Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[O:21])[CH2:16][CH2:15]2)[C:3]1=[O:28].CCN(CC)CC.[C:36](Cl)(=[O:40])[CH2:37][CH2:38][CH3:39]>C(Cl)Cl>[C:36]([N:25]1[CH2:26][CH2:27][N:22]([C:20]([C@H:17]2[CH2:18][CH2:19][C@H:14]([CH2:13][N:4]3[C:5](=[O:12])[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[N:2]([CH3:1])[C:3]3=[O:28])[CH2:15][CH2:16]2)=[O:21])[CH2:23][CH2:24]1)(=[O:40])[CH2:37][CH2:38][CH3:39]
Reactant: CCCC(=O)Cl
Reactant: Cn1c(=O)n(C[C@H]2CC[C@H](C(=O)N3CCNCC3)CC2)c(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCN(C(=O)[C@H]2CC[C@H](Cn3c(=O)c4ccccc4n(C)c3=O)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.26 mmol) of 1-Methyl-3-[trans-4-(piperazine-1-carbonyl)-cyclohexylmethyl]-1H-quinazoline-2,4-dione was dissolved in DCM (3 ml). 75 μL (0.52 mmol) of Et3N and then 41 μL (0.39 mmol) of butyryl chloride were added and the mixture was stirred at room temperature overnight. The solution was washed with a 0.4 M solution of Na2CO3, the organic phase was separated and dried over Na2SO4. The solvent was removed under reduced pressure and the crude material purified by column chromatography using acetone as eluent. In total 28 mg (yield 24%) of the titled compound were isolated.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].O.O1CCCC1.[C:15](Cl)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>[OH-].[Na+]>[C:15]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 10 °C

Procedure:
29 g of L-valine is dissolved in 250 ml of 1N aqueous NaOH, and to the solution is added water so that 400 ml of the solution is obtained. To the solution is added 150 ml of tetrahydrofuran. Then, while vigorously stirring at 10° C., to the solution are added 100 ml of Boc-Cl by 1/5 amounts at intervals of ten minutes, while 2N aqueous NaOH is added after every addition of Boc-Cl in such amount as will provide a pH value of about 8 to 9. Two hours later, the mixture is extracted with diethyl ether. The aqueous layer is acidified with an aqueous solution of 0.5 M aqueous citric acid, whereby an oily substance is precipitated. The precipitate is extracted with ethyl acetate. The extract is washed with a small amount of water, dried over Na2SP4, and concentrated under reduced pressure. To the concentrated extract is added petroleum ether, and the mixture is allowed to stand in a refrigerator, whereby a crystal is formed. The crystal is filtered off and dried. Thus, there is obtained 30 g of Boc-valine having a melting point of 78° C. The yield of the product is 55%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[NH2:6].[C:16]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C:25]1=O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(OC)C=CC=CC=1>[Pd].C(N(CC)CC)C>[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[NH:6][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16](=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C1CCCCC1C(=O)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: COc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccccc1

Procedure:
A mixture of tyrosine methyl ester hydrochloride (4.8 g), 2-benzoylcyclohexanone (5.0 g), palladium on carbon (1.0 g, 10%), triethylamine (2.9 ml) and anisole (70 ml) was heated at reflux for 20 hours. The reaction mixture was filtered and the filtrate was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using hexane: ethyl acetate=3:1 as the eluant to afford the title compound (1.83 g, Rf=0.39: thin layer chromatography on a silica gel plate using hexane: ethyl acetate=3:1 as the eluant).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[H-].[Na+].I[CH3:15]>CN(C)C=O>[CH3:15][N:6]1[C:5]2[CH:9]=[C:10]([CH3:11])[C:2]([CH3:1])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: CI
Reactant: Cc1cc2nc[nH]c2cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2ncn(C)c2cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
In an oven dried nitrogen purged 3 neck 50 mL round bottom flask, 5.00 g (34.20 mmol) of 5,6-dimethylbenzimidazole in 20 mL of dry dimethylformamide is reacted with 1.51 g (37.62 mmol) of sodium hydride at room temperature for 4 h. 2.34 mL (37.62 mmol) of iodomethane is added and reaction is allowed to stir at room temperature overnight. Reaction is quenched with water, layers are separated, extract aqueous 3×50 mL ethyl acetate, dry (MgSO4), and concentrate. The crude mixture is purified by chromatography using dichloromethane: methanol as a solvent system. Product containing fractions are combined to obtain 3.75 g of the title compound, 68% yield. MS, ES+=161.1. H1NMR (CDCl3) δ 7.98 (s, 1H); 7.37 (s, 1H); 7.29 (s, 1H); 3.74 (s, 3H); 2.31 (s, 3H); 2.28 (s, 3H) ppm
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>[OH-].[Na+].C1(C)C=CC=CC=1>[S:13]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: C[C@H](N)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)O)cc1
Temperature: 5 °C
Reaction time: 20 h

