Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)/[C:5](/[CH3:20])=[CH:6]/[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[N+:17]([O-])=O)C>[Pd].C(O)C>[CH3:20][CH:5]1[CH2:6][C:7]2[C:8](=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=2)[NH:17][C:4]1=[O:3]
Reactant: CCOC(=O)/C(C)=C/c1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc2c(c1)NC(=O)C(C)C2

Procedure:
Methyl 4-[(1E)-3-ethoxy-2-methyl-3-oxoprop-1-en-1-yl]-3-nitrobenzoate and palladium/carbon were added to ethanol and the whole was stirred under a hydrogen atmosphere to obtain methyl 3-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]([OH:12])[CH2:9][CH:10]=[CH2:11])=[N:6][C:5]([Cl:13])=[C:4]([Cl:14])[N:3]=1.C[C:16](C)=[O:17]>[O-2].[O-2].[Mn+4]>[NH2:1][C:2]1[C:7]([C:8](=[O:12])[CH2:9][CH:10]=[CH:11][CH:16]=[O:17])=[N:6][C:5]([Cl:13])=[C:4]([Cl:14])[N:3]=1
Reactant: CC(C)=O
Reactant: C=CCC(O)c1nc(Cl)c(Cl)nc1N
Agent: [Mn+4]
Agent: [O-2]
Product: Nc1nc(Cl)c(Cl)nc1C(=O)CC=CC=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In 8 ml of acetone there was dissolved 2-amino-5,6-dichloro-3-(1-hydroxy-3-butenyl)pyrazine (120 mg) prepared in Step A above, after which there was added manganese dioxide (480 mg), followed by stirring for 6 hours at room temperature. The manganese dioxide was then filtered, the precipitate washed well with acetone, and the filtrate concentrated. The remaining material was then passed through a silica gel column and eluted with dichloromethane to give the product (23 mg).
Reaction SMILES: C([O-])=O.[NH4+].C([O:12][C:13]1[CH:18]=C(OCC2C=CC=CC=2)[C:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:15][C:14]=1[C:33]1[O:37]N=[C:35]([CH3:38])[C:34]=1[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1)C1C=CC=CC=1.C(OCC)(=O)C.[CH3:53][OH:54]>[Pd]>[OH:54][C:53]1[CH:18]=[C:13]2[C:14]([C:33](=[O:37])[C:34]([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)=[C:35]([CH3:38])[O:12]2)=[CH:15][C:16]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(-c2c(C)noc2-c2cc(-c3ccccc3)c(OCc3ccccc3)cc2OCc2ccccc2)cc1
Reactant: CO
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(C)oc3cc(O)c(-c4ccccc4)cc3c2=O)cc1
Temperature: 60 °C

Procedure:
Ammonium formate (3.2 g, 50 mmol) was added to a solution of 5-(4,6-bis-benzyloxy-biphenyl-3-yl)-4-(4-methoxy-phenyl)-3-methyl-isoxazole (1.4 g, 2.5 mmol) in methanol (20 ml)/ethyl acetate (10 ml) under a nitrogen atmosphere. Palladium on carbon (10%) (cat.) was added and the suspension heated, at 60° C. for ˜18 hrs. The suspension was allowed to cool and ethyl acetate (150 ml) added, and the suspension filtered. The filtrate was washed with water (3×100 ml) and saturated aqueous sodium chloride solution (50 ml). The solution was dried over anhydrous magnesium sulphate and concentrated to give a pale brown gum. Trituration with methanol gave 7-hydroxy-3-(4-methoxy-phenyl)-2-methyl-6-phenyl-chromen-4-one as an off-white solid, dried in vacuo.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1.[N+:18]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1F)([O-:20])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:18]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[O:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1)([O-:20])=[O:19]
Reactant: Cc1ccccc1NC(=O)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccccc1NC(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 90.6 %

