Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:16])=[C:4]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:17]([N:24]1[C@@H:29]([CH3:30])[CH2:28][C:27](=O)[CH2:26][C@H:25]1[CH3:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.C(O)(C(F)(F)F)=O>[CH2:17]([N:24]1[C@H:29]([CH3:30])[CH2:28][CH:27]([NH:1][C:2]2[C:3]([CH3:16])=[C:4]([CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:26][C@H:25]1[CH3:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(N)c1C
Reactant: C[C@@H]1CC(=O)C[C@H](C)N1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(C(F)(F)F)cc(NC2C[C@@H](C)N(Cc3ccccc3)[C@H](C)C2)c1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a stirred solution of methyl 3-amino-2-methyl-5-(trifluoromethyl)benzoate (400 mg, 1.72 mmol) in THF (15 mL) and TFA (491 uL) was added (2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-one (410 mg, 1.89 mmol) at 0° C. The mixture was stirred at 60° C. for 1 hour under nitrogen atmosphere. Then the mixture was cooled to 0° C. in an ice bath, sodium triacetoxyborohydride (765 mg, 3.43 mmol) was added. The reaction mixture was stirred at 23° C. for 2 hours. Then aq. NaHCO3 was added at 0° C. until pH8-9, and the content was extracted with ethylacetate. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH—SiO2; heptane/ethylacetate=3/1) to give the titled compound as a colorless oil. (278 mg, 37% yield). 1H-NMR (400M Hz, CDCl3) δppm; 7.21-7.40 (m, 6H), 6.90 (s, 1H), 3.95 (d, J=14.0 Hz, 1H), 3.90 (s, 3H), 3.60-3.73 (m, 2H), 3.46 (d, J=14.0 Hz, 1H), 3.08-3.12 (m, 1H), 2.98-3.03 (m, 1H), 2.30 (s, 3H), 2.02-2.08 (m, 1H), 1.83-1.88 (m, 1H), 1.52-1.60 (m, 1H), 1.17-1.26 (m, 1H), 1.11 (d, J=6.8 Hz, 3H), 1.13 (d, J=6.4 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:7]=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=1.C(N(CC)CC)C.O>CS(C)=O>[CH:2]([C:3]1[CH:7]=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=1)=[O:1]
Reactant: O=C(Nc1cc(CO)nn1-c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1cc(NC(=O)c2ccccc2)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.5 %

Procedure:
N-[3-(Hydroxymethyl)-1-phenyl-1H-pyrazol-5-yl]benzamide (384 mg) and triethylamine (2 mL) were dissolved in dimethyl sulfoxide (5 mL), and sulfur trioxide•pyridine complex (417 mg) was added at room temperature. After stirring at room temperature for 18 hr, sulfur trioxide•pyridine complex (417 mg) was further added at room temperature and the mixture was stirred for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with 2-propanol to give the title compound as a pale-yellow powder (yield 303 mg, yield 79%).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13]C)[CH:8]=1)=[O:5].[Si](I)(C)(C)C>C(#N)C>[F:1][C:2]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=1)=[O:5]
Reactant: COc1cc(NC(=O)c2cc(OC(F)(F)F)ccc2F)ccn1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: O=C(Nc1cc[nH]c(=O)c1)c1cc(OC(F)(F)F)ccc1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
To 2-fluoro-N-(2-methoxy-4-pyridyl)-5-(trifluoromethoxy)benzamide (5.0 g, 15.23 mmol) in acetonitrile (167.6 mL) was added TMSI (5.6 mL, 39.60 mmol). The reaction was stirred at 50° C. overnight. The acetonitrile was evaporated and the crude re-dissolved in ethyl acetate. The organics were washed with water, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography a gradient of ethyl acetate in hexanes (0-100%) followed by methanol in dichloromethane (0-20%) yielded 2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-5-(trifluoromethoxy)benzamide (3 g, 62%), as a grey solid. ESI-MS m/z calc. 316.05. found 317.1 (M+1)+; Retention time: 1.39 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 7.73 (m, 1H), 7.67 (dd, J=8.7, 3.7 Hz, 1H), 7.55 (t, J=9.1 Hz, 1H), 7.48 (d, J=7.1 Hz, 1H), 6.96 (d, J=2.0 Hz, 1H), 6.55 (dd, J=7.2, 2.1 Hz, 1H) ppm.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[C:10]([O:16][CH3:17])=[CH:9][C:8]=1[CH3:18])=[O:5]>CO.[Pd]>[NH2:13][C:11]1[C:10]([O:16][CH3:17])=[CH:9][C:8]([CH3:18])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][N:2]([CH3:19])[CH3:1])[CH:12]=1
Reactant: COc1cc(C)c(NC(=O)CN(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1cc(C)c(NC(=O)CN(C)C)cc1N
Reaction time: 8 h
Yield: 76.3 %

