Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][CH2:15][N:16]1[CH2:20][C@@H:19]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH2:18][C@H:17]1[C:31](=[O:34])[NH:32][CH3:33]>O1CCCC1>[CH3:8][S:9]([O:13][CH2:14][CH2:15][N:16]1[CH2:20][C@@H:19]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH2:18][C@H:17]1[C:31](=[O:34])[NH:32][CH3:33])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1CCOS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
1.06 ml of triethylamine and subsequently 584 μl of methanesulfonyl chloride were added, whilst ice-cooling, to a solution of 2.13 g of (2S, 4S)-1-(2-hydroxyethyl)-4-(4-methoxybenzylthio)-2-methylcarbamoyl-pyrrolidine dissolved in 45 ml of dry tetrahydrofuran, and the mixture was stirred at 0° to 5° C. for 30 minutes. At the end of this time, the crystals which precipitated were collected by filtration and washed with tetrahydrofuran. The filtrate and washings were combined and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure, to afford 2.50 g of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:22])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:21])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:20])=[CH:11]/[CH2:12][S:13][CH2:14][C@H:15]([NH2:19])[C:16]([OH:18])=[O:17].[CH2:23]1[C@H:30]([N:31]2[C:40](=[O:41])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:32]2=[O:33])[C:28](=[O:29])[O:27][C:25](=[O:26])[CH2:24]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:16]([C@@H:15]([NH:19][C:25](=[O:26])[CH2:24][CH2:23][C@H:30]([N:31]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:32]1=[O:33])[C:28]([OH:29])=[O:27])[CH2:14][S:13][CH2:12]/[CH:11]=[C:10](\[CH3:20])/[CH2:9][CH2:8]/[CH:7]=[C:6](\[CH3:21])/[CH2:5][CH2:4][CH:3]=[C:2]([CH3:22])[CH3:1])([OH:18])=[O:17]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Reactant: O=C1CC[C@H](N2C(=O)c3ccccc3C2=O)C(=O)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)CC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of S-trans, trans-farnesyl-L-cysteine (325 mg, 1 mmol) and N-phthaloyl-L-glutamic anhydride (259 mg, 1 mmol) in CH2Cl2 (10 mL) was added N,N-diisopropyl-ethyl-amine (0.87 mL, 5 mmol). The solution was stirred at room temperature for 2 h. The reaction was quenched with 1N HCl (10 mL) and the pH was adjusted to 2.0-3.0. The mixtures were extracted with ethyl acetate (15 mL×3). The organic layer was dried over Na2SO4 and concentrated in vacuo and the residue was purified by preparative HPLC (350 mg, 60%) to yield Compound C-2, which is identical to the S—R stereoisomer of the Compound C racemate in Examples 5 and 5a. 1H-NMR (500 MHz, CDCl3): δ 1.50 (s, 3H), 1.52 (s, 3H), 1.55 (s, 3H), 1.60 (s, 3H), 1.86-1.98 (m, 8H), 2.33-2.43 (m, 2H), 2.54-2.57 (m, 2H), 2.78 (dd, J=5.0, 15.0 Hz, 1H), 2.91 (dd, J=5.0, 15.0 Hz, 1H), 3.06 (dd, J=5.0, 10.0 Hz, 1H), 3.14 (dd, J=5.0, 10.0 Hz, 1H), 4.65 (dd, J=5.0, 10.0 Hz, 1H), 4.96 (t, J=5.0 Hz, 1H), 5.00 (m, 2H), 5.11 (t, J=5.0 Hz, 1H), 6.79 (d, J=10.0 Hz, 1H), 7.63-7.65 (m, 2H), 7.74-7.76 (m, 2H), 8.00 (broad, 2H). 13C-NMR (125 MHz, CDCl3): δ 16.06, 16.18, 17.76, 25.19, 25.78, 26.47, 26.73, 29.77, 32.59, 32.79, 39.65, 39.72, 51.10, 51.85, 119.37, 123.76, 123.80, 124.36, 131.39, 131.62, 134.40, 135.36, 140.24, 167.75, 172.78, 173.05, 174.51; ES-MS: mass calcd for Chemical Formula: C31H40N2O7S 584.72. Found (M+) m/z 585.3, (M+Na) m/z 607.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#N)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][N:15](C)C=O.[BH4-].[Na+].ClCC#N>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:14]#[N:15])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CN(C)C=O
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: N#CCCl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: N#CCSc1ccc(N)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
4.4 G. of 1-amino-2-nitro-4-thiocyanatobenzene in 10 ml. of dimethylformamide is treated under nitrogen with 0.85 g. of sodium borohydride in 10 ml. of DMF at not greater than 30° C. The mixture is stirred at 15° C. to 20° C. for one hour, then treated with 5 g. of chloroacetonitrile at 20° C. to 25° C. The mixture is treated overnight at room temperature and poured into water. Filtration and recrystallization from methanol affords 1-amino-2-nitro-4-cyanomethylthiobenzene.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[N:3]=1.[CH3:16][O:17][CH2:18][CH2:19][NH2:20].C(O)C>O>[Cl:8][C:6]1[CH:7]=[C:2]([NH:20][CH2:19][CH2:18][O:17][CH3:16])[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[N:5]=1
