Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]([NH:18][C:19](=[O:21])[CH3:20])[CH:11]=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15].C=O.[BH3-][C:25]#N.[Na+]>CC#N.CC(O)=O>[CH3:25][N:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]([NH:18][C:19](=[O:21])[CH3:20])[CH:11]=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15]
Reactant: CC(=O)Nc1ccc(C(F)(F)F)c(OC[C@H]2CCCN2)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(=O)Nc1ccc(C(F)(F)F)c(OC[C@H]2CCCN2C)c1
Reaction time: 1 h

Procedure:
To a solution of (R)-N-[3-(pyrrolidin-2-ylmethoxy)-4-trifluoromethyl-phenyl]-acetamide (0.85 g, 2.81 mmol) in 25 mL CH3CN was added 1.13 mL formaldehyde (37% in H2O) and NaBH3CN (0.28 g, 4.50 mmol). The reaction was stirred for 1 h, and the pH of the reaction was neutralized every 15 min by introducing several drops of AcOH. The reaction was concentrated in vacuo and dissolved into Et2O and 6 N NaOH. The layers were separated, and the organic layer was washed twice with 6N NaOH and extracted with 6 N HCl twice. The acidic aqueous layer was basified with NaOH pellets and extracted 4 times with CH2Cl2. The CH2Cl2 layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to yield the title compound.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]1[O:6][C:7](=[O:21])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:4].Cl[C:23]1[C:24]2[CH:31]=[CH:30][S:29][C:25]=2[N:26]=[CH:27][N:28]=1.C(N(CC)CC)C>CC(O)(C)C>[C:15]1([C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:21])[O:6][C:5]=2[CH:3]([NH:2][C:23]2[C:24]3[CH:31]=[CH:30][S:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH3:4])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(N)c1oc(=O)c2ccccc2c1-c1ccccc1
Reactant: Clc1ncnc2sccc12
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: CC(Nc1ncnc2sccc12)c1oc(=O)c2ccccc2c1-c1ccccc1
Yield: 46.7 %

Procedure:
3-(1-aminoethyl)-4-phenyl-1H-isochromen-1-one hydrochloride (intermediate E2 50 mg, 0.166 mmol), 4-chlorothieno[2,3-d]pyrimidine (36.8 mg, 0.215 mmol), triethylamine (0.046 ml, 0.331 mmol) were reacted in 2-methylpropan-2-ol (1 ml) at 80° C. for 6 hrs and at 50° C. for 60 hrs. 4-Chlorothieno[2,3-d]pyrimidine (5.7 mg, 0.033 mmol), triethylamine (0.09 ml, 0.066 mmol) were added and the mixture reacted at 90° C. for 4 hrs. The crude was purified via reverse phase chromatography with a Biotage C18 30 g SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) to give the title compound (31 mg, 47%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@@H:17]2[O:35][C@H:18]2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][O:37][CH:38]([O:41][CH3:42])[CH2:39][NH2:40].ClCCl>C(O)C>[CH2:28]([O:27][C:21]1[CH:20]=[C:19]([C@H:18]([OH:35])[C@@H:17]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[NH:40][CH2:39][CH:38]([O:41][CH3:42])[O:37][CH3:36])[CH:24]=[CH:23][C:22]=1[O:25][CH3:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1ccc([C@@H]2O[C@H]2c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1
Reactant: COC(CN)OC
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc([C@@H](NCC(OC)OC)[C@@H](O)c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1

Procedure:
Mixture: 187.2 g (0.4 mol) of rel-(S,S)-3,3'-dibenzyloxy-4,4'-dimethoxystilbene oxide, 210 g (2 mol) of aminoacetaldehyde dimethyl acetal, 5 l of dichloromethane, 3 l of ethanol.
Reaction SMILES: [CH2:1]([N:8](C)[CH2:9][CH2:10][C:11]([NH:13][CH2:14][CH2:15][O:16][CH3:17])=[O:12])C1C=CC=CC=1>CO.[Pd]>[CH3:17][O:16][CH2:15][CH2:14][NH:13][C:11](=[O:12])[CH2:10][CH2:9][NH:8][CH3:1]
Reactant: COCCNC(=O)CCN(C)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNCCC(=O)NCCOC
Reaction time: 2 h
Yield: 28.4 %