Procedure:
L-alanine (100 g; 1.11 moles) was dissolved in 2.25 L of 1N sodium hydroxide (aq), cooled to 5° C. and stirred while a solution of p-toluenesulfonyl chloride (218 g; 1.11 moles) dissolved in 450 mL of toluene was added slowly. The mixture was stirred at ambient temperature for 20 hr. The layers were separated and the chilled aqueous layer acidified to pH 1 with concentrated hydrochloric acid. The white solid title compound was collected by filtration, washed with water and dried. Yield 178.5 g (66%) mp 134°-5° C. IR (CHCl3) cm-1 1726, 1340, 1165, 1095; 1H NMR (DMSO-D6) δ 1.20 (d, J=7, 3H), 2.40 (s, 3H), 3.85 (p, J=8, 1H), 6.4 (br s, 1H) (CO2H), b 7.41 (d, JAB =8, 2H) and 7.75 (d, JAB =8, 2H) [center of pattern: 7.58; ΔVAB =20.49 Hz], 8.03 (br d, J=8, 1H) (NH).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.O.[NH2:15][NH2:16]>O1CCOCC1>[NH:15]([C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1)[NH2:16]
Reactant: NN
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(NN)c2cccc(O)c2n1

Procedure:
A mixture of 4-chloro-2-methyl-quinolin-8-ol (0.10 g, 0.51 mmol) and hydrazine monohydrate (0.75 mL, 15 mmol) in dioxane (10 mL) was heated to reflux for 4 d. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (elution with DCM/methanol/conc. aqueous NH3 5:1:0.033) to give the title compound. MS (m/z): 190.1 [M+H+].
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH2:20][CH3:21])[CH:14]=1>C(Cl)Cl>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:1](=[O:3])[CH3:2])=[C:15]([CH2:20][CH3:21])[CH:14]=1
Reactant: CCc1cc(Br)ccc1O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(Br)ccc1OC(C)=O
Reaction time: 2 h
Yield: 80.9 %

Procedure:
Acetyl chloride (1.06 mL, 14.9 mmol) followed by triethylamine (2.08 mL, 14.9 mmol) were added to a cooled 0° C. solution of 4-Bromo-2-ethyl-phenol (2.5 g, 12.4 mmol, from Step 1) dissolved in CH2Cl2. The reaction was stirred for 2 hrs and then partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to a brown oil. The oil was purified by silica gel chromatography (0% to 10% EtOAc in hexanes) to give the title compound as a clear oil (2.44 g, 81%). 1H NMR (CDCl3): δ 1.19 (t, 3H, J=7.7 Hz), 2.32 (s, 3H), 2.52 (q, 2H, J=7.7 Hz), 6.89 (d, 1H, J=8.5 Hz), 7.32 (dd, 1H, J=8.5, 2.2 Hz), 7.38 (d, 1H, J=2.2 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:10]1([CH:20]=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:20]([OH:21])[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(Br)c1
Reactant: O=Cc1cccc2ccccc12
Solvent: C1CCOC1
Product: COc1cccc(C(O)c2cccc3ccccc23)c1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
To a solution of 3-bromoanisole (5.61 g, 30.0 mmol) in dry THF (80 mL) was dropwise added n-butyl lithium-hexane solution (1.6 M, 37.5 mL, 60 mmol) under nitrogen at −78° C. The reaction mixture was allowed to warm to r.t. in 2 h and cooled down again to −78° C. prior to addition of 1-naphthaldehyde (4.69 g, 30.0 mmol, in 10 mL THF). The mixture was warmed to r.t. in 3 h, and then quenched with aqueous NH4Cl solution, extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine, dried over MgSO4. Removal of solvents in vacuo provided 3-methoxy-α-(1-naphthyl)benzyl alcohol (4.25 g, 54%). GC-MS (Rt=10.41 min) 264 (M+), 245, 231, 215, 202, 155, 135, 128, 109.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8](=[O:12])[CH2:9][C:10]#[N:11])[CH3:2].C1(C)C=CC=CC=1.[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(N(CC)CC)C>[CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8](=[O:12])[CH:9]([C:27](=[O:28])[NH:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:10]#[N:11])[CH3:2]
Reactant: CCn1cccc1C(=O)CC#N
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCn1cccc1C(=O)C(C#N)C(=O)Nc1ccccc1
Reaction time: 8 h

