Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)=O.CCOCC.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[OH:2][CH2:3][C:5]12[CH2:14][CH:9]3[CH2:8][CH:7]([CH2:13][CH:11]([CH2:10]3)[CH2:12]1)[CH2:6]2
Reactant: COC(=O)C12CC3CC(CC(C3)C1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCC12CC3CC(CC(C3)C1)C2
Reaction time: 2 h

Procedure:
Methyl-1-adamantanecarboxylate (104 gm.) dissolved in 465 ml. anhydrous ether was added over a 2 hour period to 37.5 gm. lithium aluminum hydride in 753 ml. anhydrous ether. The mixture was stirred an additional 2 hours, cooled and water added gradually. The ether was separated. The water was extracted twice with ether and the combined ether layers dried and concentrated. The residual solid was dissolved in methanol and water was added to precipitate the product which was filtered and dried over P2O5 to give 80 gm., m.p. 113.5°-15.5°.
Reaction SMILES: [CH2:1]([N:5]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[C:8]([O:14][CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:20]([C:22]1[C:23](=[C:33]([C:36]#[N:37])[C:34]#[N:35])[O:24][C:25]([CH3:32])([C:28]([F:31])([F:30])[F:29])[C:26]=1[CH3:27])#[N:21]>C(O)C>[CH2:1]([N:5]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH:27][C:26]2[C:25]([CH3:32])([C:28]([F:31])([F:29])[F:30])[O:24][C:23](=[C:33]([C:36]#[N:37])[C:34]#[N:35])[C:22]=2[C:20]#[N:21])=[C:8]([O:14][CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1ccc(C=O)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC2=C(C#N)C(=C(C#N)C#N)OC2(C)C(F)(F)F)c(OC)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
In 5 ml of ethanol were dissolved 149 mg (0.57 mmol) of 4-dibutylamino-2-methoxybenzaldehyde and 158 mg (0.62 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. After the mixture was stirred at 50° C. for 2 hours, ethanol was evaporated off. The residue was purified by silica gel column chromatography to give 262 mg of a dark brown crystal (yield: 92.9%; mp: 211-213° C.)
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:29][CH2:30][N:31]([CH2:34][CH:35]3[CH2:37][CH2:36]3)[C:32](=[O:33])[C:10]=12)C1C=CC=CC=1.OS(O)(=O)=O.CO.CCCCCC>C(O)(=O)C.ClCCl>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:17]2([CH2:16][C:12]3[N:11]4[CH2:29][CH2:30][N:31]([CH2:34][CH:35]5[CH2:36][CH2:37]5)[C:32](=[O:33])[C:10]4=[C:9]([OH:8])[C:14](=[O:15])[N:13]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:23][CH:24]=1
Reactant: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccc(Cl)cc4)CCCC3)n2CCN1CC1CC1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCCCCC
Product: O=C1c2c(O)c(=O)nc(CC3(c4ccc(Cl)cc4)CCCC3)n2CCN1CC1CC1
Yield: 52.9 %

Procedure:
To a solution of 9-benzyloxy-6-[1-(4-chlorophenyl)-cyclopentylmethyl]-2-cyclopropylmethyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (331) (200 mg, 0.38 mmol) in acetic acid (6.0 mL) was added H2SO4 (0.05 mL) at 0° C. and the reaction mixture was stirred at room temperature for 2 h (TLC; 5% methanol in dichloromethane/UV/SiO2, Rf=0.3). The reaction mixture was quenched with NaHCO3 solution, diluted with water and extracted with ethyl acetate (2×50 mL). The organic part was washed with water (40 mL) and brine (40 mL). The organic phase was thereafter dried and concentrated in vacuo to get a brownish gummy mass which was dissolved in dichloromethane (1 mL). 5 mL of hexane was added to the solution and the solid formed was allowed to settle down. The liquid phase was removed by decantation and the solid was triturated with diethyl ether and n-pentane to get pure 6-[1-(4-chlorophenyl)-cyclopentylmethyl]-2-cyclopropylmethyl-9-hydroxy-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (332) (86 mg, 52%) as a light brown solid.
Reaction SMILES: [C:1]([CH:4]([S:9][CH2:10][C@@H:11]([C:22]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:23])[NH:12][C:13](=[O:21])[CH2:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17])[CH2:5][C:6]([OH:8])=[O:7])([OH:3])=[O:2].C(=O)([O-])[O-].[Ca+2:33].C(=O)=O>O>[Ca:33].[C:1]([CH:4]([S:9][CH2:10][C@@H:11]([C:22]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:23])[NH:12][C:13](=[O:21])[CH2:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17])[CH2:5][C:6]([OH:8])=[O:7])([OH:3])=[O:2]
Reactant: [Ca+2]
Agent: N[C@@H](CCC(=O)N[C@@H](CSC(CC(=O)O)C(=O)O)C(=O)NCC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: O
Product: [Ca]