Reactant: Cc1ccc(-c2nc(Cl)cc(Cl)n2)cc1
Reactant: COCCN
Solvent: CCO
Solvent: O
Product: COCCNc1cc(Cl)nc(-c2ccc(C)cc2)n1

Procedure:
A solution of 7.2 g. of 4,6-dichloro-2-(p-tolyl)pyrimidine and 4.5 g. of β-methoxyethylamine in 35 ml. of absolute ethanol is refluxed for 15 minutes. Pouring of the resulting solution into 700 ml. of water causes separation of a gummy material which solidifies on standing. The crude product weighs 7.3 g. and recrystallization from n-heptane affords 4-chloro-6-[2-(methoxy)ethylamino]-2-(4-tolyl)pyrimidine, 70°-72°C.
Reaction SMILES: [O-2].[Ca+2:2].[CH2:3]([C:9](=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:10]([OH:17])[C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].ClCCl>O>[OH:17][CH:10]([C:9](=[CH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:11]([CH3:15])([CH3:16])[C:12]([O-:14])=[O:13].[OH:17][CH:10]([C:9](=[CH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:11]([CH3:15])([CH3:16])[C:12]([O-:14])=[O:13].[Ca+2:2]
Reactant: CCCCCCC(=Cc1ccccc1)C(O)C(C)(C)C(=O)O
Agent: [Ca+2]
Agent: [O-2]
Solvent: O
Solvent: ClCCl
Product: CCCCCCC(=Cc1ccccc1)C(O)C(C)(C)C(=O)[O-]
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A 1 g (0.018 mole) quantity of calcium oxide was suspended in 100 mL of distilled water, and 4 g (0.013 mole) of 4-hexyl-3-hydroxy-2,2-dimethyl-5-phenyl-4-pentenoic acid was added to the suspension. After stirring for 4 days at room temperature, 50 mL of dichloromethane was added to the suspension and the mixture was stirred vigorously for 30 minutes. Another 50 mL of dichloromethane was added and the aqueous layer was separated. The aqueous phase was washed with 50 mL of dichloromethane, and the combined organic phase was evaporated to dryness to provide 4.8 g of crude product.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[C@H:15]([OH:16])[CH2:14][CH2:13][CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].O>CN(C)C=O>[CH2:1]([O:8][CH2:9][C@H:10]1[C@H:15]([O:16][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])[CH2:14][CH2:13][CH2:12][O:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: O[C@@H]1CCCO[C@H]1COCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCCO[C@@H]1CCCO[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.22 g of dl-trans-2-benzyloxymethyl-3-hydroxytetrahydropyran (prepared as described in Preparation 6) in 10 ml of dimethylformamide was added dropwise, with ice-cooling, to 10 ml of dimethylformamide containing suspended in it 0.480 g of a 55% w/w suspension of sodium hydride in mineral oil. The reaction mixture was stirred at room temperature for 60 minutes, after which 5.49 g of hexadecyl bromide were added, and the resulting mixture was stirred for a further 4 hours. Finally, the mixture was stirred at 60° C. for 60 minutes and then cooled. It was then poured into 100 ml of water, and extracted twice with ethyl acetate. The extract was washed with water, dried and condensed by evaporation under reduced pressure. The oily residue was subjected to column chromatography resulting through 100 g of silica gel. The fraction eluted with mixtures of diethyl ether and hexane ranging from 1:20 to 1:10 by volume gave 3.82 g of the title compound as a solid having a low melting point, melting at 28.5°-29.5° C. (cold methanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:14]1([C:20]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]3[CH:24]([CH2:25][NH:26][CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH2:9][C:10]([N:26]1[CH2:25][CH:24]2[CH:28]([C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:21][CH2:22][C:23]2=[O:29])[CH2:27]1)=[O:12]
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: O=C(O)Cc1c(F)cccc1F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3c(F)cccc3F)CC12
Reaction time: 0.75 h
Yield: 67.6 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-(2,6-difluorophenyl)acetic acid (1.2 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 45 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.3 g) and triethylamine (0.98 cc) in dichloromethane (40 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with distilled water (2×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from ethyl acetate (10 cc). The crystals obtained are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-2-[(2,6-difluorophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (2.1 g) melting at 218° C. is obtained.