Procedure:
The mixture of 2.1 g of 1-ethyl-β-oxo-2-pyrrolpropionitrile, 25 ml of toluene and 1.6 g of triethylamine is treated with 1.6 g of phenylisocyanate while stirring. It is allowed to stand overnight at room temperature, evaporated and the residue dissolved in methanol. The solution is poured into 300 ml of water containing 5 ml of 5 N hydrochloric acid and the precipitate is collected. It is dissolved in 5% aqueous sodium hydroxide, the solution filtered, the filtrate re-acidified, the solids collected, washed with water, dried and recrystallized from ethanol, to yield the 1-ethyl-β-oxo-α-phenylcarbamoyl-2-pyrrolpropionitrile melting at 144°-145°.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([NH:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])([CH3:5])[CH3:4].FC(F)(F)C(O)=O>ClCCl>[OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([NH:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])([CH3:4])[CH3:5]
Reactant: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3cccnc3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1c[nH]c2ncc(Nc3cccnc3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
N-(1-Hydroxy-2-methylpropan-2-yl)-2-(pyridin-3-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (32 mg, 70.1 μmol) was dissolved in dichloromethane (1.2 mL) and treated with trifluoroacetic acid (160 mg, 108 μL, 1.4 mmol). The mixture was stirred at room temperature for 16 h. The mixture was concentrated then re-dissolved in dichloromethane (1 mL), methanol (0.5 mL) and ammonium hydroxide (0.2 mL) and the mixture stirred at room temperature for 1 h. The mixture was concentrated in vacuo then triturated with water and filtered. The solid obtained was washed with ether then dried to give N-(1-hydroxy-2-methylpropan-2-yl)-2-(pyridin-3-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (21 mg, 64.3 μmol, 92%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d) 6 ppm: 12.39 (s, 1H), 9.66 (s, 1H), 8.85 (d, J=2.5, 1 H), 8.21 (m, 1H), 8.16 (dd, J=4.7, 1.6, 1 H), 8.04 (s, 1H), 8.03 (s, 1H), 7.67 (s, 1H), 7.33 (m, 1H), 5.05 (t, J=5.6, 1 H), 3.58 (d, J=5.9, 2 H), 1.36 (s, 6H); MS (EI/CI) m/z: 327.1 [M+H].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:24]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:19][S:29]([C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)(=[O:31])=[O:30])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccnc3)c2)c(-c2ccnc(Cl)n2)s1
Yield: 72 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (3 g, 9.1 mmol) and pyridine-3-sulfonyl chloride (1.93 g, 10.9 mmol) the title compound was obtained (3.1 g, 72% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.57-10.63 (br, 1H), 8.84 (d, J=2.2 Hz, 1H), 8.74-8.78 (m, 1H), 8.50 (d, J=5.3 Hz, 1H), 8.07-8.12 (m, 1H), 7.55-7.59 (m, 1H), 7.31-7.37 (m, 1H), 7.17-7.28 (m, 3H), 6.92 (d, J=5.3 Hz, 1H), 3.24-3.34 (m, 1H), 1.34 (d, J=6.8 Hz, 6H). MS (ES+): 472 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH3:27])[CH:3]=1.C([Li])CCC.CN(C)[CH:35]=[O:36].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Si:10]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH:35]=[O:36])=[CH:3][C:4]=1[CH3:27])([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)ccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-bromo-4-(tert-butyldiphenylsilyloxymethyl)-3-methylbenzene (2.19 g) in tetrahydrofuran (30 ml) was added 1.6 M butyllithium in hexane (4.69 ml) by syringe under nitrogen atmosphere at −78° C. After 30 minutes of stirring at −78° C., N,N-dimethylformamide (1.16 ml) was added to the solution at −78° C. and then the mixture was allowed to warm to 5° C. over 1.5 hours. Saturated ammonium chloride solution (10 ml) was added to the mixture and the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give 4-(tert-butyldiphenylsilyloxymethyl)-3-methylbenzaldehyde (1.90 g) as a colorless oil.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[C:6]([NH:9][C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][O:13][C:14](=[O:16])[CH3:15])(=[O:8])[CH3:7]>OS(O)(=O)=O>[C:6]([NH:9][C:10]1[C:20]([N+:1]([O-:4])=[O:2])=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][O:13][C:14](=[O:16])[CH3:15])(=[O:8])[CH3:7]
Reactant: CC(=O)Nc1ccc(Cl)cc1COC(C)=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)Nc1c(COC(C)=O)cc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 19.8 %

