Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BrH:1].[CH3:2][O:3][CH2:4][C@H:5]([NH:30][C:31]([C:33]1[S:37][C:36]([CH3:38])=[N:35][CH:34]=1)=[O:32])[C:6]([NH:8][C@@H:9]([CH2:27][O:28][CH3:29])[C:10]([NH:12][C@@H:13]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:14]([C@@:16]1([CH3:19])[CH2:18][O:17]1)=[O:15])=[O:11])=[O:7]>O1CCOCC1.C(Cl)Cl>[Br:1][CH2:18][C@:16]([OH:17])([CH3:19])[C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[C@@H:5]([NH:30][C:31]([C:33]1[S:37][C:36]([CH3:38])=[N:35][CH:34]=1)=[O:32])[CH2:4][O:3][CH3:2])[CH2:27][O:28][CH3:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@]1(C)CO1
Reactant: Br
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
Hydrobromic acid (2 eq., 0.314 mL) was added to N—((S)-3-methoxy-1-(((S)-3-methoxy-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide (1.0 g, 1.88 mmol) in dioxane (20 mL) at 0° C., the reaction allowed to warm to room temperature and stirred overnight. The mixture was diluted with DCM, washed with aqueous saturated sodium bicarbonate, brine, dried (Na2SO4) and evaporated. The residue was purified by Biotage flash column chromatography to give product as a white solid (0.722 g, 48%); 1H NMR (CDCl3): δ 8.06(s, 1H), 7.28-7.18 (m, 6H), 7.02 (d, J=7.6 Hz, 1H), 6.85 (d, J=6.4 Hz, 1H), 5.45-5.40 (m, 1H), 4.71-4.66(m, 1H), 4.53-4.48 (m, 1H), 4.20 (s, 1H), 3.85-3.75 (m, 3H), 3.57-3.52 (m, 2H), 3.44-3.39 (m, 4H), 3.31 (s, 3H), 3.23-3.18 (m, 1H), 2.94-2.89 (m, 1H), 2.75 (s, 3H), 1.18 (s, 3H); MS for C25H33BrN4O7S m/z 614 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:8]([NH:9][CH2:10][CH2:11][NH:12][C:13](=O)OCC2C=CC=CC=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#N.Cl.[OH2:24].[CH3:25][OH:26]>>[CH3:13][NH:12][CH2:11][CH2:10][NH:9][C:8]1[C:3]([C:1]([O:26][CH3:25])=[O:24])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O
Reactant: N#Cc1ncccc1NCCNC(=O)OCc1ccccc1
Reactant: CO
Agent: Cl
Product: CNCCNc1cccnc1C(=O)OC

Procedure:
In a manner similar to that described in example 2, benzyl 2-[(2-cyanopyridin-3-yl)amino]ethylcarbamate (11.9 g, 38.3 mmol) was dissolved in MeOH and treated with HCl gas and water to give the ester. The reaction was concentrated, dissolved in MeOH and adsorbed to silica gel. The product was eluted with CHCl3 saturated with NH3, the fractions were collected and evaporated to give the product as a yellow oil that crystallized upon sitting.
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])[CH:6]=1)C.C1COCC1.O.O.[OH-].[Li+].Cl>O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:4]([OH:22])=[O:3])=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=1
Reactant: CCOC(=O)c1cccc(Oc2ccc(F)cc2[N+](=O)[O-])c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(Oc2ccc(F)cc2[N+](=O)[O-])c1
Temperature: 60 °C
Yield: 97.5 %

Procedure:
The product from Example 181a (3.0 g, 9.8 mmol) was added to a solution of THF/H2O (5:1). Lithium hydroxide monohydrate (0.82 g, 19.5 mmol) was added in one portion. The solution was warmed to 60° C. for 2 h. The reaction was cooled. Distilled water was added. The pH was adjusted to 4.0 with 10% HCl. The mixture was extracted with ethyl acetate. The combined organic phases were washed with water, saturated NaHCO3, water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound (2.65 g, 97%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N-:14]=[N+:15]=[N-:16].[Na+]>O1CCCC1.C(O)C.O>[N:14]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:4])=[N+:15]=[N-:16]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=NCC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.33 h