Reaction SMILES: [CH:1]1([C:4]2([CH:18]3[CH2:20][CH2:19]3)[C:9]3[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][C:8]=3[NH:7][C:6](=[O:17])[O:5]2)[CH2:3][CH2:2]1.Br[C:22]1[CH:23]=[C:24]([C:27]#[N:28])[S:25][CH:26]=1>>[CH:1]1([C:4]2([CH:18]3[CH2:20][CH2:19]3)[O:5][C:6](=[O:17])[NH:7][C:8]3[CH:13]=[CH:12][C:11]([C:22]4[CH:23]=[C:24]([C:27]#[N:28])[S:25][CH:26]=4)=[CH:10][C:9]2=3)[CH2:3][CH2:2]1
Reactant: O=C1Nc2ccc(B(O)O)cc2C(C2CC2)(C2CC2)O1
Reactant: N#Cc1cc(Br)cs1
Product: N#Cc1cc(-c2ccc3c(c2)C(C2CC2)(C2CC2)OC(=O)N3)cs1

Procedure:
The title compound was prepared according to Procedure B from (4,4-dicyclopropyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 4-bromo-2-thiophene carbonitrile. A white solid: mp 244-245° C.; 1H-NMR (DMSO-d6) δ10.25 (s, 1H), 8.49 (d, 1H, J=0.87 Hz), 8.33 (s, 1H), 7.74 (d, 1H, J=1.44 Hz), 7.67 (dd, 1H, J=8.28, 1.54 Hz), 6.90 (d, 1H, J=8.28 Hz), 1.53 (m, 2H), 0.59-0.41 (m, 6H), 0.31-0.24 (m, 2H); MS (ESI) m/z 335 ([M−H]−, 100%); Anal. Calc. For C19H16N2O2S: C, 67.84, H, 4.79, N, 8.33. Found: C, 64.92, H, 4.66, N, 7.71.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:54]=[CH:53][C:10]([CH2:11][NH:12][C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[C:25]([N:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)[CH:24]=[CH:23][C:22]=4[NH:33][C:34]([C:36]4[CH:37]=[C:38]([CH:50]=[CH:51][CH:52]=4)[CH2:39][S:40][CH2:41][CH2:42][C:43]([O:45]C(C)(C)C)=[O:44])=[O:35])[CH:16]=3)=[O:14])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:54]=[CH:53][C:10]([CH2:11][NH:12][C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[C:25]([N:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)[CH:24]=[CH:23][C:22]=4[NH:33][C:34]([C:36]4[CH:37]=[C:38]([CH:50]=[CH:51][CH:52]=4)[CH2:39][S:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[O:35])[CH:16]=3)=[O:14])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3ccc(N4CCOCC4)cc3)ccn2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3ccc(N4CCOCC4)cc3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.3 %

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 3-(3-(2-(4-(4-morpholinobenzylcarbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenylcarbamoyl)-benzylthio)propanoate (170 mg, 0.20 mmol, 1.00 equiv, 86%) in dichloromethane (20 mL), and trifluoroacetic acid (2 mL). The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The solution was adjusted to pH 7-8 with NaHCO3 (aq). The resulting solution was extracted with 3×30 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×30 mL of brine, dried over NaSO4 and concentrated under vacuum. The crude product (120 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 17 mg (13%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 8.96 (s, 1H), 8.49 (m, 1H), 8.34 (s, 1H), 7.79 (m, 4H), 7.54 (m, 3H), 7.16 (m, 2H), 6.89 (m, 2H), 4.42 (s, 2H), 3.86 (s, 2H), 3.70 (m, 5H), 3.49 (s, 4H), 3.04 (m, 4H), 2.60 (m, 2H), 1.78 (m, 6H). MS (ES, m/z): 694 [M+H]+.