Procedure:
N2,N2-dimethyl-N1-[2-methyl-4-(methyloxy)-5-nitrophenyl]glycinamide (0.642 mg, 2.4 mmol) was suspended in methanol (20 ml) and Pd/C (65 mg) was added. The reaction vessel was subjected to H2 at 60 psi on a Fisher Porter apparatus. After stirring overnight, the reaction was not complete so more Pd (from a new bottle) was added and the vessel resubjected to H2 at 60 psi on a Fisher Porter apparatus for an additional 18 h. Pd/C was removed from the reaction by filtering through a pad of celite and washing with MeOH. Solvents were removed under reduced pressure and the residue was purified by SiO2 chromatography to afford N1-[5-amino-2-methyl-4-(methyloxy)phenyl]-N2,N2-dimethylglycinamide (435 mg, 1.83 mmol) as a orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.05 (s, 3 H) 2.30 (s, 6 H) 3.00 (s, 2 H) 3.72 (s, 3 H) 4.54 (s, 2 H) 6.62 (s, 1 H) 6.90 (s, 1 H) 8.97 (s, 1 H).
Reaction SMILES: CO.[CH3:3][S:4][C:5]([C:11]1[S:12][C:13]([C:16](OC)([O:23]C)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][CH:15]=1)([CH3:10])[C:6]([O:8][CH3:9])=[O:7].Cl>O>[CH3:3][S:4][C:5]([C:11]1[S:12][C:13]([C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][CH:15]=1)([CH3:10])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C(C)(SC)c1ccc(C(OC)(OC)c2ccccc2)s1
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)C(C)(SC)c1ccc(C(=O)c2ccccc2)s1
Yield: 97.2 %

Procedure:
Methanol (5 ml) and 1 ml of water were added to 887 mg of methyl α-methylthio-α-[5-(α,α-dimethoxybenzyl)-2-thienyl]propionate, and 0.2 ml of conc. hydrochloric acid was added. The mixture was heated under reflux for 1 hour. After cooling, the mixture was concentrated under reduced pressure. The residue was chromatographed on a silica gel column using benzene as an eluent to afford 754 mg of methyl α-methylthio-α-(5-benzoyl-2-thienyl)propionate as an oil in a yield of 97%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[C:4](Br)[CH:3]=1.[Li]CCCC.C([O:23][B:24](OCC(C)C)[O:25]CC(C)C)C(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([B:24]([OH:25])[OH:23])[CH:5]=[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:7]=1
Reactant: CC(C)COc1cc(Br)cc(Br)c1
Reactant: CC(C)COB(OCC(C)C)OCC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)COc1cc(Br)cc(B(O)O)c1
Temperature: -70 °C

Procedure:
1,3-Dibromo-5-isobutoxy-benzene (1. g; 3.3 mmol) was dissolved in dry THF (30 ml) in a dry reaction under stirring. The reaction mixture was cooled to −70° C. and n-BuLi (2M; 2.44 ml) was added. The reaction mixture was stirred for 15 min. and triisobutylborate (1.50 ml; 6.5 mmol) was added at −70° C. The temperature was raised to −30° C. and stirred for 1½ hour followed by a temperature increase to room temperature. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate (about 3 ml) and evaporated to dryness. The crude product was purified by prep HPLC (method B). Yield: 430 mg; 49%. HPLC-MS: m/z: 272.9 (M+); Rt: 2.08 min
Reaction SMILES: COS([O-])(=O)=O.[CH3:7][C:8]1[N:9]=[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]2[C:20]=1[CH2:21][N+](C)(C)C.[CH3:26][C:27]1[NH:28][CH:29]=[CH:30][N:31]=1>C(O)C>[CH3:7][C:8]1[N:9]=[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]2[C:20]=1[CH2:21][C:27]1([CH3:26])[N:31]=[CH:30][CH:29]=[N:28]1
Reactant: Cc1nc2c3ccccc3ccn2c1C[N+](C)(C)C
Reactant: Cc1ncc[nH]1
Agent: COS(=O)(=O)[O-]
Solvent: CCO
Product: Cc1nc2c3ccccc3ccn2c1CC1(C)N=CC=N1
Reaction time: 4 h
Yield: 37.5 %