Procedure:
To a mixture of 2-bromo-1-(4-nitro-phenyl)-ethanone (2.0 g, 8.2 mmol) in tetrahydrofuran (15 ml) and ethanol (15 ml) was added a solution of sodium azide (586 mg, 9.8 mmol) in water (1.5 ml). After stirring for 20 minutes, the mixture was concentrated under reduced pressure. The residue was treated with saturated aqueous sodium chloride solution (200 ml) and extracted with ethyl acetate (200 ml). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give crude 2-azido-1-(4-nitrophenyl)-ethanone.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[OH:13][C:14]([CH3:19])([CH3:18])[C:15](O)=[O:16].[C:20]([C:24]1[O:28][C:27]([C:29]2[C:30]([NH2:47])=[N:31][CH:32]=[C:33]([C:35]3[N:39]([CH3:40])[N:38]=[C:37]([CH:41]4[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]4)[N:36]=3)[N:34]=2)=[N:26][N:25]=1)([CH3:23])([CH3:22])[CH3:21].OC1C=CC=C[N+]=1[O-].N1C=CC=CC=1>CN1C(=O)CCC1>[NH2:47][C:30]1[N:31]=[CH:32][C:33]([C:35]2[N:39]([CH3:40])[N:38]=[C:37]([CH:41]3[CH2:46][CH2:45][N:44]([C:15](=[O:16])[C:14]([OH:13])([CH3:19])[CH3:18])[CH2:43][CH2:42]3)[N:36]=2)=[N:34][C:29]=1[C:27]1[O:28][C:24]([C:20]([CH3:23])([CH3:21])[CH3:22])=[N:25][N:26]=1
Reactant: Cn1nc(C2CCNCC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Reactant: CC(C)(O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [O-][n+]1ccccc1O
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: Cn1nc(C2CCN(C(=O)C(C)(C)O)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.2 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol) was added in one portion to 2-hydroxy-2-methylpropanoic acid (38.0 mg, 0.37 mmol), 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(1-methyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine (100 mg, 0.26 mmol) and 2-hydroxy-pyridine N-oxide (57.9 mg, 0.52 mmol) dissolved in NMP (1.2 mL) under argon. The resulting solution was stirred at 25° C. for 3 hours. Pyridine (100 μL, 1.24 mmol) was added and the mixture was stirred for 18 hours. Additional 2-hydroxypyridine 1-oxide (57.9 mg, 0.52 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol) was added. The mixture was then heated up to 70° C. for 48 hours, more 2-hydroxy-2-methylpropanoic acid (15 mg, 0.14 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 2-hydroxypyridine 1-oxide (25.0 mg, 0.23 mmol) were added and the mixture was then kept to 70° C. for 8 hours. The solution was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent to afford the title compound (71 mg, 58%) as a pale yellow solid. 1H NMR Spectrum: (CDCl3) 1.55 (15H, s br), 1.90 (2H, m), 2.15 (2H, m), 3.05-3.3 (4H, m), 4.32 (3H, s), 4.6 (1H, m), 9.03 (1H, s); Mass Spectrum [M+H]+=470.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[CH:11]=[O:12].[F:13][CH:14]([F:23])[O:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-:25].[K+].[K+]>>[F:13][CH:14]([F:23])[O:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[O:22][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[C:11]([OH:12])=[O:25]
Reactant: Oc1cccc(OC(F)F)c1
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(C(F)F)c(C=O)c1Cl
Agent: [K+]
Product: Cn1nc(C(F)F)c(C(=O)O)c1Oc1cccc(OC(F)F)c1

Procedure:
The title compound was prepared using 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde and 3-difluoromethoxyphenol in the manner similar to the method in Production Example 1 above except potassium carbonate was used instead of potassium hydroxide.
Reaction SMILES: [P:1]([O:8]CC)([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[CH:11](N(C(C)C)CC)(C)C.[OH2:20]>>[OH:20][CH2:11][P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4]
Reactant: CCOP(OCC)OCC
Reactant: CCN(C(C)C)C(C)C
Reactant: O
Product: CCOP(=O)(CO)OCC

Procedure:
Reaction Procedure Incorporating Triethyl Phosphite as an Acid/Water Reducer and Using Diisopropylethylamine as a Hindered Amine Catalyst (Controlled Addition/Exotherm)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1(N)CCCCC1.C(OCC)(=O)C>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2cccc(Cl)c2)cc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: NC1CCCCC1
Product: O=C(O)CCC(O)c1ccc(-c2cccc(Cl)c2)cc1
Yield: 65 %

