Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:18][C:19]#[CH:20]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][O:11][C:18]#[C:19][CH3:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC#COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
N-tert-butoxycarbonyl L-serine 12 (25.42 g, 0.1239 mol) was dissolved in DMF (190 mL) and the solution cooled to 0° C. (ice bath). Sodium hydride (60% (w/w) dispersion in mineral oil, 10.90 g, 0.2725 mol) was added over 15 min and the reaction mixture stirred for 1 h at 0° C. 3-Bromopropyne (80% (w/w) solution in toluene, 20.25 g, 0.1362 mol) was added dropwise over 15 min. The reaction mixture was stirred for 1 h at 0° C., after which the ice bath was removed and stirring continued for 3 h 40 min at room temperature. The solvent was evaporated and the residue dissolved in H2O (800 mL). The solution was washed with Et2O (3×350 mL) and acidified to pH 2 by addition of 3 M HCl. The resulting mixture was extracted with EtOAc (5×350 mL). The combined organic extracts were dried with anhydrous MgSO4 and the solvent evaporated affording a yellow/orange viscous oil (30.51 g). A portion of the oil (8.70 g) was purified by flash column chromatography (eluent: EtOAc/hexane/AcOH (23:27:1)). The fractions containing reasonably pure compound by TLC (total volume: 950 mL) were washed with 0.5 M HCl (3×500 mL). The solution was dried with anhydrous MgSO4 and the solvent evaporated affording a pale yellow, viscous oil (6.58 g, corresponds to 23.03 g from the given amounts of starting materials, 77%), with spectral characteristics in accordance with literature data10; 1H NMR (200 MHz, DMSO-d6) δ 12.62 (br s, 1H, COOH), 6.88 (d, J=8.2 Hz, 1H, NH (rotomer 1)), 6.53 (d, J=6.4 Hz, 1H, NH (rotomer 2)), 4.21-4.06 (m, 1H, CαH), 4.13 (d, J=2.4 Hz, 2H, CH2CCH), 3.66 (d, J=5.4 Hz, 2H, CH2), 3.40 (t, J=2.4 Hz, 1H, CCH), 1.38 (s, 9H, (CH3)3); 13C NMR (75 MHz, DMSO-d6) δ 171.8, 155.4, 79.9, 78.3, 77.4, 68.8, 57.7, 53.6, 28.2; HRMS (m/z): [M+Na]+ calcd. for C11H17NO5Na, 266.1004. found, 266.1010; Anal. Calcd. for C11H17NO5: C, 54.31; H, 7.04; N, 5.76. Found: C, 54.7; H, 7.1; N, 5.5.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)=[O:25])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([OH:19])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:43](=[O:50])([O:47][CH2:48][CH3:49])[O:44][CH2:45]Cl>CN(C)C=O>[Cl:1][C:2]1[CH:23]=[C:22]([C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)=[O:25])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([O:19][CH2:45][O:44][C:43]([O:47][CH2:48][CH3:49])=[O:50])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5]
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1
Reactant: CCOC(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)OCOC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 60 °C

Procedure:
A mixture of N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine (Example 303; 1 mmol), potassium carbonate (1.1 mmol), potassium iodide (0.2 mmol), and chloromethyl ethyl carbonate (which is prepared according to Boehme, H. et al. Synthesis 1971, 588-590; 1.1 mmol) in N,N-dimethylformamide (10 mL) is heated at 60° C. for 3 h. The reaction mixture is concentrated to remove N,N-dimethylformamide. Water (50 mL) is added and the mixture is extracted with ethyl acetate (3×50 mL). The combined ethyl acetate layers are washed with brine (100 mL), dried (MgSO4), filtered, evaporated and chromatographed to give N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine, [(ethoxycarbonyl)oxy]methyl ester.
Reaction SMILES: [CH2:1]([C:3]1([C:20]([O:22]CC)=[O:21])[CH:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:11]=32)[CH2:6][CH2:5][CH2:4]1)[CH3:2].[OH-].[K+]>C(O)C>[CH2:1]([C:3]1([C:20]([OH:22])=[O:21])[CH:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:11]=32)[CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: CCOC(=O)C1(CC)CCCN2CCc3c([nH]c4ccccc34)C21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCC1(C(=O)O)CCCN2CCc3c([nH]c4ccccc34)C21
Yield: 66 %

