Butyl-3-oxopiperazine-1-carboxylate (15.0 g, 0.728 mol). After 1 h, tert-butyl(3-bromomethyl-4-chlorophenoxy) diphenylsilane (33.34 g, 0.0728 mol) in DMF (50 mL) was added dropwise, and the reaction mixture was left to warm to room temperature overnight. The reaction mixture partitioned between EtOAc/hexane (50/50) and H2O, the aqueous layer washed with EtOAc/hexane, the organics combined, washed with H2O, brine, and dried (Na2SO4). Filtration and concentration to dryness gave the title compound which was used without purification.