Procedure:
Prepared analogous to Example 25 from 4-(3'-chloro-4-biphenylyl)-4-oxo-butyric acid. Melting point of the cyclohexylamine salt: 160°-161° C. (from ethyl acetate by addition of methanol). Yield: 65% of theory.
Reaction SMILES: CN.[C:3](N1C=CN=C1)([N:5]1C=CN=[CH:6]1)=[O:4].[CH2:15]([C@:17]1([C:42]#[N:43])[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([N:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)=[CH:31][CH:30]=3)[N:23]=2)[C:18]1=[O:41])[CH3:16].O>O1CCCC1>[C:42]([C@@:17]1([CH2:15][CH3:16])[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([N:35]4[CH2:40][CH2:39][N:38]([C:3]([NH:5][CH3:6])=[O:4])[CH2:37][CH2:36]4)=[CH:33][CH:34]=3)[N:23]=2)[C:18]1=[O:41])#[N:43]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC[C@]1(C#N)CCN(c2ccnc(Nc3ccc(N4CCNCC4)cc3)n2)C1=O
Agent: CN
Solvent: O
Solvent: C1CCOC1
Product: CC[C@]1(C#N)CCN(c2ccnc(Nc3ccc(N4CCN(C(=O)NC)CC4)cc3)n2)C1=O
Reaction time: 0.17 h
Yield: 96 %

Procedure:
To a solution of 2 M methylamine in tetrahydrofuran (0.28 mL) were added 1,1′-carbonyldiimidazole (91 mg) and tetrahydrofuran (3.0 mL) in an ice bath, and the mixture was stirred at the same temperature for 10 min. To the reaction mixture was added (3R)-3-ethyl-2-oxo-1-(2-((4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)pyrrolidine-3-carbonitrile (200 mg) obtained in Example 220, and the mixture was stirred at 70° C. for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate). To a solution of the obtained purified product (290 mg) in ethanol (3 mL) was added 1 M hydrochloric acid (0.64 mL), and the mixture was stirred at room temperature for 5 min. The solvent was evaporated under reduced pressure, and the residue was recrystallized (ethanol/diisopropyl ether) to give the title compound (220 mg)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[N:13]=[N:12][C:11]([N:14]([CH2:22][C:23]3([C:27]4[C:32]([F:33])=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:26][CH2:25][CH2:24]3)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:10][CH:9]=2)=[N:5][CH:4]=1.[C:34](O)(=[O:37])[CH2:35][OH:36].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(OCC)(=O)C.CN(C=O)C>[F:33][C:32]1[C:27]([C:23]2([CH2:22][N:14]([C:11]3[N:12]=[N:13][C:8]([C:6]4[S:7][C:3]([CH2:2][NH:1][C:35](=[O:36])[CH2:34][OH:37])=[CH:4][N:5]=4)=[CH:9][CH:10]=3)[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])[CH2:26][CH2:25][CH2:24]2)=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)CO
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(CN)s2)nn1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(CNC(=O)CO)s2)nn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
t-butyl 6-(5-(aminomethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (4.8 g, 10 mmol), glycolic acid (0.9 g, 12 mmol), HOBt (1.6 g, 12 mmol), EDC (2.3 g, 12 mmol), DMF (50 mL), and TEA (5.9 mL) were added to a 250 mL round bottom flask and the reaction was heated to 60° C. and stirred for 1 h. The reaction was poured into ethyl acetate (400 mL), washed with water (3×100 mL), and the combined organic layers were separated, dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (EtOAC/hexanes) to afford 3.9 g of t-butyl (1-(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-(5-((2-hydroxyacetamido)methyl)thiazol-2-yl)pyridazin-3-yl)carbamate as a white solid. This compound was dissolved in 30% TFA/CH2Cl2 (30 mL) and stirred for 1 h. The reaction was concentrated, dissolved in EtOAc (200 mL), washed with potassium carbonate (3×30 mL), concentrated, and then recrystallized with ethanol to give a white solid that was further purified with reverse phase chromatography to give 305 mg of N-((2-(6((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)thiazol-5-yl)methyl)-2-hydroxyacetamide as a white solid (M+H=429.1).
Reaction SMILES: C([CH:4]1[C:16]2[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH2:7][CH2:6][NH:5]1)(=O)C.Cl>[OH-].[Na+].CO.O.C(OCC)C>[CH2:17]([N:15]1[C:16]2[CH2:4][NH:5][CH2:6][CH2:7][C:8]=2[C:9]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)C1NCCc2c1n(Cc1ccccc1)c1ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: c1ccc(Cn2c3c(c4ccccc42)CCNC3)cc1