Procedure:
To a solution of 3-(benzyl(methyl)amino)-N-(2-methoxyethyl)propanamide (1.1 g, 4.39 mmol, 1.00 equiv) in methanol (50 mL) was added 5% palladium-on-carbon (50 mg) and the suspension stirred under a hydrogen atmosphere for 2 h. The solids were filtered out and the mixture was concentrated under vacuum to afford 200 mg (28%) of the product as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[N+:21]([O-])=O)[CH2:12][C@H:11]([CH3:24])[C@H:10]1[O:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[NH2:21][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[C@@H:13]1[CH2:12][C@H:11]([CH3:24])[C@@H:10]([O:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:14]1
Reactant: COC(=O)CCO[C@@H]1[C@@H](C)CC(c2ccncc2[N+](=O)[O-])=C[C@H]1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCO[C@@H]1[C@@H](C)C[C@@H](c2ccncc2N)C[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of (+/−)-methyl 3-((1R,2R,6S)-2-(tert-butoxycarbonylamino)-6-methyl-4-(3-nitropyridin-4-yl)cyclohex-3-enyloxy)propanoate (1.0 equiv.) in degassed EtOH (0.07 M) was added Pd/C (0.3 equiv.). The mixture was purged with H2, and allowed to stir under H2 overnight at RT. The reaction was filtered through a pad of celite and the cake was washed with MeOH. The organics were concentrated and purified by ISCO SiO2 chromatography to yield (+/−)-methyl 3-((1R,2R,4R,6S)-4-(3-aminopyridin-4-yl)-2-(tert-butoxycarbonylamino)-6-methylcyclohexyloxy)propanoate in 100% yield. LC/MS (m/z)=408.2 (MH+), Rt=0.62 min.
Reaction SMILES: C(N(CC)CC)C.S(Cl)(Cl)=O.[CH3:12][C:13]1([CH3:35])[S:17][C@@H:16]2[C@H:18](NC([C@H](N)C3C=CC=CC=3)=O)[C:19](=[O:20])[N:15]2[C@H:14]1[C:32]([OH:34])=[O:33].N1C(=O)C=CN1>ClCCl.Cl>[CH3:12][C:13]1([CH3:35])[S:17][C@@H:16]2[CH2:18][C:19](=[O:20])[N:15]2[C@H:14]1[C:32]([OH:34])=[O:33]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: Cl
Agent: O=c1cc[nH][nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CC1(C)S[C@@H]2CC(=O)N2[C@H]1C(=O)O
Reaction time: 0.5 h
Yield: 11.6 %