Procedure:
Potassium nitrate (1.01 g, 10 mmol) was added to conc. H2SO4 (10 ml) at 0° C. This mixture was stirred at 0° C. for 15 min, then acetic acid 2-acetylamino-5-chloro-benzyl ester (1.92 g, 8 mmol) was added in small portions over 15 min. The reaction mixture was stirred at 0° C. for a further 1 h, and then poured onto crushed ice. The precipitate formed was collected by filtration to give a mixture of isomers, which were separated by column chromatography eluting with a gradient of 0-60% ethyl acetate in petroleum ether to give the desired acetic acid 2-acetylamino-5-chloro-3-nitro-benzyl ester as a yellow solid (0.454 g, 20%).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:28][C@H:29]([C:37]([CH:39]1[CH:46]2[CH2:47][CH:42]3[CH2:43][CH:44]([CH2:48][C:40]1([NH2:49])[CH2:41]3)[CH2:45]2)=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[C:1]([NH:8][CH2:9][C:10]([NH:28][C@H:29]([C:37]([CH:39]1[CH:46]2[CH2:47][CH:42]3[CH2:43][CH:44]([CH2:48][C:40]1([NH2:49])[CH2:41]3)[CH2:45]2)=[O:38])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:12])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)C1C2CC3CC(C2)CC1(N)C3
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)C1C2CC3CC(C2)CC1(N)C3
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A solution of 1.42 g of Boc-glycine and 0.90 ml of N-methylmorpholine in 10 ml of dry methylene chloride under nitrogen is allowed to react with 1.05 ml of isobutylchloroformate at -45° C. The reaction mixture is allowed to warm to -20° C. then recooled to -40° C. To this solution is added 2.38 g of L-phenylalanyl-1-aminoadamantane. The cooling bath is removed and the reaction mixture is allowed to stand overnight at room temperature. The reaction mixture is filtered, diluted with 20 ml of methylene chloride and washed with 10 ml of cold 1 M potassium bisulfate solution followed by washing with 10 ml of cold 2 M potassium carbonate solution and 10 ml of saturated sodium chloride solution. The reaction mixture is dried over sodium sulfate, filtered and concentrated. The product separates as crystals upon addition of ether. The crystalline material is collected to give Boc-glycyl-L-phenylalanyl-1-aminoadamantane. A dry solution of 2.8 g of Boc-glycol-L-phenylalanyl-1-aminoadamantane in 15 ml of methylene chloride under a nitrogen atmosphere at 5° C. is allowed to react with 10 ml of trifluoroacetic acid. The reaction mixture is allowed to stand for 30 minutes at room temperature. The solution is concentrated under reduced pressure then diluted with 10 ml of 5 M potassium carbonate solution and extracted with methylene chloride. The reaction mixture is dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure to give glycyl-L-phenylalanyl-1-aminoadamantane which is represented by the following formula ##STR37##
Reaction SMILES: [OH: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][C:15]([CH3:17])=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:16][C:15](=[CH2:14])[CH2:17][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=C(C)COc1ccc(C(=O)O)cc1