Reaction SMILES: [C@H:1]1([NH2:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:18](Br)[CH:19]=[CH2:20]>C(Cl)Cl>[CH2:20]([NH:10][C@H:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: N[C@@H]1CCc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN[C@@H]1CCc2ccccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (1R)-indan-1-amine (1.00 g, 7.51 mmol) and triethylamine (1.52 g, 15.0 mmol) in DCM (75 mL) was added allyl bromide (1.36 g, 11.3 mmol) and the mixture was allowed to stir at ambient temperature for 3 days. An additional 1.5 equivalents of allyl bromide and 0.5 equivalents of triethylamine were then added, and the reaction mixture was stirred an additional 24 hours. LCMS analysis now indicates the reaction mixture is a 27:35:38 mixture of starting material:desired product:bis-allylation product. Use this solution as is.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Cl:9][CH2:10][CH2:11][C:12](O)=[O:13].FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[Cl:9][CH2:10][CH2:11][C:12]([C:6]1[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=1[OH:5])=[O:13]
Reactant: Oc1cccc(O)c1
Reactant: O=C(O)CCCl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCCl)c1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred mixture of resorcinol (5 g, 45.5 mmol) and 3-chloropropionic acid (5.2 g, 48 mmol), is added trifluoromethanesulfonic acid (25 g, 166 mmol) in one portion. The mixture is stirred at room temperature for 10 min, then heated at 80° C. for 30 min. The reaction is cooled to room temperature and the mixture is diluted with DCM (200 mL). The solution is slowly poured into ice water (200 mL). The bi-layer is separated, and the aqueous phase is extracted with DCM (2×40 mL). The combined organic phase is washed with brine and dried over sodium sulfate. The crude 3-chloro-1-(2,4-dihydroxy-phenyl)-propan-1-one is obtained as orange solid (6.9 g) after evaporation of solvent and carried on as is.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH3:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][NH2:25].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][NH:25][C:15]([CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1)=[O:17]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: CC(C)(C)CCN
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)NCCC(C)(C)C)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 3,3-dimethyl-butylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C18H27NO5 [M−H]−: 338.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]([CH3:25])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][CH2:18][C@@H:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br-].C1C(C(OOC(C)(C)C)=O)=CC=CC=1.O>C1C=CC=CC=1>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]([CH3:25])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1COC(c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)=N1
Agent: CC(C)(C)OOC(=O)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1coc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)n1
Yield: 46.7 %

Procedure:
A solution of 6.80 g (0.0181 mol) of methyl (S)-2-(7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl)-4,5-dihydro-oxazole-4-carboxylate in 700 ml of hot benzene was treated with 2.86 g (0.0199 mol) of copperl bromide and 5.1 ml (0.0272 mol) of tert-butyl perbenzoate according to the method described in Tetr. Letters 1994, 35, 2481. The mixture was boiled at reflux for 20 min., cooled and treated with 300 ml of water. The mixture was filtered, extracted with dichloromethane and chromatographed over silica gel with ethyl acetate as the eluent. There were obtained 3.15 g (47%) of methyl 2-(7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl)-oxazole-4-carboxylate as white crystals; m.p. 266-268°.