Procedure:
The pyrazolinone acid obtained in (b) (0.10 g, 0.46 mmol) in dry dichloromethane (5 ml) was treated with triethylamine (0.10 ml, 0.7 mmol) and the solution cooled to -20° and treated with thionyl chloride(0.040 ml, 0.56 mmol) in dichloromethane (0.5 ml). The solution was then stirred 30 min. at -10°. Anhydrous ampicillin (0.15 g., 0.43 mmol) in dichloromethane (5 ml) was meanwhile separately treated with triethylamine (0.07 ml, 0.5 mmol); the suspension was stirred 20 mins. when further triethylamine (0.06 ml) was added to give a solution. This was cooled to 0° and the above pyrazolinone solution added dropwise. The whole was stirred 90 mins. at room temperature; 1 drop of 5 N HCl was added, the solution concentrated to low volume, ethyl acetate and water were added and the pH of the aqueous layer adjusted to 7.5 with sodium bicarbonate solution. The aqueous layer was separated, acidified to pH 1.5 (5 N HCl) and extracted with ethyl acetate. Drying (Na2SO4) and evaporation of the organic layer gave a crude product which was triturated with ethyl acetate (0.5 ml) to leave the desired title product as the solid free penicillanic acid (10 mg.) δ ((CD3)2CO+D2O) 1.49, 1.55 (2×3H, 2s, (CH3)2), 2.54 (3H, s, CH3 --C=), 4.29 (1H, s, C3 -penicillanic proton), 5.56 (2H, m, C5 and C6 -penicillanic protons), 5.89 (1H, s, --CH--CON--), 7.58 (11 H, complex, aryl and ring NH protons), 8.14 (partially exchanged --C--NH--CO). The free acid was converted to the sodium salt by suspension in water, addition of dilute sodium bicarbonate solution until, on shaking, dissolution occurred at pH 6.5, and freeze-drying.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([Cl:6])=[O:5].Cl.[C:8]([N:11]1[C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[S:13][CH:12]1[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[O:29][CH2:30][CH2:31][CH2:32][N:33]([CH2:37][CH2:38][OH:39])[CH:34]([CH3:36])[CH3:35])(=[O:10])[CH3:9].C(N(CC)CC)C.O>C(Cl)Cl>[ClH:6].[C:8]([N:11]1[C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[S:13][CH:12]1[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[O:29][CH2:30][CH2:31][CH2:32][N:33]([CH:34]([CH3:35])[CH3:36])[CH2:37][CH2:38][O:39][C:4](=[O:5])[CH2:3][O:2][CH3:1])(=[O:10])[CH3:9]
Reactant: COc1ccc(OCCCN(CCO)C(C)C)c(C2Sc3cc(Cl)ccc3N2C(C)=O)c1
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)OCCN(CCCOc1ccc(OC)cc1C1Sc2cc(Cl)ccc2N1C(C)=O)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methoxyacetyl chloride (0.08 ml, 0.87 mmol) was added to a solution of 3-acetyl-6-chloro-2-[2-(3-(N-(2-hydroxyethyl)-N-isopropylamino)propoxy)-5-methoxyphenyl]benzothiazoline hydrochloride (300 mg, 0.58 mmol) in triethylamine (0.41 ml, 2.90 mmol) and methylene chloride (1.0 ml) under ice-cooling. The mixture was stirred at room temperature for two hours, then water (50 ml) was added to the reaction mixture, and the whole was extracted with ethyl acetate (50 ml). The ethyl acetate layer was washed with saturated brine (50 ml) and dehydrated with anhydrous magnesium sulfate. Ethyl acetate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol=50/1). The obtained oily matter was dissolved in ethyl acetate (1 ml), and then a 4 N solution (0.2 ml) of hydrogen chloride in ethyl acetate was added thereto under ice-cooling. The mixture was concentrated under reduced pressure to give 340 mg (quantitatively) of the target compound.
Reaction SMILES: [CH3:1][C@H:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)OC(=O)[NH:3]1.[H][H]>CO.CC(O)=O.[Pd]>[NH2:3][C@@H:2]([CH3:1])[CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@@H]1NC(=O)OC1(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@H](N)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
A suspension of (S)-4-methyl-5,5-diphenyl-2-oxazolidinone (11) (3.52 g, 13.90 mmol) in MeOH/AcOH and a 10% Pd (148 mg, 1.39 mmol) on activated carbon was shaken for 45 h under 4–5 atm pressure of hydrogen at room temperature. The catalyst was filtered off over Hyflo Super Cell and organic solvents were evaporated under reduced pressure. The resulting residue was treated with HCl (2M, 100 ml), stirred overnight at room temperature, made basic with NaOH pellets, and saturated with K2CO3. The organics were then extracted into diethyl ether (3×100 ml), dried over MgSO4/K2CO3 and concentrated under reduced pressure to obtain a crude product. Impurities were washed with AcOEt over silica gel by means of dry-flash column chromatography, and then further elution with a mixture of MeOH and AcOEt, ranging from 5% up to 30%, gave the title compound (12) (1.90 g, 65%) as a white solid. m.p. 76–77° C. [α]D25=−19.32 (c, 0.10765 in CHCl3). δH 1.04 (3H, d, 3J=6.30 Hz, CH3), 1.31 (2H, broad s, NH2), 3.55 (1H, d, J=9.90 Hz, CH—Ph2), 3.73 (1H, dq, 3J=6.30 and 10.20 Hz, CH—NH2), 7.10–7.40 (10H, m, Ar—H). δC 22.4 (CH3), 50.3 (CH—NH2), 62.4 (CH—Ph2), 126.5, 126.8, 128.2, 128.5, 128.7 and 129.0 (o-, m- and p-Ar), 143.3 and 143.7 (α-Ar). Anal. Calcld for C15H17NO: C 85.26; H 8.11; N 6.63. Found: C 85.10; H 8.08; N 6.36. ir 3343 (NH2). m/e (CI—NH3) 212 (MH+, 100%).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C(N(CC)CC)C.[C:29]([Si:35]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])Cl)([CH:32]([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C1(C)C=CC=CC=1>[C:1]([O:5][Si:35]([C:29]([CH:32]([CH3:34])[CH3:33])([CH3:31])[CH3:30])([CH:40]([CH3:41])[CH3:42])[CH:37]([CH3:38])[CH3:39])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Reactant: CC(C)C(C)(C)[Si](Cl)(C(C)C)C(C)C
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)O[Si](C(C)C)(C(C)C)C(C)(C)C(C)C
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 14.4 g (0.2 mol) of acrylic acid, 120 ml of toluene, and 0.06 g of 2,6-di-tert-butyl-4-methylphenol. At room temperature, 22.3 g (0.22 mol) of triethylamine was added dropwise over one hour. At the end of dropwise addition, the flask was heated at 80° C. After the internal temperature became constant, 47.0 g (0.20 mol) of thexyldiisopropylchlorosilane was added dropwise over two hours. After the completion of dropwise addition, the reaction solution was stirred for 5 hours at 80° C. The reaction solution was then cooled to room temperature, and the resulting hydrochloric acid salt removed by filtration. The filtrate was distilled, collecting 38.6 g of a fraction having a boiling point of 87-92° C./0.13 kPa.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:18])[CH:9]=[C:8]([CH3:10])[CH2:7][C:6]([CH3:12])([CH3:11])[CH:5]1[C:13](=[CH2:17])[CH2:14][CH2:15][OH:16].[CH3:19]I>CCCCCC.C1COCC1>[CH3:19][O:16][CH2:15][CH2:14][C:13](=[CH2:17])[CH:5]1[C:6]([CH3:11])([CH3:12])[CH2:7][C:8]([CH3:10])=[CH:9][C:4]1([CH3:18])[CH3:3]
Reactant: CI
Reactant: C=C(CCO)C1C(C)(C)C=C(C)CC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C(CCOC)C1C(C)(C)C=C(C)CC1(C)C
Yield: 465.3 %