Procedure:
In 40 ml of water is dissolved 2 g of S-(α,β-dicarboxyethyl)glutathione followed by addition of 1 g of calcium carbonate. The mixture is stirred under warming. When the evolution of carbon dioxide gas has ceased, the excess of calcium carbonate is filtered off and the filtrate is concentrated under reduced pressure. To the concentrate is added ethanol and the resulting white crystals are collected by filtration and recrystallized from water-ethanol. Thus is obtained 2.2 g of the title compound as white powdery crystals.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH3:32])[C:16](=[O:31])[C:17]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[CH:23]=3)=[C:18]([C:20]#[N:21])[N:19]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>CC(=O)OCC>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH3:32])[C:16](=[O:31])[C:17]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[CH:23]=3)=[C:18]([C:20]#[N:21])[N:19]=2)[CH2:10][CH2:9]1
Reactant: COc1ccc(-c2c(C#N)nc(N3CCC(NC(=O)OC(C)(C)C)CC3)n(C)c2=O)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(C#N)nc(N3CCC(N)CC3)n(C)c2=O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.4 %

Procedure:
A mixture of {1-[4-cyano-5-(3-fluoro-4-methoxy-phenyl)-1-methyl-6-oxo-1,6-dihydro-pyrimidin-2-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester (100 mg, 0.23 mmol) in EA (5 mL) was added a 5N HCl solution in EA (5 mL) was stirred at RT for 2 h. The solvent was concentrated in vacuo to give 85 mg of the title product as the HCl salt (93%). 1H NMR (400 MHz, CD3OD): δ 1.71-1.75 (m, 2H), 1.89-2.03 (m, 2H), 2.96-3.02 (m, 2H), 3.27-3.31 (m, 1H), 3.42 (s, 3H), 3.69-3.73 (m, 2H), 3.83 (s, 3H), 7.06 (t, J=8.0 Hz, 1H), 7.17-2.01 (m, 2H). [M+H] Calc'd for C18H20FN5O2, 358. Found, 358.
Reaction SMILES: [NH2:1][C:2]1[S:6][CH:5]=[C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[C:3]=1[C:12]([O:14]CC)=O.[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:18]>Cl.C(O)(=O)C>[O:14]=[C:12]1[NH:18][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:1][C:2]2[S:6][CH:5]=[C:4]([C:7]3[S:8][CH:9]=[CH:10][CH:11]=3)[C:3]1=2
Reactant: CCOC(=O)C#N
Reactant: CCOC(=O)c1c(-c2cccs2)csc1N
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1nc2scc(-c3cccs3)c2c(=O)[nH]1
Temperature: 90 °C
Yield: 88.5 %

Procedure:
Ethyl 5′-amino-2,3′-bithiophene-4′-carboxylate (3.00 g, 11.842 mmol) was suspended in 1N hydrogen chloride-acetic acid solution (30 mL), ethyl cyanoformate (1.29 g, 13.026 mmol) was added, and the mixture was stirred under heating at 90° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, and concentrated under reduced pressure. The residue was suspended in diethyl ether, and the insoluble material was collected by filtration, washed with water to give the title compound as a brown powder (3.21 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][C:3]=1[CH3:21].[F:22][C:23]1[C:28]([C:29](O)=[O:30])=[C:27]([F:32])[CH:26]=[CH:25][N:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:29](=[O:30])[C:28]3[C:27]([F:32])=[CH:26][CH:25]=[N:24][C:23]=3[F:22])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:4][C:3]=1[CH3:21]
Reactant: Cc1cc(-c2cc(N)cnc2OCC(F)(F)F)ccc1Cl
Reactant: O=C(O)c1c(F)ccnc1F
Product: Cc1cc(-c2cc(NC(=O)c3c(F)ccnc3F)cnc2OCC(F)(F)F)ccc1Cl