Procedure:
A mixture of 2-methyl-3-trimethylammoniomethylimidazo[2,1-a]isoquinoline methylsulfate (3 g) and 2-methylimidazole (1.6 g) in ethanol (50 ml) was refluxed with stirring for 4 hours and evaporated in vacuo. To the residue was added water and the resulting precipitates were collected by filtration, dried and recrystallized from ethyl acetate to give 2-methyl-3-(2-methyl-1-imidazolylmethyl)imidazo[2,1-a]isoquinoline (0.85 g).
Reaction SMILES: N[C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([O:10][CH3:11])=[CH:4][N:3]=1.S(=O)(=O)(O)[OH:13].N([O-])=O.[Na+].NC(N)=O>O>[OH:13][C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([O:10][CH3:11])=[CH:4][N:3]=1
Reactant: O=S(=O)(O)O
Reactant: COc1cnc(N)c(OC)n1
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1cnc(O)c(OC)n1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
A solution of 2-amino-3,5-dimethoxypyrazine (0.02 mole) in 300 ml. of 6M sulfuric acid at 0°-5° C. is treated with 0.022 mole sodium nitrite in 25 ml. of water at such a rate to insure that the termperature of the reaction mixture does not rise above 5° C. After standing 45 minutes at 0°-5°C., a little urea is added to destroy excess nitrous acid and the mixture then is treated with sodium hydroxide solution until strongly basic. The reaction mixture is warmed to 60° C. for 1 hour and then brought to pH 8.5. The mixture is concentrated to a third of the original volume and cooled in the refrigerator overnight. The product is separated by filtration and dried in vacuo, recrystallized from a suitable solvent to give 2-hydroxy-3,5-dimethoxypyrazine.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[C:16](O)(=[O:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:16]([O:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])[CH2:4][CH2:3]1)(=[O:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC1CCC(O)CC1
Reactant: CC(=O)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)OC1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.2 %

Procedure:
To a solution of tert-butyl N-(4-hydroxycyclohexyl)carbamate (15 g, 69.67 mmol, 1.00 equiv), acetic acid (16.7 g, 278.09 mmol, 4.00 equiv) and triphenylphosphane (73 g, 278.32 mmol, 4.00 equiv). In tetrahydrofuran (200 mL) was added diethyl azodicarboxylate (48.55 g, 278.78 mmol, 4.00 equiv) dropwise with stiffing at 0° C. The resulting solution was stirred overnight at room temperature and then 200 mL of aqueous sodium bicarbonate solution was added. The resulting mixture was extracted with 3×100 mL of ethyl acetate. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was triturated with 500 mL of a 1:1 mixture of ether and hexane. The solid triphenylphosphine oxide was removed by filtration. The filtrate was concentrated under vacuum and purified on a silica gel column eluted with ethyl acetate/petroleum ether (1:15) to give 3.8 g (21%) of 4-[[(tert-butoxy)carbonyl]amino]cyclohexyl acetate as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N+:13]([O-])=[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]2=[N:10]1.C1(C)C=CC=CC=1.CNC.[H][H]>[C].[Pd].O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]2=[N:10]1
Reactant: Cc1ccc(O)c(-n2nc3ccccc3[n+]2[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: CNC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Yield: 89 %

Procedure:
24.1 g (0.1 mol) of 2-(2'-hydroxy-5'-methylphenyl)benzotriazole-N-oxide, 0.125 g of 5% palladium carbon, 150 ml of a solvent mixture comprising toluene and water (ratio by volume, 4:1) and 7 g of 50% dimethylamine were charged into a 500-ml four neck flask. After the air in the flask had been replaced by nitrogen, the resultant mixture was agitated at room temperature. Hydrogen was then supplemented to allow for the amount of hydrogen absorbed by the mixture, which was then subjected to reaction until no more hydrogen was absorbed by it. After the reaction had been completed, the catalyst was filtered off, and part of the filtrate was subjected to quantitative analysis using gas chromatography (GC). The results revealed a yield of 89% of 2-(2'-hydroxy-5'-methylphenyl)benzotriazole. The solvent was then distilled off from the filtrate, and the residual solid was crystallized using ethanol and then washed with ethanol to obtain 18 g of 2-(2'-hydroxy-5'-methylphenyl) benzotriazole (yield, 80%; melting point, 128° to 130° C.).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:19][S:20][C:21]2[NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[N:22]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][C:11]1([CH2:16][CH2:17][CH3:18])[O:15][CH2:14][CH2:13][O:12]1.ClC1C=CC=C(C(OO)=[O:38])C=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CO>[CH3:1][C:2]1[C:3]([CH2:19][S:20]([C:21]2[NH:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)=[O:38])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][C:11]1([CH2:16][CH2:17][CH3:18])[O:12][CH2:13][CH2:14][O:15]1
Reactant: CCCC1(CCOc2ccnc(CSc3nc4ccccc4[nH]3)c2C)OCCO1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCCO1
Reaction time: 2 h
Yield: 64.3 %