Procedure:
Into a solution of 6.8 g of 1-ethyl-1-ethoxycarbonyl-indolo(2,3-a)quinolizidine (12b-H; 1-C2H5 cis-isomer) obtained in the preceding example (d), in 100 ml of 95% ethanol, there are added 6.8 g of potassium hydroxide. The mixture is refluxed for 12 hours, the solvent evaporated under reduced pressure and the residue taken up in ice water and acidified with HCl to pH=4.5. The precipitated product is separated, washed and dried. 4.1 g of acid are thus obtained.
Reaction SMILES: C(=[N:8][N:9]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH3:16])[C:10]1=[N:17][CH3:18])C1C=CC=CC=1.I.[ClH:20]>O.O.[Cl-]>[NH2:8][N:9]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH3:16])[C:10]1=[N:17][CH3:18].[ClH:20]
Reactant: CCCN1CCN(N=Cc2ccccc2)C1=NC
Agent: Cl
Agent: I
Agent: [Cl-]
Solvent: O
Product: CCCN1CCN(N)C1=NC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.70 g of 1-benzylideneamino-2-methylimino-3-propyl-imidazolidine in the form of a hydroiodide in 20 ml of water H2O with 10 ml of an anion exchange resin in chloride form (Amberlite IRA-400 (Cl)R) is stirred for ca. 3 hours at room temperature, the anion exchange resin is filtrated off and the filtrate obtained is treated with 3.6 ml of 2 M HCl. Benzaldehyde is distilled off from the mixture obtained by steam distillation. From the remaining mixture the solvent is evaporated off. 1-Amino-2-methylimino-3-propyl-imidazolidine in the form of a hydrochloride is obtained in the form of an oil.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH:24]=[CH:25][C:26](=[O:28])[CH3:27]>C(O)C>[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH:24]1[CH2:3][C:2](=[O:1])[CH2:27][C:26](=[O:28])[CH2:25]1
Reactant: CC(=O)C=Cc1cc(F)ccc1F
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CCO
Product: O=C1CC(=O)CC(c2cc(F)ccc2F)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 20% solution of sodium ethoxide in ethanol (27.7 g) was combined at room temperature with diethyl malonate (13.0 g) and then with 4-(2,5-difluorophenyl)-3-buten-2-one (13.8 g) in portions. The reaction mixture was stirred at room temperature for 30 minutes and then heated with stirring for 2 hours. After allowing to stand to cool, the solvent was distilled off, and the residue was combined with water, and the aqueous layer was washed with ethyl acetate and concentrated. 2N Sodium hydroxide (42 ml) was added and the mixture was heated under reflux for 2 hours. After allowing to stand to cool, 2.5 M sulfuric acid (42 ml) was added over a period of 10 minutes, and then the mixture was heated under reflux for 3 hours. After allowing to stand to cool, the precipitated crystal was recovered by a filtration and washed successively with water and isopropyl ether to obtain 5-(2,5-difluorophenyl)cyclohexane-1,3-dione (11.6 g) as a colorless crystal.
Reaction SMILES: [O:1]1[CH2:13][CH:2]1[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>Cl>[C:14]([NH:18][CH2:13][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)N
Reactant: O=Cc1ccc(OCC2CO2)cc1
Agent: Cl
Product: CC(C)(C)NCC(O)COc1ccc(C=O)cc1

Procedure:
To 4-(2,3-epoxypropoxy)benzaldehyde (20 g.) is added tert. butylamine (50 ml.) and the resulting solution is refluxed 17 hours. The excess tert. butylamine is removed by heating at atmospheric pressure to yield a solid residue. To this residue is added 6 N hydrochloric acid (200 ml.) and the resulting mixture is heated 5 hours on a steam bath. The solution is cooled and concentrated to 100 ml. on a steam bath under reduced pressure (20 mm. Hg.). The concentrated solution is made basic to pH 10 with saturated aqueous sodium carbonate and extracted with chloroform. The chloroform extract is concentrated to a solid which after recrystallization from acetonitrile yields 18 g. of 4-(3-tert.butylamino-2-hydroxypropxy)benzaldehyde, m.p. 123°-125.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:20][CH2:21][CH2:22][OH:23])=[C:6]([NH:8][C:9](=O)[CH2:10][NH:11]C(=O)OC(C)(C)C)[CH:7]=1>Cl>[NH2:11][CH2:10][C:9]1[N:20]([CH2:21][CH2:22][OH:23])[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=2[N:8]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1cc(Br)ccc1NCCO
Agent: Cl
Product: NCc1nc2cc(Br)ccc2n1CCO
Yield: 66.2 %