Procedure:
0.990 g (4.356 mmol) of 4-hydroxy-2′-methylbenzanilide and 0.811 g (4.358 mmol) of 2,4-dinitrofluorobenzene were dissolved into 20 ml of acetone. The solution was stirred for one hour at reflux temperature after the addition of 0.6 g (4.3 mmol) of potassium carbonate. The reaction solution was filtered and precipitate was thoroughly washed with acetone. Filtrate was concentrated and purified through column chromatography (developing solvent: chloroform) to yield 1.553 g of 4-(2,4-dinitrophenoxy)-2′-methybenzanilide shown in the structural formula 11 above in light yellow solid (Yield: 90.63%).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[C:17]([C:22]([F:25])([F:24])[F:23])=[N:16][N:15]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.O1CCCCC1[O:34][CH2:35][CH2:36][N:37]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[N:38]1.O1CCCCC1OC1CCCCO1.Cl>>[CH:19]([N:18]1[C:17]([C:22]([F:24])([F:25])[F:23])=[N:16][N:15]=[C:14]1[C:8]1[S:9][C:10]2[CH2:11][CH2:12][O:13][C:4]3[CH:3]=[C:2]([C:40]4[CH:39]=[N:38][N:37]([CH2:36][CH2:35][OH:34])[CH:41]=4)[CH:27]=[CH:26][C:5]=3[C:6]=2[N:7]=1)([CH3:21])[CH3:20]
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: CC(C)n1c(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)nnc1C(F)(F)F
Agent: C1CCC(OC2CCCCO2)OC1
Agent: Cl
Product: CC(C)n1c(-c2nc3c(s2)CCOc2cc(-c4cnn(CCO)c4)ccc2-3)nnc1C(F)(F)F

Procedure:
Similarly to as described in General Procedure C, 8-bromo-2-(4-isopropyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. Subsequent to the Suzuki coupling, deprotection of the tetrahydropyranyl ether was accomplished by adding 2N HCl to the crude reaction mixture. Purification by reverse phase HPLC gave 346 as a colorless solid (112 mg). LCMS: 491.1. 1H NMR (400 MHz, DMSO) δ 8.27 (d, J=13.7 Hz, 1H), 8.23 (s, 1H), 7.95 (s, 1H), 7.44 (dd, J=8.3, 1.7 Hz, 1H), 7.32 (d, J=1.7 Hz, 1H), 5.45-5.29 (m, 1H), 4.91 (t, J=5.3 Hz, 1H), 4.41 (t, J=5.0 Hz, 2H), 4.16 (t, J=5.6 Hz, 2H), 3.77 (q, J=5.5 Hz, 2H), 3.48 (t, J=5.0 Hz, 2H), 1.70 (t, J=11.9 Hz, 6H)
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:7]=1[CH2:16][CH2:17][NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21].O>CS(C)=O>[C:1]([CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:7]=1[CH2:16][CH2:17][NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])#[N:2]
Reactant: [C-]#N
Reactant: COc1cc(CCl)c(CCNC(=O)C(F)(F)F)cc1OC
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(CC#N)c(CCNC(=O)C(F)(F)F)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
In a three-necked flask stir, at ambient temperature, a suspension of sodium cyanide (9.8 g, 200 mmoles) in 160 mL of DMSO. Add to the suspension, dropwise, a solution of N-{2-[2-(chloromethyl)-4,5-dimethoxyphenyl]ethyl}-2,2,2-trifluoroacetamide (26 g, 798 mmoles) in 80 mL of DMSO. After being in contact for 1 hour 30 minutes at ambient temperature, hydrolyse the mixture using 300 mL of water and extract the mixture with dichloromethane (3×150 mL). Combine the organic phases and wash them with 10% aqueous solution of NaOAc (150 mL) and saturated aqueous NaCl solution (4×150 mL), then dry them over MgSO4 and carry out drying in vacuo. The product obtained is recrystallised from toluene (66 mL) to obtain 12.8 g of a white powder corresponding to the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].Cl[Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17]>O1CCCC1>[CH3:1][C:2]1[N:3]([Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc[nH]c1C
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccn([Si](C(C)C)(C(C)C)C(C)C)c1C
Yield: 91.5 %