Procedure:
The 2-(((3-methyl-4-(2-(2-propyl-1,3-dioxolan-2-yl)ethoxy)pyridin-2-yl)methyl)thio)-1H-benzimidazole (482 mg, 1.17 mmol) obtained in the step (3f) was dissolved in a solvent mixture of toluene (30 ml) and methanol (3 ml). The mixture was cooled in a nitrogen atmosphere. To this mixture, a methanol solution (1.3 ml) of 3-chloroperbenzoic acid (311 mg, 1.17 mmol as the content was regarded as 65%) was added at an inner temperature of below −70° C. and stirred below −60° C. for 2 hours. To the reaction mixture, an aqueous solution of sodium hydrogen carbonate and ethyl acetate were added. The organic layer was separated and washed with a saturated saline solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in methylene chloride and subjected to silica gel column chromatography using NH silica gel (elution solvent: methylene chloride/methanol=1/0→100/1→100/5) to obtain the title compound (323 mg, yield: 64.3%).
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([Se:14][C:15]#[C:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)[CH:5]=[C:4]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=3)[C:3]1=2.[OH-].[Na+]>>[Br:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][O:27][C:4]2[C:3]3[C:2]([CH3:1])([CH3:36])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=3[CH:7]=[C:6]([Se:14][C:15]#[C:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)[CH:5]=2)=[CH:34][CH:33]=1
Reactant: COC(=O)c1ccc(C#C[Se]c2cc(OCc3ccc(Br)cc3)c3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CCC(C)(C)c2c(OCc3ccc(Br)cc3)cc([Se]C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
In a manner similar to that of Example 1g, by reacting 320 mg (0.5 mmol) of methyl 4-[5,5,8,8-tetramethyl-4-(4-bromobenzyloxy)-5,6,7,8-tetrahydro-2-naphthylselanylethynyl]benzoate with 110 mg of sodium hydroxide. A white crystallized solid is obtained (m=240 mg; yield=66%; m.p.=265° C.).
Reaction SMILES: O=[C:2]1O[C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([O-])=[C:3]1O.C[N:14](CC1C=CC=CC=1)[CH2:15][C:16]#C.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[NH2:14][CH2:15][CH2:16][C:5]1[CH2:7][CH:9]([C:11](=[CH:2][CH:3]=1)[OH:12])[OH:10]
Reactant: C#CCN(C)Cc1ccccc1
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: NCCC1=CC=C(O)C(O)C1

Procedure:
3H-DA was obtained from NEN (Boston, Mass.). Ascorbate, pargyline, BZT, and glucose were obtained from Sigma (St. Louis, Mo.). The ultimagold scintillation fluid was purchased from Packard (Sterling, Va.).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[C:5]([C:18]3[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:25][N:26]([CH3:54])[C:27](=[O:53])[C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)=[O:36])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[OH:24][C:20]1[CH:19]=[C:18]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[N:3]=[C:2]([C:41]2[CH:40]=[CH:39][C:38]([NH:37][C:35](=[O:36])[NH:34][C:31]4[CH:30]=[CH:29][C:28]([C:27]([N:26]([CH3:54])[CH3:25])=[O:53])=[CH:33][CH:32]=4)=[CH:43][CH:42]=2)[N:11]=[C:10]3[N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:23]=[CH:22][CH:21]=1
Reactant: Oc1cccc(-c2cccc3c(N4CCOCC4)nc(Cl)nc23)c1
Reactant: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)c4cccc(-c5cccc(O)c5)c4n3)cc2)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 10.9 %