Procedure:
tert-Butyl 2-(5-bromo-2-(2-hydroxyethylamino)phenylamino)-2-oxoethylcarbamate (1.26 g, 3.24 mmol) was stirred in 6 N hydrochloric acid (15 mL) at 120° C. for 2 h and then concentrated. The residue was made basic with methanol/ammonium hydroxide (9:1), re-concentrated and purified by column chromatography eluting with methylene chloride and a 9:1 methanol/ammonium hydroxide mixture; gradient 100% methylene chloride to 85% methylene chloride, to provide the title compound (579 mg, 60%) as a yellow oil: ESI MS m/z 270 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([CH3:12])[CH:8]=[C:9]([NH2:11])[CH:10]=1)=[O:5].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([Cl:21])=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO>[Cl:13][C:14]1[N:19]=[C:18]([NH:11][C:9]2[CH:10]=[C:6]([C:4]([O:3][CH3:2])=[O:5])[N:7]([CH3:12])[CH:8]=2)[C:17]([Cl:21])=[CH:16][N:15]=1
Reactant: COC(=O)c1cc(N)cn1C
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1cc(Nc2nc(Cl)ncc2Cl)cn1C
Temperature: 40 °C

Procedure:
The mixture of 4-amino-1-methyl-pyrrole-2-carboxylic acid methyl ester hydrochloride (95 mg, 0.5 mmol), 2,4,5-trichloropyrimidine (57 μL, 0.5 mmol), and sodium carbonate (106 mg, 1.0 mmol) in 3 mL of EtOH is heated at 40° C. overnight. The precipitate is filtered, washed by cold EtOH, and dried in vacuo to afford methyl 4-(2,5-dichloropyrimidin-4-ylamino)-1-methyl-1H-pyrrole-2-carboxylate; ESMS m/z 301.0 (M+H+).
Reaction SMILES: [CH:1]([C:4]1([CH3:22])[C:8](=[O:9])[NH:7][C:6]([C:10]2[C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=[CH:15][C:11]=2[C:12](O)=[O:13])=[N:5]1)([CH3:3])[CH3:2].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH:1]([C:4]1([CH3:22])[N:5]2[C:12](=[O:13])[C:11]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][O:19][C:18]=4[C:10]=3[C:6]2=[N:7][C:8]1=[O:9])([CH3:3])[CH3:2]
Reactant: CC(C)C1(C)N=C(c2c(C(=O)O)ccc3c2OCO3)NC1=O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC(C)C1(C)C(=O)N=C2c3c(ccc4c3OCO4)C(=O)N21
Reaction time: 8 h

Procedure:
A mixture of 2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-3,4-(methylenedioxy) benzoic acid (4.11 g, 13.5 mmol) and acetic anhydride (100 mL, 1.06 mol) is stirred overnight at reflux temperature and concentrated in vacuo to give a residue which is chased twice with toluene to give a pale yellow solid. Recrystallization from ethyl acetate affords the title product as a pale yellow solid, 2.77 g (69.9%), mp 158°-160° C., identified by NMR spectral analysis.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][C:18]([OH:29])([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)(OC)=[O:2].[NH3:30]>>[NH2:30][C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][C:18]([OH:29])([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)=[O:2]
Reactant: N
Reactant: COC(=O)COc1ccc(CC(C)N2CCOC(O)(c3cccc(Cl)c3)C2)cc1
Product: CC(Cc1ccc(OCC(N)=O)cc1)N1CCOC(O)(c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.03 g. (4.76 mmol) of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)morpholine is dissolved in 20 ml of ammonia-saturated methanol and stirred for 24 hours at ambient temperature. The mixture is then evaporated down and the evaporation residue is purified by column chromatography on silica gel (eluant: ethyl acetate/cyclohexane=3:1).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22](/[C:27](/[CH3:35])=[CH:28]\[CH2:29]OS(C)(=O)=O)[C:21]=1[CH3:36])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]1(=[O:47])[NH:41][C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12.[K].O>CN(C)C=O>[Si:1]([O:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22](/[C:27](/[CH3:35])=[CH:28]\[CH2:29][N:41]2[C:37](=[O:47])[C:38]3=[CH:46][CH:45]=[CH:44][CH:43]=[C:39]3[C:40]2=[O:42])[C:21]=1[CH3:36])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C/C(=C/COS(C)(=O)=O)c1ccc(C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: C/C(=C/CN1C(=O)c2ccccc2C1=O)c1ccc(C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
To a solution of 1-tert-butyldiphenylsilyloxymethyl-2,6-dimethyl-3-((Z)-3-methanesulfonyloxy-1-methyl-1-propenyl)benzene (132 mg) in N,N-dimethylformamide was added potassium phthalimide (55 mg) at ambient temperature under nitrogen atmosphere, and the mixture was stirred at the same temperature overnight. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (n-hexane:ethyl acetate=4:1, V/V) to give 1-tert-butyldiphenylsilyloxymethyl-2,6-dimethyl-3-((Z)-1-methyl-3-phthalimido-1-propenyl)benzene (99 mg) as colorless oil.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([NH:8][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: NCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(NCc2ccccc2)c1
Temperature: 25 °C
Yield: 107.7 %