Procedure:
Sodium hydride (0.6 g of 60% oil dispersion, 0.015 mol) was washed with hexane (2×3 mL) and suspended in THF (10 mL). A solution of 2,2,4,6,6-pentamethyl-γ-methylene-3-cyclohexene-1-propanol (1.11 g, 0.005 mol) in THF (5 mL) was added, followed by methyl iodide (1.4 g, 0.001 mol). The mixture was heated at reflux for 4 hr. Afterwhich, work-up, chromatography and kugelrohr distillation gave 1.10 g of 2,2,4,6,6-pentamethyl-γ-methylene-3-cyclohexene-1-propanol methyl ether. 1H-NMR (60 MHz, CDCl3) δ0.95 (6H, s), 1.03 (6H, broad s), 1.63 (3H, broad s), 1.5-2.6 (5H, m), 3.33 (3H, s) 3.58 (2H, t, J=7 Hz), 4.85-5.15 (3H, m); IR (film) vmax 2960, 1640, 1440, 1380, 1360 cm-1 ; MS m/e 236, 221, 204, 189, 140, 125, 96.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[CH2:31](Cl)[O:32][CH2:33][CH2:34][O:35][CH3:36]>>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: COCCOCCl
Reactant: COC(=O)c1cccc(O)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Product: COCCOCOc1cccc(C(=O)OC)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 94 %

Procedure:
In the same manner as described in Example 38, 0.40 g (0.937 mmol) of the product of Example 37 and 0.134 mL (1.171 mmol) of MEM-Cl provided 0.454 g (94%) of the desired product as a colorless oil. Electrospray Mass Spec: 516.2 (M+H)+
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[C:15](Cl)(=[O:18])[CH:16]=[CH2:17]>C1COCC1>[C:15]([O:7][CH2:1][CH2:2][O:3][CH2:4][CH2:5][OH:6])(=[O:18])[CH:16]=[CH2:17]
Reactant: OCCOCCO
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCOCCO
Reaction time: 2 h
Yield: 48.9 %