Reaction SMILES: [CH3:1][C:2]([C@:4]1([OH:25])[C@@:8]2([CH3:24])[CH2:9][C@H:10]([OH:23])[C@@H:11]3[C@:21]4([CH3:22])[C:15](=[CH:16][C:17]([CH2:19][CH2:20]4)=[O:18])[CH2:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3].[C:26](OC(=O)C)(=[O:28])[CH3:27].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O>[C:26]([O:23][C@H:10]1[CH2:9][C@@:8]2([CH3:24])[C@@H:7]([CH2:6][CH2:5][C@:4]2([OH:25])[C:2](=[O:3])[CH3:1])[C@H:12]2[C@H:11]1[C@:21]1([CH3:22])[C:15]([CH2:14][CH2:13]2)=[CH:16][C:17](=[O:18])[CH2:19][CH2:20]1)(=[O:28])[CH3:27]
Reactant: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)O[C@H]1C[C@@]2(C)[C@@H](CC[C@]2(O)C(C)=O)[C@@H]2CCC3=CC(=O)CC[C@]3(C)[C@H]21
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
A mixture of 4-pregnene-11β,17α-diol-3,20-dione (2) (2 g), acetic anhydride (10 ml), pyridine (20 ml) and 4-dimethylaminopyridine (20 mg) was stirred for 6 hours at room temperature. The reaction mixture was diluted with water (50 ml) and extracted with chloroform. The chloroform layer was sequentially washed with 10% HCl, a 5% aqueous NaHCO3 solution, and brine, dried over Na2SO4, and concentrated. The residue was subjected to column chromatography (silica gel, 150 g) using 70% chloroform/hexane as eluant, thereby obtaining an acetylated derivative (3) (2.24 g, 100%). Recrystallization from ethyl acetate/hexane afforded white crystals having a melting point of 159.5°-160° C.
Reaction SMILES: C([NH:8][C@H:9]([C:24]([NH:26][C@H:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:28][OH:29])=[O:25])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(OC(C)(C)C)=O.[ClH:36].CCOC(C)=O>CO>[ClH:36].[C:14]([NH:13][CH2:12][CH2:11][CH2:10][C@@H:9]([C:24]([NH:26][C@H:27]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:28][OH:29])=[O:25])[NH2:8])([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)c1ccccc1

Procedure:
Prepared according to the method described in Example 1(b) above from (R)-N2 -(Boc)-N5 -(Cbz)-(S)-N-(2-hydroxy-1-phenylethyl)ornithine amide (3.2 g; 6.6 mmol; from step (a) above), 25 mL of MeOH and 100 mL of HCl/EtOAc, yielding 2.0 g of the sub-title compound as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N([O-])=O.[Na+].[N-:23]=[N+:24]=[N-].[Na+]>>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:10]=[N+:23]=[N-:24])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1cc(N)ccc1Nc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Product: COC(=O)c1cc(N=[N+]=[N-])ccc1Nc1ccccc1

Procedure:
The same procedures as in Example A were repeated except that 10 parts of 2-phenylamino-5-aminobenzoic methyl ester were used as the starting compound, and the aqueous solution of 10% sodium nitrite and the aqueous solution of 10% sodium azide were used in amount of 28 parts and 33.2 parts, respectively, 2-phenylamino-5-azidobenzoic methyl ester having a melting point of 64° to 65° C was obtained at an amount of 9.5 parts.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:28]([Cl:29])=[C:27]([CH3:30])[S:26][C:17]=2[N:18]=[C:19]([C:21]2[O:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[O:25]1[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[C:28]([Cl:29])=[C:27]([CH3:30])[S:26][C:17]=3[N:18]=2)=[CH:22][CH:23]=[N:24]1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3ccno3)nc(NCCc3ccc4c(c3)OCCO4)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-ethylenedioxyphenethylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH:16]2[O:18][CH2:17]2)=[CH:6][CH:7]=1.[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20]>CO>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH:16]([OH:18])[CH2:17][NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:6][CH:7]=1
Reactant: CC(C)(C)N
Reactant: Clc1ccc(-c2ccccc2OCC2CO2)nn1
Solvent: CO
Product: CC(C)(C)NCC(O)COc1ccccc1-c1ccc(Cl)nn1

Procedure:
A mixture of 3-chloro-6-(2-epoxypropoxyphenyl)pyridazine (0.7 g.), methanol (7 ml.) and t-butylamine (1.7 ml.) was stirred and heated under reflux for 1.25 hours. The mixture was evaporated under reduced pressure at 50° and the residue was recrystallized from toluene to give 3-chloro-6-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]pyridazine, m.p. 136.5°-137.5°. A sample of this product was treated with hydrochloric acid (1.0 N, 3.62 ml.), the solution was extracted with dichloromethane and the aqueous solution was evaporated under reduced pressure and the residue was recrystallized from ethanol/ether to give the monohydrochloride salt, m.p. 193.5°-194.5°.