Procedure:
A portion of the Orude -acetyl 9-benzyl-1,2,3,4-tetrahydro-β-carboline (1.7 g) was heated at reflux for 4.5 hours in 2 N NaOH (50 mL) in methanol:water 2:3, v/v). The methanol was removed by evaporation under vacuum, and the crude 9-benzyl-1,2,3,4-tetrahydro-β-carboline free base was extracted into chloroform. This extract was dried over anhydrous MgSO4, filtered, and the filtrate evaporated under vacuum. The hydrochloride salt was prepared by passing dry HCl through a solution of the crude free base in diethyl ether. The resulting precipitate was filtered and recrystallized from acetonitrile to yield pure 9-benzyl-1,2,3,4-tetrahydro-β-carboline.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.CS(O[CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CS(=O)(=O)OCCCOCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncnc2ccn(CCCOCCOC3CCCCO3)c12
Temperature: 40 °C
Reaction time: 4.5 h
Yield: 84.4 %

Procedure:
4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (203.6 mg), 3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]propyl methanesulfonate (559.3 mg) was dissolved in N,N-dimethylformamide (4 mL), cesium carbonate (1.30 g) was added, and the mixture was stirred at 40° C. for 4.5 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=67:33→20:80) to give the title compound (380.2 mg) as a colorless oil.
Reaction SMILES: [C:1]([O:4][CH2:5]/[CH:6]=[C:7](/[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])C)\[CH3:8])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:8])[CH2:9][CH2:10][CH:11]1[O:23][CH:12]1[CH3:14])(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)OC/C=C(\C)CCC=C(C)C
Solvent: ClCCl
Product: CC(=O)OCC=C(C)CCC1OC1C
Temperature: -20 °C

Procedure:
To a solution of geranyl acetate (1.5 g) in CH2Cl2 (30 ml) is added m-chloroperbenzoic acid (1.3 g) under stirring at -20° C. The mixture is stirred for 90 minutes, at the end of which time it is concentrated under reduced pressure and the residue is dissolved in hexane. The insoluble matter is filtered off, the filtrate evaporated to dryness under reduced pressures and the residue purified by column chromatography on silica gel (30 g) with CCl4 -ethyl acetate (10:1). The above procedure provides a colorless oil of 1-acetoxy-3-methyl-6,7-epoxy-2-octene. A solution of the above product (780 mg) in ether (10 ml) is added to a solution of LiAlH4 (290 mg) in ether (30 ml) under ice-cooling and stirring. The mixture is stirred for 30 minutes, at the end of which time the excess LiAlH4 is decomposed with cold water. To this reaction mixture is added a saturated aqueous solution of sodium hydrogen carbonate (5 ml), the ether layer is separated, and the water layer is extracted with ethyl acetate. The ether layer and the extract are pooled and worked up in the conventional manner. The residue is purified by column chromatography on silica gel (15 g) with CCl4 -acetone (3:1) as the eluent. The procedure yields a colorless oil of 3,7-dimethyl-2-octene-1,7-diol (XI, n=O). 2,3-Dimethoxy-5-methyl-1,4-benzoquinone (336 mg) is reduced with Na2S2O4 (4 g) and the resultant VI (R=H3CO, X=Y=OH) (309 mg) and XI (309 mg) are dissolved in dioxane (10 ml). Under stirring in nitrogen gas stream and at room temperature, a solution of BF3 -ether (1.5 ml) in dioxane (2 ml) is added. The mixture is stirred for 2 hours, whereupon IIId (R=H3CO, X=Y=OH, n=O, m=3) is obtained.
Reaction SMILES: [F:1][C:2]1[C:12]([F:13])=[C:11]([F:14])[CH:10]=[CH:9][C:3]=1[NH:4][C@@H:5]([CH3:8])[CH2:6][OH:7].C(O[CH:18]=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])C>>[F:1][C:2]1[C:12]([F:13])=[C:11]([F:14])[CH:10]=[CH:9][C:3]=1[N:4]([CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C@@H:5]([CH3:8])[CH2:6][OH:7]
Reactant: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CN(c1ccc(F)c(F)c1F)[C@@H](C)CO)C(=O)OCC
Temperature: 100 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To the compound (103 mg) obtained in Example 51 was added diethyl ethoxymethylenemalonate (127 mg). Then the obtained mixture was stirred for 1 hour while heating to 100° C. under atmospheric pressure. Further, it was stirred at the same temperature for 1.5 hour under reduced pressure and then under atmospheric pressure for additional 16 hours. By analyzing reversed phase HPLC with the use of the compound of Example 63 as a specimen, the obtained product corresponded to 142 mg (78%) of the title compound.
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8](=O)[CH:9]([O:11][N:12]1[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]1([CH3:21])[CH3:20])[CH3:10])([CH3:6])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.ClC(OCC)=O>CC(C)=O>[CH3:1][C:2]1([CH3:6])[C:3](=[O:4])[O:5][C:8]([CH:9]([O:11][N:12]2[C:13]([CH3:20])([CH3:21])[CH2:14][CH2:15][CH2:16][C:17]2([CH3:18])[CH3:19])[CH3:10])=[N:7]1
Reactant: CC(ON1C(C)(C)CCCC1(C)C)C(=O)NC(C)(C)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(ON1C(C)(C)CCCC1(C)C)C1=NC(C)(C)C(=O)O1
Reaction time: 2 h
Yield: 63.3 %