Procedure:
25 g (0.235 mol) of diethylene glycol was dissolved in 150 mL of THF. 18 mL of (0.13 mol) of triethyl amine was added, followed by the dropwise addition of 10.8 g (8 mL, 0.12 mol) of acryloyl chloride. The reaction temperature was kept below 30° C. The reaction was allowed to continue for 2 hours at room temperature. The precipitated triethyl amine hydrochloride was removed by filtration, 100 mg BHT was added and the solvent was removed under reduced pressure. Diethylene glycol monoacrylate was purified on a Prochrom LC80-system, using Kromasil 60A 10 μm spherical silica. Methylene chloride/ethyl acetate 60/40 was used as eluent at a flow rate of 200 mL/min. 10 mg BHT was added before evaporation of the eluent. 9.4 g of diethylene glycol monoacrylate was isolated.
Reaction SMILES: Cl.O1CCOCC1.[C:8]([C:12]([CH2:14][N:15]1[C:21]2[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=2[N:19]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:18][CH:17]([NH:33]C(OC(C)(C)C)=O)[C:16]1=[O:41])=[O:13])([CH3:11])([CH3:10])[CH3:9]>C(O)C>[C:8]([C:12]([CH2:14][N:15]1[C:21]2[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=2[N:19]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:18][CH:17]([NH2:33])[C:16]1=[O:41])=[O:13])([CH3:11])([CH3:9])[CH3:10]
Reactant: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(NC(=O)OC(C)(C)C)CN2C1CCCCC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(N)CN2C1CCCCC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
4N HCl-dioxane (7 ml) was added to a solution of 1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (517 mg) in ethanol (20 ml), the mixture was stirred at 50° C. for one hour. The reaction mixture was concentrated under reduced pressure, neutralized with saturated aqueous sodium bicarbonate, and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography(chloroform:methanol=20:1), to thereby obtain 400 mg of the title compound (Yield: 98%).
Reaction SMILES: C1(C2C=CC=CC=2)C=CC(O)=CC=1.BrCCCCCCCCCO.[C:25]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][OH:41])=[CH:27][CH:26]=1.C1(C2C=CC=CC=2)C=CC(OCCCCCCCCC(O)=O)=CC=1.Cl.Cl.[CH2:74]([O:81][C:82](=[O:90])[CH2:83][C@@H:84]([NH2:89])[CH2:85][N:86]([CH3:88])[CH3:87])[C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1>>[CH2:74]([O:81][C:82](=[O:90])[CH2:83][C@@H:84]([NH:89][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[CH:30][CH:29]=1)[CH2:85][N:86]([CH3:87])[CH3:88])[C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: OCCCCCCCCCOc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: O=C(O)CCCCCCCCOc1ccc(-c2ccccc2)cc1
Agent: OCCCCCCCCCBr
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCOc1ccc(-c2ccccc2)cc1

Procedure:
The title compound, m/e=455.3 ([M+H]+), was produced in analogy with example 18, steps 1 to 4. Thus, biphenyl-4-ol was alkylated in step 1 with 9-bromo-1-nonanol, leading to 9-(biphenyl-4-yloxy)-nonan-1-ol, which was oxidized in step 2 to 9-(biphenyl-4-yloxy)-nonanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-[9-(biphenyl-4-yloxy)-nonanoylamino]-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=[O:20])[CH:11]([C:13]2[N:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH3:12])=[N:6][CH:7]=1.N([C:23]1C=CC=CN=1)N>>[Cl:19][C:16]1[N:15]=[N:14][C:13]([C:11]([CH3:23])([CH3:12])[C:10]([NH:9][NH:8][C:5]2[CH:4]=[CH:3][CH:2]=[CH:7][N:6]=2)=[O:20])=[CH:18][CH:17]=1
Reactant: CC(C(=O)NNc1ccc(Br)cn1)c1ccc(Cl)nn1
Reactant: NNc1ccccn1
Product: CC(C)(C(=O)NNc1ccccn1)c1ccc(Cl)nn1