Procedure:
A solution of benzylamine (0.77 mL, 7.0 mmol), ethyl 3-fluoro-4-nitrobenzoate (1.0 g, 4.7 mmol) and TEA (2 mL) was heated in DMF (10 mL) for 18 hr at 70° C. The solution was cooled to room temperature, diluted with ethyl acetate (200 mL) and washed with H2O (2×100 mL) then 1N HCl (2×100 mL). The organic layer was dried (MgSO4), filtered and then concentrated to provide 1.52 g (˜100%) of crude ethyl 3-(benzylamino)-4-nitrobenzoate as an orange solid. This material was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:30]1(O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Reactant: Oc1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccccc3)c3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and phenol: ESMS m/e: 535.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:26](COCC[Si](C)(C)C)[C:25]4[C:24](=[O:35])[N:23]([CH2:36][CH2:37][CH3:38])[C:22](=[O:39])[N:21]([CH2:40][CH2:41][CH3:42])[C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:7][N:6]1C(OC(C)(C)C)=O)=[O:4]>CO.Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[NH:26][C:25]4[C:24](=[O:35])[N:23]([CH2:36][CH2:37][CH3:38])[C:22](=[O:39])[N:21]([CH2:40][CH2:41][CH3:42])[C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:7][NH:6]1)=[O:4]
Reactant: CCCn1c(=O)c2c(nc(-c3ccc(OCC4CC(C(=O)OC)N(C(=O)OC(C)(C)C)C4)cc3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Agent: Cl
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(-c3ccc(OCC4CNC(C(=O)OC)C4)cc3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-{4-[2,6-Dioxo-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]-phenoxymethyl}-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (100 mg) in methanol (3 ml), methanolic HCl (3 N, 0.5 ml) was added at 0° C., reaction mixture was stirred at room temperature for 2 hrs. The reaction mixture was evaporated and the residue obtained was purified by column chromatography to offer 4-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-phenoxymethyl]-pyrrolidine-2-carboxylic acid methyl ester as a yellow solid (50 mg, 74%).
Reaction SMILES: C(O)C[OH:3].[C:5]([N:9]1[C:14](=[O:15])[C:13]([CH3:16])=[C:12](Cl)[CH:11]=[N:10]1)([CH3:8])([CH3:7])[CH3:6].[OH-].[K+].Cl>O>[C:5]([N:9]1[C:14](=[O:15])[C:13]([CH3:16])=[C:12]([OH:3])[CH:11]=[N:10]1)([CH3:8])([CH3:7])[CH3:6]
Reactant: OCCO
Reactant: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1c(O)cnn(C(C)(C)C)c1=O
Temperature: 130 °C
Reaction time: 4 h

Procedure:
To 30 ml of ethylene glycol were added 20 g (0.01 mol) of 2-t-butyl-5-chloro-4-methyl-3(2H)-pyridazinone and 2.8 g (0.05 mol) of potassium hydroxide and the mixture was stirred at 130° C. for 4 hours. After allowing to cool, the mixture was poured into 200 ml of water and added with 20 ml of 6N hydrochloric acid. The precipitated crystals were gathered by filtration. After drying, the crystals were washed with 30 ml of hot isopropyl ether to obtain 1.7 g of 2-t-butyl-5-hydroxy-4-methyl-3(2H)-pyridazinone, m.p. 236.0°~239.0° C.
Reaction SMILES: [CH:1]([CH:3]([C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4]O)=[CH2:2].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH:1]([CH:3]([C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][N:18]1[C:14](=[O:24])[C:15]2[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17]1=[O:19])=[CH2:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CC(C#Cc1ccccc1)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CC(C#Cc1ccccc1)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.8 %