Procedure:
Ethyl 2-methyl-1H-pyrrole-3-carboxylate (1 g, 6.53 mmol) in tetrahydrofuran (15 mL) at 0° C. was treated with sodium hydride (60% oil dispersion, 0.39 g, 9.8 mmol), stirred for twenty minutes, and then treated with chlorotriisopropylsilane (1.676 mL, 7.83 mmol). The reaction mixture was stirred for three hours and allowed to reach ambient temperature. The reaction mixture was partitioned between ethyl acetate and water, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 1-8% ethyl acetate in hexanes) to give 1.85 g (91%) of the title compound.
Reaction SMILES: CC1C=CC(S([CH:11]([N+:20]#[C-:21])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)(=O)=O)=CC=1.[CH3:22][S:23][C:24]1[C:25]2[CH:32]=[C:31]([CH:33]=[N:34][CH3:35])[S:30][C:26]=2[N:27]=[CH:28][N:29]=1.COC1C=C(C=CC=1OC)CN=CC1SC2N=CN=CC=2C=1>>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]2[N:20]=[CH:21][N:34]([CH3:35])[C:33]=2[C:31]2[S:30][C:26]3[N:27]=[CH:28][N:29]=[C:24]([S:23][CH3:22])[C:25]=3[CH:32]=2)=[CH:17][CH:16]=1
Reactant: CN=Cc1cc2c(SC)ncnc2s1
Reactant: [C-]#[N+]C(c1ccc(OC)cc1)S(=O)(=O)c1ccc(C)cc1
Agent: COc1ccc(CN=Cc2cc3cncnc3s2)cc1OC
Product: COc1ccc(-c2ncn(C)c2-c2cc3c(SC)ncnc3s2)cc1
Yield: 39 %

Procedure:
The title compound was prepared by a similar process to that described for Example 6 but using isocyano(4-methoxyphenyl)methyl 4-methylphenyl sulfone (Intermediate 104) in place of PhTosMIC and N-[4-(methylthio)thieno[2,3-d]pyrimidin-6-ylmethylidene]methanamine (intermediate 16) in place of N-(3,4-dimethoxybenzyl)-N-[thieno[2,3-d]pyrimidin-6-ylmethylidene]amine (intermediate 14) to afford the title compound as a solid (2.69 g, 39%);
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[NH:10][C:6]=2[CH:5]=[C:4]([C:14]([OH:16])=[O:15])[CH:3]=1.Cl.[CH3:18]O>>[CH3:18][O:15][C:14]([C:4]1[CH:3]=[C:2]([CH3:1])[C:7]2[N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[NH:10][C:6]=2[CH:5]=1)=[O:16]
Reactant: CCCc1nc2c(C)cc(C(=O)O)cc2[nH]1
Reactant: CO
Agent: Cl
Product: CCCc1nc2c(C)cc(C(=O)OC)cc2[nH]1

Procedure:
7-Methyl-2-propyl-3H-benzoimidazole-5-carboxylic acid (30.0 g, 137 mmol) was dissolved in MeOH (550 mL) and added to a round bottom flask, followed by the addition of 20 mL of a hydrogen chloride solution (30:70, conc. HCl:water). The mixture was refluxed for 12 hours then concentrated under reduced pressure to afford the title compound as a yellow solid (31.8 g, 137 mmol). MS m/z: [M+H+] calcd for C13H16N2O2, 233.12. found 233.2.
Reaction SMILES: S(=O)(=O)(O)O.C([O:8][C:9]([C:11]1[C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][C:14]([CH2:22][CH3:23])=[CH:13][N:12]=1)=[O:10])C.[CH:24]1(C(O)=O)[CH2:26][CH2:25]1.C(=O)=O>O.[N+]([O-])([O-])=O.[Ag+]>[CH2:22]([C:14]1[CH:15]=[C:16]([C:17]([OH:19])=[O:18])[C:11]([C:9]([OH:8])=[O:10])=[N:12][C:13]=1[CH:24]1[CH2:26][CH2:25]1)[CH3:23]
Reactant: O=C(O)C1CC1
Reactant: CCOC(=O)c1cc(CC)cnc1C(=O)OCC
Agent: [Ag+]
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCc1cc(C(=O)O)c(C(=O)O)nc1C1CC1
Yield: 42.7 %