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-3-methyl-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example 57 a) and 2,4-difluoro-3-pyridinecarboxylic acid (CAN 849937-90-2) as starting materials; MS (EI) 458.2 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[C:20](=[O:21])[N:19]([CH2:22][CH2:23][N:24]5C(=O)C6C(=CC=CC=6)C5=O)[N:18]=[C:17]4[CH2:35][C@@H:36]4[CH2:40][CH2:39][N:38]([C:41]([CH:43]5[CH2:45][CH2:44]5)=[O:42])[CH2:37]4)=[CH:12][CH:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.O.NN.C1(=O)NC(=O)C2=CC=CC=C12>C(O)C>[NH2:24][CH2:23][CH2:22][N:19]1[C:20](=[O:21])[N:16]([C:13]2[CH:14]=[CH:15][C:10]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH:2]=[CH:3][C:4]=4[CH:9]=3)=[CH:11][CH:12]=2)[C:17]([CH2:35][C@@H:36]2[CH2:40][CH2:39][N:38]([C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[CH2:37]2)=[N:18]1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2nn(CCN3C(=O)c4ccccc4C3=O)c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Agent: NN
Agent: O=C1NC(=O)c2ccccc21
Solvent: CCO
Solvent: O
Product: NCCn1nc(C[C@@H]2CCN(C(=O)C3CC3)C2)n(-c2ccc(-c3ccc4occc4c3)cc2)c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a 50 mL round bottom flask containing 2-[2-(4-[4-(1-benzofuran-5-yl)phenyl]-3-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)ethyl]-1H-isoindole-1,3(2H)-dione (130 mg, 0.216 mmol) and ethanol (4 mL) was added hydrazine monohydrate (82 mg, 2.55 mmol, 11 eq). The flask was equipped with a condenser and the reaction was stirred at 60° C. for 1 h. Analysis by LC/MS displayed the phthalimide deprotection was complete. The reaction was cooled to room temperature and concentrated in vacuo. The residue was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 10-45% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions were neutralized with the addition of saturated aq sodium bicarbonate, combined, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (65 mg, 63%). MS(ES)+ m/e 472.2 [M+H]+.
Reaction SMILES: [C:1]1([CH2:10][CH2:11]O)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][OH:9])[CH:2]=1.[BrH:13]>C1(C)C=CC=CC=1>[Br:13][CH2:11][CH2:10][C:1]1[CH:2]=[C:3]([CH2:7][CH2:8][OH:9])[CH:4]=[CH:5][CH:6]=1
Reactant: OCCc1cccc(CCO)c1
Reactant: Br
Solvent: Cc1ccccc1
Product: OCCc1cccc(CCBr)c1
Temperature: 87 °C
Yield: 97.5 %