Procedure:
To a stirred mixture of 2-methyl-2-[2-(2,2,6,6-tetramethylpiperidin-1-yloxy)-propionylamino]-propionic acid (0.50 g; 0.0016 mol), triethylamine (0.16 g; 0.0016 mol) and acetone (5 ml) there was added ethyl chloroformate (0.17 g; 0.0016 mol). After 2 hours, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was mixed with hexane (5 ml) and the solution was decanted from the precipitated solid. The decanted solution was concentrated under vacuum to give 0.30 g (64% yield) of 4,4-dimethyl-2-[1-(2,2,6,6-tetramethylpiperidin-1-yloxy)-ethyl]-4H-oxazol-5-one (AzTEMPO) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([CH:6]=[C:7]2[C:16]3[N:15]=[C:14]4[CH:17]=[CH:18][C:19]([C:21]([OH:23])=[O:22])=[CH:20][N:13]4[C:12](=[O:24])[C:11]=3[CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].N1C=CC=CC=1>CN(C)C=O>[C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[C:7]2[C:16]3[N:15]=[C:14]4[CH:17]=[CH:18][C:19]([C:21]([OH:23])=[O:22])=[CH:20][N:13]4[C:12](=[O:24])[C:11]=3[CH2:10][CH2:9][CH2:8]2)=[CH:25][CH:26]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C=C2CCCc3c2nc2ccc(C(=O)O)cn2c3=O)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C=C2CCCc3c2nc2ccc(C(=O)O)cn2c3=O)cc1

Procedure:
4-(4-amino-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid (1 g) in dimethylformamide (40 ml) was reacted with acetic anhydride (4 ml) in the presence of pyridine (8 ml) at 60° C. for 7 hours. After cooling and dilution with ice water, the precipitate was filtered and washed with water: crystallization from dimethylformamide-ethanol gave 0.7 g of 4-(4-acetylamino-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([CH:20]1[CH2:24][O:23][CH:22]([OH:25])[CH2:21]1)=[CH:13][CH:12]=3)=[O:5])[CH3:2].[C:26]1(C)C=CC(S(O)(=O)=O)=C[CH:27]=1.C(OCC)(OCC)OCC>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([CH:20]1[CH2:24][O:23][CH:22]([O:25][CH2:26][CH3:27])[CH2:21]1)=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(C4COC(O)C4)cc3c2c1C
Solvent: CCOC(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncc2[nH]c3ccc(C4COC(OCC)C4)cc3c2c1C
Yield: 135.5 %

Procedure:
100 mg (0.29 mmol) of 6-(2-hydroxytetrahydrofuran-4-yl)-4-methyl-β-carboline-3-carboxylic acid ethyl ester is refluxed in 5 ml of toluene with 10 mg of p-toluenesulfonic acid and 52 mg (0.35 mmol) of triethyl orthoformate for 1.5 hours. After concentration, the mixture is chromatographed over silica gel with toluene:glacial acetic acid:water=10:10:1 thus obtaining 29 mg (27% of theory) of 6-(2-ethoxytetrahydrofuran-4-yl)-4-methyl-β-carboline-3-carboxylic acid ethyl ester as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1.[Li+].[OH-].C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(Oc2ccccn2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(Oc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
A mixture of 44b (430 mg, 1.87 mmol), LiOH (180 mg, 7.5 mmol), THF (3 mL), MeOH (3 mL), and H2O (3 mL) was stirred at room temperature for 4 h. Then the reaction mixture was acidified with 15% citric acid (10 mL). The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give 44c (350 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:25][C:10]2[N:11]=[C:6]([CH2:5][C:4]3[CH:17]=[CH:18][CH:19]=[C:2]([F:1])[CH:3]=3)[NH:7][C:8](=[O:16])[C:9]=2[C:14]#[N:15])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CSc1nc(Cc2cccc(F)c2)[nH]c(=O)c1C#N
Reactant: NC1CCCC1
Product: N#Cc1c(NC2CCCC2)nc(Cc2cccc(F)c2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.36 mmol) of 2-(3-fluorobenzyl)-4-(methyl-sulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 309 mg (3.63 mmol) of cyclopentylamine to give 12 mg (11% of theory) of the title compound.