Procedure:
There is added to a solution of 32 ml of concentrated sulphuric acid and 6.8 g of silver nitrate (AgNO3) in 400 ml of water first of all 50 g of 5-ethylpyridine-2,3-dicarboxylic acid diethyl ester and, when a homogeneous solution has been obtained, 25.8 g of cyclopropanecarboxylic acid. The solution is then heated to 70° and a solution of 68.2 g of ammonium peroxydisulphate (NH4)2S2O8 is added dropwise thereto while stirring vigorously. When the evolution of CO2 has ceased, the reaction mixture is stirred for a further 20 minutes, then cooled to 15° and extracted twice with 200 ml of methylene chloride each time. The methylene chloride extract is dried over magnesium sulphate, filtered and concentrated. The oily residue is purified by chromatography over a column of silica gel using ether/hexane 1:1. Evaporation of the solvent yields 20 g of 5-ethyl-6-cyclopropyl-pyridine-2,3-dicarboxylic acid in the form of a yellow oil.
Reaction SMILES: C([NH:8][C:9]1[C:18]([F:19])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([Br:20])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd].CO>[NH2:8][C:9]1[C:18]([F:19])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([Br:20])[CH:10]=1
Reactant: [H][H]
Reactant: COC(=O)c1cc(F)c(NCc2ccccc2)cc1Br
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(F)c(N)cc1Br
Yield: 73.8 %

Procedure:
A suspension of the methyl 4-(benzylamino)-2-bromo-5-fluorobenzoate (2.4 g, 7.10 mmol) in acetic acid was treated with 10% palladium on charcoal (250 mg) and stirred at room temperature under 2 bar hydrogen for 18 hours. The reaction mixture was then diluted with methanol, filtered through celite and evaporated to low volume. The residue was suspended in water (50 mL) and basified with 5% sodium carbonate solution then was extracted with ethyl acetate (2×). The combined organic phases were dried (sodium sulfate) and evaporated to a sandy solid. This crude solid was dissolved in the methanol and passed down an SCX cartridge. Evaporation of the methanol eluents gave the title compound (1.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1.[CH:14](OCC)=[O:15]>>[OH:15][CH:14]=[C:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]1=[O:13]
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: CCOC=O
Product: COc1ccc2c(c1)C(=O)C(=CO)CC2

Procedure:
The expected product is prepared from 7-methoxy-1-tetralone and ethyl formate according to the procedure described in Organic Synthesis 1959, 39, 27.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Mg+].[Br-].[CH3:17]COCC.[NH4+].[Cl-]>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH3:17])([OH:13])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC1(O)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
A stirred solution of 1-benzyl-3-pyrrolidinone (8.36 g, 47.7 mmol) in dry THF (100 mL) was cooled to −70° C. and 3 M MeMgBr in ether (30 mL, 90 mmol) was added over 5 min. The cooling bath was allowed to expire and the mixture was stirred overnight at rt. The mixture was poured into satd aq NH4Cl (300 mL) and extracted with ether (3×100 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4 and concentrated to leave 1-benzyl-3-methylpyrrolidin-3-ol (8.98 g) as an oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:57][CH3:58])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH:34]=[CH:35][CH:36]=2)[C:16]([N:18]([CH2:20][CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][C@H:23]2[C:27]([O:29]C(C)(C)C)=[O:28])[CH3:19])=[O:17])=[O:12])=[C:6]([C:37]2[CH:42]=[C:41]([C:43](=[O:56])[NH:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:55])([F:54])[F:53])[CH:47]=3)[CH:40]=[CH:39][N:38]=2)[CH:5]=1)[CH3:2].Cl>C(Cl)Cl.O1CCOCC1>[CH2:57]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH:34]=[CH:35][CH:36]=2)[C:16]([N:18]([CH2:20][CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][C@H:23]2[C:27]([OH:29])=[O:28])[CH3:19])=[O:17])=[O:12])=[C:6]([C:37]2[CH:42]=[C:41]([C:43](=[O:56])[NH:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:55])([F:53])[F:54])[CH:47]=3)[CH:40]=[CH:39][N:38]=2)[CH:5]=1)[CH3:58]
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCC[C@H]3C(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCC[C@H]3C(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of (S)-tert-butyl 1-(2-(3-((4-(diethylamino)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)-N-methylbenzamido)ethyl)pyrrolidine-2-carboxylate in DCM (3 mL) was added 4M HCl in dioxane (40 mL). The mixture was stirred at room temperature for 3 h and concentrated to give a yellow solid, which was used without further purification.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.[NH:9]1[C:18](=[O:19])[C:17]2[NH:16][CH:15]=[N:14][C:13]=2[N:12]=[C:10]1[NH2:11].C(OC[O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][C:32](=O)C1C=CC=CC=1)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[OH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][N:14]1[CH:15]=[N:16][C:17]2[C:18](=[O:19])[NH:9][C:10]([NH2:11])=[N:12][C:13]1=2
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: CC(=O)OCOCCOCCOC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: Nc1nc2c(ncn2COCCOCCO)c(=O)[nH]1
Temperature: 120 °C
Reaction time: 18 h
Yield: 6.2 %