Procedure:
A suspension of 2,2′-(1,3-phenylene)diethanol (step c) (1.03 kg, 6.22 mol, 1.0 equiv.) in toluene (13.49 L, 15.0 vols) and 48% HBr (1.44 L, 12.75 mol, 2.05 equiv.) was heated at 87° C. for 14 h. Additional 48% w/w HBr (0.35 L 3.11 mol, 0.5 equiv.) was charged and the mixture was stirred at reflux for a further 24 h. The mixture was cooled to ambient and the layers were separated. The organic layer was concentrated to afford 1.39 kg of material. The purification was split into two equal batches of 800 g. The crude meta-bromoalcohol (800 g) was dissolved in DCM (1.6 L, 2 vols w.r.t. the mass of crude material) and charged to a dry pad of silica gel (3.6 kg, 4 wt equiv.). The pad was eluted with 10% IPAc/Heptane (16 L) to remove the fast running impurities then 50% IPAc/Heptane (20 L) to wash off the product. The product containing fractions from each of the silica pads were combined, concentrated at 40-45° C. and then dried to constant weight to afford 1.32 kg (81% Th.) of meta-bromoalcohol as a pale yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH:5]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=1)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH2:16][CH3:17])[C:7]=1[F:18])C.[Li+].[OH-].Cl.C(OCC)(=O)C>C1COCC1>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([NH:19][CH:5]([C:6]2[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH2:16][CH3:17])[C:7]=2[F:18])[C:4]([OH:28])=[O:3])=[CH:21][CH:22]=1)#[N:27]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(OCC)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc(OCC)c(F)c(C(Nc2ccc(C#N)cc2)C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.5 %

Procedure:
The (RS)-(4-cyano-phenylamino)-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid ethyl ester (1.02 g) described in example 2.2 was dissolved in THF. 1 M LiOH (3.96 ml) was added and the mixture was stirred for 2 h at room temperature. 1 M HCl (4 ml) was added. The product was isolated by extraction with ethyl acetate to give 970 mg of (RS)-(4-cyano-phenylamino)-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid which was used for the next step without further purification. MS: 357 ([M−H]−)
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[O:14]CC1C=CC=CC=1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C>[Pd].CO>[C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[OH:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1O
Reaction time: 4 h
Yield: 94.9 %

Procedure:
To a solution of (1R,2R) (2-benzyloxycyclohexyl) carbamic acid tert-butyl ester (7 g, 23 mmoles) in a 9:1 mixture of ethyl acetate and methanol (80 mL), 10% Pd—C (1.13 g) was added and hydrogenated at 35 psi for 4 h. The catalyst was removed by filtration through a celite pad. The filtrate was concentrated to give the title compound as an oil (4.7 g, 95%). MS: (M+1): 215.95
Reaction SMILES: CN(C1C=CC=CC=1)/[CH:3]=[CH:4]/[CH:5]=[CH:6]/[CH:7]=[O:8].[CH2:15]([N:19]([CH2:26][CH2:27][CH2:28][CH3:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:16][CH2:17][CH3:18].P(Cl)(Cl)(Cl)=O>C1COCC1>[CH2:15]([N:19]([CH2:26][CH2:27][CH2:28][CH3:29])[C:20]1[CH:25]=[CH:24][C:23](/[CH:3]=[CH:4]/[CH:5]=[CH:6]/[CH:7]=[O:8])=[CH:22][CH:21]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCN(CCCC)c1ccccc1
Reactant: CN(/C=C/C=C/C=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(/C=C/C=C/C=O)cc1
Temperature: 50 °C
Reaction time: 0.58 h
Yield: 13 %