Procedure:
The reaction of Ethyl 4-hydroxyl-benzoate and 3-Bromo-2-methyl-propene in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 4-(2-Methyl-allyloxy)-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO):12.59 (s, —CO2H); 7.86 (d-like, J=8.0, 2 arom. H); 7.02 (d-like, J=8.0, 2 arom. H); 5.04, 4.96 (2 s, —C(CH3)═CH2); 4.53 (s, CH2—C(CH3)═CH2); 1.72 (s, C(CH3)═CH2). 13C-NMR (100 MHz, d6-DMSO): 166.93 (—C═O); 161.87; 140.39; 131.27 (2 arom. C); 123.05; 114.42 (2 arom. C); 112.52; 70.97; 19.12.
Reaction SMILES: [O:1]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH2:28][CH2:29][NH2:30])[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][CH:19]4[CH:18]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH:17]=[CH:16][C@@H:15]35)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.Cl.[N:49]1(C(N)=N)[CH:53]=CC=[N:50]1>CN(C)C=O>[O:1]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH2:28][CH2:29][NH:30][CH:53]=[N:49][NH2:50])[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][CH:19]4[CH:18]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[CH3:34])[CH:17]=[CH:16][C@@H:15]35)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: N=C(N)n1cccn1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c3c1OC1C(O[Si](C)(C)C(C)(C)C)C=C[C@H]4[C@@H](C2)N(CCCN)CC[C@]314
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c3c1OC1C(O[Si](C)(C)C(C)(C)C)C=C[C@H]4[C@@H](C2)N(CCCNC=NN)CC[C@]314
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Anhydrous dimethylformamide (2 ml) was added to a mixture of 3,6-bis(t-butyldimethylsiloxy)-7,8-didehydro-4,5-epoxy-17-aminopropylmorphinan (0.2 g, 0.359 mmol), diisopropylethylamine (0.07 ml, 0.39 mmol), and 1H-pyrazole-1-carboxamidine hydrochloride (0.06g, 0.39 mmol) and the reaction mixture was stirred overnight at room temperature under nitrogen. The reaction mixture was evaporated to dryness under reduced pressure, and the crude product was chromatographed on silica gel (yield=0.155 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:15])=O>>[Cl:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([Cl:15])=[O:6]
Reactant: COc1c(Cl)cccc1C(=O)O
Reactant: O=S(Cl)Cl
Product: COc1c(Cl)cccc1C(=O)Cl

Procedure:
A solution of 0.5 g (0.0027 mole) of 3-chloro-2-methoxybenzoic acid in 10 mL of thionyl chloride was heated under reflux for 2 hours and then evaporated to yield 3-chloro-2-methoxybenzoic acid chloride. The residual oil was dissolved in 20 mL of methlene chloride containing 0.4 g (0.003 mole) of 2-aminomethyl-1-ethyl-pyrrolidine and 1 mL of triethylamine. After 1 hour at room temperature, the solution was evaporated and treated with water. The oil which precipitated was taken up in methylene chloride, dried and evaporated. The residue was crystallized from ether-pentane to obtain 0.55 g (69%) of the invention compound, m.p. 55°-58°.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][N:14]=2)[C:10]#[N:11])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH3:19][C:20]([CH3:22])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[CH:20]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][N:14]=2)[C:10]#[N:11])[CH2:6][CH2:5]1)([CH3:22])[CH3:19]
Reactant: N#Cc1ccnc(N2CCNCC2)c1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N1CCN(c2cc(C#N)ccn2)CC1
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a solution of 2-piperazin-1-yl-isonicotinonitrile (10 g, 53 mmol), glacial acetic acid (4.26 ml, 4.5 g, 74.4 mmol, 1.4 equiv) and acetone (4.29 ml, 3.39 g, 58 mmol, 1.1 equiv) in anhydrous dichloromethane was added sodium triacetoxyborohydride (13.5 g, 63.8 mmol, 1.2 equiv). The reaction was stirred overnight, then an aqueous solution of 1 N NaOH solution was added (150 ml) and the mixture was extracted once with dichloromethane, then twice with a solution of 10% methanol/dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash column chromatography (5% methanol/CH2Cl2 grading to 10% methanol/CH2Cl2) provided the desired product (6.52 g, 59%).