Procedure:
The title compound was synthesized using an analogous procedure to that described in the preparation of Compound 48C using 2-hydrazinylpyridine.
Reaction SMILES: [NH2:1][C:2]([CH3:12])=[CH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].O[C:14](=[C:17]1C(=O)OC(C)(C)[O:19][C:18]1=O)[CH2:15][CH3:16]>>[C:4]([C:3]1[C:18](=[O:19])[CH:17]=[C:14]([CH2:15][CH3:16])[NH:1][C:2]=1[CH3:12])(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCC(O)=C1C(=O)OC(C)(C)OC1=O
Reactant: CC(N)=CC(=O)c1ccccc1
Product: CCc1cc(=O)c(C(=O)c2ccccc2)c(C)[nH]1
Temperature: 120 °C
Yield: 27.6 %

Procedure:
A mixture of 3-amino-1-phenyl-2-buten-1-one (2.3 g) and 5-(1-hydroxypropylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (4.0 g) was heated at 120° C. for 1 hour. The mixture was cooled to ambient temperature and the residue was purified by flash chromatography eluting with dichloromethane/methanol (19:1 v/v) to give 3-benzoyl-1,4-dihydro-6-ethyl-2-methyl-4-oxopyridine (0.95 g) as a solid, m.p. 203° C.; NMR (d6 -DMSO): 1.2(t, 3H), 2.07(s, 3H), 2.5(q, 2H), 5.96(s, 1H), 7.44-7.50(m, 2H), 7.57-7.60(m, 1H), 7.72-7.76(m, 2H), 11.3(broad s, 1H); mass spectrum (chemical ionisation, ammonia): 242(M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([C:14]1[NH:13][CH:17]=[CH:16][CH:15]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: c1cc[nH]c1
Solvent: Cc1ccccc1
Product: O=C(c1cccc([N+](=O)[O-])c1)c1ccc[nH]1

Procedure:
Alternatively, about 0.5 to 2 molar equivalents of m-nitrobenzoyl chloride (Formula ;b 7 where Z is chloro) (available from Aldrich) is added to pyrrole or an optionally substituted pyrrole (represented by Formula 8, prepared, e.g., as described in Reaction Schemes 1 and 2) dissolved in an inert organic solvent (preferably toluene) and heated, preferably to the reflux temperature of the solvent used, in an inert atmosphere (e.g., under nitrogen). The reaction takes place over a period of about 1 to 30 hours, preferably 10 to 25 hours, and most preferably about 18 hours. The 2-(3'-nitrobenzoyl)pyrrole intermediate of Formula 9 is isolated and purified in the usual manner.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][N:10]2[C:14](=[O:29])[C:15]([CH3:28])([CH2:18][C:19](OC3C=CC=CC=3)=[O:20])[C:16](=[O:17])[N:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:30][OH:31].Cl.NO.[OH-].[K+]>COCCOC.CO>[OH:31][NH:30][C:19]([CH2:18][C:15]1([CH3:28])[C:14](=[O:29])[N:10]2[CH2:11][CH2:12][CH2:13][CH:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[N:9]2[C:16]1=[O:17])=[O:20]
Reactant: CC(C)(C)OC(=O)C1CCCN2C(=O)C(C)(CC(=O)Oc3ccccc3)C(=O)N12
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CO
Product: CC(C)(C)OC(=O)C1CCCN2C(=O)C(C)(CC(=O)NO)C(=O)N12
Reaction time: 18 h

Procedure:
2.2 g of phenyl 5-tert.butoxycarbonyl-hexahydro-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-2-acetate in 12 ml of 1,2-dimethoxyethane were treated with 9 ml of methanolic hydroxylamine (prepared by dissolving 1.38 g of hydroxylamine hydrochloride in methanol, adding 1.12 g of potassium hydroxide pellets in methanol to a total volume of 14 ml and filtering the solution before use). After 18 hours, the solvent was removed, 300 ml of ethyl acetate were added and the mixture was washed with dilute sodium chloride solution followed by saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and evaporated, there being thus obtained an oil which crystallized from ethyl acetate to give 0.98 g of tert.butyl hexahydro-2-[(N-hydroxycarbamoyl)methyl]-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate having a melting point of 157°-165° C. (decomposition).