Procedure:
55 ml of toluene, 1.80 g of 2-vinyl-4-phenyl-3-butyn-ol, 1.93 g of phthalimide, and 3.45 g of triphenylphosphine were added to a nitrogen-substituted flask. Then, 5.30 g of diethyl azodicarboxylate (40% toluene solution) was slowly added dropwise to the above obtained solution under cooling on ice. The temperature was increased to a room temperature, and the obtained mixture was then stirred for 1 day. Thereafter, the reaction solution was concentrated, and 200 ml of diethyl ether was then added to the residue. The appearing solid was removed by filtration. The residue was concentrated, and it was then purified by flash chromatography (manufactured by Biotage AB; Isolera™), so as to obtain 1.00 g of 2-(2-vinyl-4-phenyl-3-butynyl)isoindol-1,3-dione.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH2:14][CH2:15][NH:16][C:17](=O)[CH3:18])[CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].C(Cl)Cl.[OH-].[Na+].[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38]>C(O)C>[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38].[CH3:18][C:17]1[C:11]2[N:10]([C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:21])([F:20])[F:1])=[CH:4][CH:5]=3)=[CH:13][CH:12]=2)[CH2:14][CH2:15][N:16]=1
Reactant: CC(=O)NCCn1cccc1-c1ccc(C(F)(F)F)cc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1=NCCn2c1ccc2-c1ccc(C(F)(F)F)cc1
Reaction time: 1 h
Yield: 76 %

Procedure:
N-[2-[2-[4-(Trifluoromethyl)phenyl]-pyrrol-1-yl]ethyl]acetamide (5.4 g) was treated with 25 ml of phosphorus oxychloride under argon and boiled for 1 hour while stirring. The reaction mixture was hydrolyzed at 0° C. with 100 ml of 2N sodium hydroxide solution and 150 ml of 28% sodium hydroxide methylene chloride (1×300 ml, 2×100 ml). The organic extracts were combined, dried with MgSO4 and freed from solvent. 2.5 g of a total of 5.0 g of crude product was dissolved in a 30-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There was obtained 2.7 g (76%) of 3,4-dihydro-1-methyl-6-[4-(trifluoro-methyl)phenyl]pyrrolo[1,2-a]pyrazine fumarate (1:1); m.pt.: 165°-167° C. (dec.).
Reaction SMILES: [C:1]([OH:9])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].ClCC(OC(=O)CCl)=O.[NH:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1>ClC(Cl)C>[C:1]([C:20]1[NH:19][CH:23]=[CH:22][CH:21]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: c1cc[nH]c1
Reactant: CCCCCCC(=O)O
Agent: O=C(CCl)OC(=O)CCl
Solvent: CC(Cl)Cl
Product: CCCCCCC(=O)c1ccc[nH]1
Temperature: 50 °C
Reaction time: 5.5 h
Yield: 64 %

Procedure:
In 50 ml of dichloroethane were dissolved 6.51 g (0.05 mole) of heptanoic acid and 10.26 g (0.06 mole) of monochloroacetic anhydride. To the resulting solution were added 4.36 g (0.065 mole) of pyrrole and 0.71 g of boron trifluoride-diethyl ether complex and the resulting mixture was then stirred at 50° C. for 5.5 hours. After completion of .the reaction, the reaction solution was cooled and washed successively with water, 5% aqueous sodium carbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 5.74 g of 2-heptanoyl-pyrrole.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][N:7](C(OC(C)(C)C)=O)[CH2:8][CH:4]2[CH2:3][N:2]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].Cl.C([O-])([O-])=O.[K+].[K+].O>C(OCC)(=O)C>[CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: CC(C)(C)OC(=O)N1CC2CN(C(=O)OCc3ccccc3)CC2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CC2CNCC2C1
Yield: 81.2 %

Procedure:
Benzyl tert-butyl tetrahydropyrrolo[3,4-c]pyrrole-2,5(1H, 3H)-dicarboxylate (40 mmol; from step (a) above) was dissolved in ethyl acetate. Ethyl acetate saturated with HCl (g) (500 mL) was added at 0° C. and stirred while reaching room temperature. The solvent was evaporated and the product was dissolved in CH3CN. K2CO3 (4 eq.) and water (2 mL) were added. The mixture was stirred for 2 h, before being filtered and evaporated to give 8 g (82%) of the subtitle compound which was used without further purification in the next step.