Procedure:
To a 50 mL round bottom flask, 3-(2-chloro-4-morpholin-4-ylquinazolin-8-yl)-phenol (80 mg, 0.000234 mol), N,N-dimethyl-4-[3-{4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]ureido}-benzamide (114 mg, 0.00028 mol), cesium carbonate (153 mg, 0.00047 mol), DMF (7 mL) and water (1 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (8 mg, 0.0000011 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 2-5% MeOH in chloroform) to yield the title compound [15 mg, 6%]. 1H NMR: (300 MHz, DMSO-d6): δ 9.49 (s, 1H), 9.00 (s, 1H), 8.97 (s, 1H), 8.31 (d, J=8.4 Hz, 2H), 8.00 (d, J=8.4 Hz, 1H), 7.82 (d, J=7.2 Hz, 1H), 7.50-7.59 (m, 5H), 7.29-7.35 (m, 3H), 7.16-7.22 (m, 2H), 6.83 (d, J=8.1 Hz, 1H), 3.83 (m, 8H), 2.97 (s, 6H); LC-MS (ESI): Calculated mass: 588.2; Observed mass: 588.8 [M+H]+ (RT: 0.64 min).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:50])[C@@H:14]([NH:20][C:21]([C:23]2[CH:27]=[C:26]([O:28][CH2:29][C:30]([N:32]3[CH2:36][CH2:35][CH2:34][C@H:33]3[C:37](=[O:43])[NH:38][CH:39]3[CH2:42][CH2:41][CH2:40]3)=[O:31])[N:25]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:24]=2)=[O:22])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:9][CH2:8]1)=[O:6])[CH2:2][CH3:3].[CH2:51](Cl)CCl.CO>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:50])[C@@H:14]([NH:20][C:21]([C:23]2[CH:27]=[C:26]([O:28][CH2:29][C:30]([N:32]3[CH2:36][CH2:35][CH2:34][C@H:33]3[C:37](=[O:43])[NH:38][CH:39]3[CH2:40][CH2:41][CH2:42]3)=[O:31])[N:25]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:24]=2)=[O:22])[CH2:15][CH2:16][C:17]([O:19][CH3:51])=[O:18])[CH2:9][CH2:8]1)=[O:6])[CH2:2][CH3:3]
Reactant: ClCCCl
Reactant: CCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CN(C)C=O
Product: CCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1

Procedure:
To a solution of 150 mg 4-[(S)-4-Carboxy-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid propyl ester in 3 ml DMF were added 42 mg EDC, 27 mg DMAP and 37 μl methanol. After 3 h the reaction mixture was concentrated and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 40 mg MS (ES+): m/e=710.
Reaction SMILES: [C:1]12([OH:13])[CH2:10][C:5]3([OH:11])[CH2:6][CH:7]([CH2:9][C:3]([OH:12])([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16].C12(O)CC3CC(CC(O)(C3)C1)C2.C(Cl)(=O)C=C>>[OH:13][C:1]12[CH2:10][C:5]3([O:11][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])[CH2:6][CH:7]([CH2:9][C:3]([OH:12])([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C=C(C)C(=O)Cl
Reactant: OC12CC3CC(O)(C1)CC(O)(C3)C2
Agent: C=CC(=O)Cl
Agent: OC12CC3CC(C1)CC(O)(C3)C2
Product: C=C(C)C(=O)OC12CC3CC(O)(CC(O)(C3)C1)C2

Procedure:
The title compound was prepared in the same manner as in Production Example 6, except that 1,3,5-adamantanetriol and methacrylic chloride were used instead of 1,3-adamantanediol and acrylic chloride, respectively.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.[CH3:9][C:10]1[N:11]([C:19]2[NH:27][C:26](Cl)=[N:25][C:24]3[C:20]=2[N:21]=[CH:22][N:23]=3)[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2>>[CH3:9][C:10]1[N:11]([C:19]2[N:27]=[C:26]([NH:1][C@H:2]3[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]3)[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Cc1cc2ccccc2n1-c1[nH]c(Cl)nc2ncnc1-2
Reactant: N[C@H]1CC[C@H](N)CC1
Product: Cc1cc2ccccc2n1-c1nc(N[C@H]2CC[C@H](N)CC2)nc2[nH]cnc12
Temperature: 140 °C

Procedure:
The same procedure as in stage 2 of Example 1 is carried out, starting from 684 mg of trans-1,4-diaminocyclohexane and 166 mg of the product obtained in stage 2 above, and the mixture is heated at 140° C. for 6 hours. Purification is carried out on silica with MeOH—NH4OH: 98-2 for eluent, and 51 mg of expected product are thus obtained, in the form of beige-colored crystals.