Procedure:
To a solution of the vinylogous amide 2 (1.135 g, 6.06 mmol) and dibutylaniline (1.43 g) in dry THF (6 ml) at −20° C. was added a solution of phosphorus oxychloride (1.08 g, 1.17 eq.) and dibutylaniline (1.03 g, 1.98 eq. for the sum) in THF (3.6 ml) dropwise at such a rate as to keep the mixture between −10° C. and −20° C. Following the addition, the mixture was stirred at room temperature for 2 hours and at 50° C. for 35 minutes. To the reaction mixture (a dark blue-green oil) was added petroleum ether (25 ml) and the mixture was triturated; the ether was separated and discarded. Methanol (4 ml) was then added and the mixture was neutralized with 2N NaOH. Silicagel was then added, the suspension was diluted with ethyl acetate and methanol and dried to a solid on the rotovap. The crude product was purified by MPLC using hexanes-ethyl acetate 5-30% gradient to give the desired aldehyde as an intense yellow oil (225 mg, 13%). MS (EI): 285 (M+, 45%); 242 (100%); 200 (85%); 128 (30%); 118 (40%). H-NMR (CDCl3): 0.95 (t, J=12 Hz, 6H); 1.35 (m, 4H); 1.45 (m, 4H); 3.8 (t, J=9 Hz, 4H); 6.4, (d, J=17 Hz, 1 H); 6.5-6.8 (m, 3H); 7.1 (d, J=15 Hz,1 H); 7.5 (d, J=17 Hz,1 H); 7.8 (d, J=11 Hzm 2H); 9.8 (s,1 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1>CO.[C].[Pd]>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)/C=C/c1ccc(N)nc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(N)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
Methyl(2E)-3-(6-Aminopyridin-3-yl)acrylate (1.5 g, 8.42 mmol) was dissolved in methanol (15 mL), and 10% palladium-carbon (50% water-containing product, 0.30 g) was added. The mixture was stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 16 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0%-10% methanol/ethyl acetate) to give the title compound (1.26 g, yield 83%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=2[NH2:20])[CH:5]=[C:6]([CH3:8])[CH:7]=1>[Pd](Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:20][C:12]3[C:11]([CH:10]=2)=[CH:16][C:15]([N+:17]([O-:19])=[O:18])=[CH:14][CH:13]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(C#Cc2cc([N+](=O)[O-])ccc2N)c1
Agent: Cl[Pd]Cl
Product: Cc1cc(C)cc(-c2cc3cc([N+](=O)[O-])ccc3[nH]2)c1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a stirred solution of 2-(3,5-dimethylphenylethynyl)-4-nitrophenylamine (50 mg in 3 mL of dry, nitrogen saturated acetonitrile) was added 5 mg of palladium (II) chloride and the mixture heated to reflux on an oil bath. After 3 hours the mixture was cooled to room temperature, concentrated in vacuo and purified by flash chromatography on silica gel (hexane:methylene chloride:ethyl acetate 15:8:1) to provide the title compound (46 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([NH:13][C:14](=[O:25])[C@H:15]([CH3:24])[NH:16]C(OC(C)(C)C)=O)[C:9]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:4][CH:3]=1.[ClH:32]>C(OCC)(=O)C>[ClH:32].[NH2:16][C@H:15]([C:14]([NH:13][C:10]1[C:9]([C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[NH:12][N:11]=1)=[O:25])[CH3:24]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@H](N)C(=O)Nc1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
80 mg of 5-(4-fluorophenyl)-3-(N′-carbo-t-butoxy-L-alanylamino)-4-(4-pyridyl)pyrazole was dissolved in 2 ml of ethyl acetate. Then, 5 ml of a 2.9 mol/L solution of HCl in ethyl acetate was added thereto, followed by stirring at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, the resulting residue was suspended in ethyl acetate. The precipitated powder was collected by filtration to obtain 60 mg (73% yield) of the title compound as a white powder.
Reaction SMILES: C(OC1C(=O)N=C(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)N2CCN(C3CCOCC3)C(=O)C=12)C1C=CC=CC=1.[CH2:43]([N:50]([CH2:84][CH2:85]O)[C:51]([C:53]1[C:58]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[C:57]([OH:67])[N:56]=[C:55]([CH2:68][C:69]2([C:74]3[C:83]4[C:78](=[CH:79][CH:80]=[CH:81][CH:82]=4)[CH:77]=[CH:76][CH:75]=3)[CH2:73][CH2:72][CH2:71][CH2:70]2)[N:54]=1)=[O:52])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[CH2:43]([N:50]1[CH2:84][CH2:85][N:54]2[C:55]([CH2:68][C:69]3([C:74]4[C:83]5[C:78](=[CH:79][CH:80]=[CH:81][CH:82]=5)[CH:77]=[CH:76][CH:75]=4)[CH2:73][CH2:72][CH2:71][CH2:70]3)=[N:56][C:57](=[O:67])[C:58]([O:59][CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[C:53]2[C:51]1=[O:52])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: O=C(c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)Cc1ccccc1
Agent: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4cccc5ccccc45)CCCC3)n2CCN1C1CCOCC1
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4cccc5ccccc45)CCCC3)n2CCN1Cc1ccccc1

Procedure:
This compound was prepared following the same method as described for pure 9-benzyloxy-6-(1-naphthalen-1-yl-cyclopentylmethyl)-2-(tetrahydro-pyran-4-yl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (368) from 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid benzyl-(2-hydroxyethyl)-amide (371) (155 mg, 0.26 mmol). The yield was 122 mg of a mixture of a white sticky solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH:14]=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl.[NH2:17][OH:18]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH:14]=[N:17][OH:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(C=O)o2)cc1
Reactant: NO
Agent: Cl
Solvent: O
Product: COc1ccc(-c2ccc(C=NO)o2)cc1
Reaction time: 1 h

Procedure:
A 250 ml Erlenmeyer flask was charged with 5-(4-methoxyphenyl)-2-furaldehyde (40 g, 0.20 mole) and absolute alcohol (125 ml). A solution of hydroxylamine hydrochloride (14 g, 0.20 mole) in water (25 ml) was added to this suspension. This mixture was stirred for 1 hour, cooled, filtered and washed with isopropanol, yielding 28 g (65.2%).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[O:5].Cl>C(=O)([O-])[O-].[Na+].[Na+]>[O:5]=[C:4]1[C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=2[O:1][CH:7]([C:8]([OH:10])=[O:9])[CH2:6]1
Reactant: O=C(O)C=CC(=O)c1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C1CC(C(=O)O)Oc2ccccc21
Yield: 66.6 %

Procedure:
A solution of 3-(2-hydroxybenzoyl)acrylic acid (3.02 g) in aqueous sodium carbonate (5%, 55 ml) was stirred at room temperature for 15 hours, acidified with 2N HCl and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and then treated with activated charcoal, after which the solvent was distilled off, to yield 2,3-dihydro-4-oxo-4H-1-benzopyran-2-carboxylic acid (2.01 g, 67%), which was then recrystallized from ethyl acetate-hexane to yield colorless prisms having a melting point of 170° to 171° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[S:11][CH2:12][C:13]([O:15]CC)=O>C(O)(=O)C.[Fe]>[Br:1][C:2]1[C:3]2[S:11][CH2:12][C:13](=[O:15])[NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CSc1c(Br)cccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1CSc2c(Br)cccc2N1
Temperature: 90 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
A mixture of ethyl 2-((2-bromo-6-nitrophenyl)thio)acetate (3.64 g, 11.37 mmol) and iron (6.35 g, 114 mmol) in acetic acid (56.8 ml) was stirred at 90° C. for 1.5 h and at room temperature overnight. The mixture was filtered through CELITE®, washed with methanol, followed by hot CHCl3:MeOH:AcOH (1:1:1) till most of the compound came off the CELITE®. The filtrated was concentrated and re-dissolved in EtOAc. The organic solution was washed with water, dried over MgSO4, filtered, and concentrated to afford the title compound (2.59 g, 90% yield). LCMS, [M+H]+=246.0. 1H NMR (400 MHz, DMSO-d6) δ 7.27 (dd, J=8.0, 1.0 Hz, 1H), 7.10 (t, J=8.0 Hz, 1H), 6.97 (dd, J=8.0, 1.0 Hz, 1H), 3.53 (s, 2H).
Reaction SMILES: [C:1]([O:5]O)(C)([CH3:3])[CH3:2].[CH2:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH3:12]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClC(Cl)C>[CH3:2][C:1](=[O:5])[CH2:3][CH2:7][CH2:8][CH3:9].[CH2:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC(C)(C)OO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(Cl)Cl
Solvent: C=CCCCC
Product: CCCCC(C)=O
Reaction time: 4 h

Procedure:
30 cm3 of 80% tert-butyl hydroperoxide (0.225 mole), 10 cc of 1-hexene (0.064 mole), 20 cc of dichloroethane and 220 mg of palladium acetate (0.001 mole) are introduced into a heat-insulated glass reactor. An argon atmosphere is applied and stirring is performed at a temperature of 60° C. After 4 hours, it is found that 66% of 1-hexene were converted and that 2-hexanone was formed with a molar selectivity of 83% with respect to the converted 1-hexene.