Procedure:
A mixture of guanine diacetate (1.31 g), 2-(2-benzoyloxyethoxy)ethoxymethyl acetate (2.37 g), p-toluenesulfonic acid (32 mg) and mineral oil (5.2 g) was heated at 120° C. with stirring for 18 hours. The reaction mixture was cooled and the mineral oil decanted off. The residue was triturated with benzene and the benzene decanted off. To the residue was added 40% aqueous methylamine (10 ml), and the mixture was heated in a steam bath for 30 minutes. The water and methylamine were removed under reduced pressure and the residue extracted with hot ethanol. The ethanol-insoluble material was dissolved in boiling methanol, filtered, concentrated to 125 ml and cooled to room temperature, precipitating an impure product (166 mg) which was unmoved by filtration. The filtrate was chilled and 9-[2-(2-hydroxyethoxy)ethoxymethyl]guanine (80 mg, m.p. 184°-187° C.) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:21][CH2:22][CH2:23][OH:24]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([NH:21][CH2:22][CH2:23][OH:24])=[O:15])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(Br)cc1
Reactant: NCCO
Product: COc1ccc(C(=O)NCCO)cc1/C=C/c1ccc(Br)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-bromophenyl)vinyl]benzoic acid obtained in step B of Example 2-2-43 and 2-aminoethanol in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([N:13]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])[CH2:10][CH:9]1[C:29]([OH:31])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[C:42]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)#[N:43].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCN(CC)CC>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([N:13]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]([O:16][CH2:17][C:18]([Cl:19])([Cl:21])[Cl:20])=[O:15])[CH2:10][CH:9]1[C:29]([N:53]1[CH2:52][CH2:51][N:50]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[C:42]#[N:43])[CH2:55][CH2:54]1)=[O:31])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC(N(Cc2ccccc2)C(=O)OCC(Cl)(Cl)Cl)CC1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(N(Cc2ccccc2)C(=O)OCC(Cl)(Cl)Cl)CC1C(=O)N1CCN(c2ccccc2C#N)CC1
Reaction time: 8 h

Procedure:
To a solution of 4-[(benzyl)-(2,2,2-trichloro-ethoxycarbonyl)-amino]-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester, HOBt, 1-(2-cyanophenyl)piperazine in DCM are added Et3N and EDC.HCl. The mixture is stirred overnight, then washed with citric acid, Na2CO3, brine, dried and concentrated to give 2-[4-(2-cyano-phenyl)-piperazine-1-carbonyl]-4-[(benzyl)-(2,2,2-trichloroethoxycarbonyl)-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester (21)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:10]([CH3:11])=[CH:9][C:8](=[O:12])[C:7]([C:13]([OH:15])=[O:14])=[CH:6]1.[I:16]N1C(=O)CCC1=O>C(O)(C(F)(F)F)=O.ClCCl.O>[I:16][C:9]1[C:8](=[O:12])[C:7]([C:13]([OH:15])=[O:14])=[CH:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:10]=1[CH3:11]
Reactant: O=C1CCC(=O)N1I
Reactant: COCCn1cc(C(=O)O)c(=O)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COCCn1cc(C(=O)O)c(=O)c(I)c1C

Procedure:
A solution 1-(2-methoxy-ethyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (150 mg, 0.71 mmol) and N-iodosuccinimide (200 mg, 0.89 mmol) in TFA (1 mL) and dichloromethane (1 mL) is stirred for 5 days at room temperature. The reaction mixture is diluted with water and extracted with dichloromethane. The organic layer is evaporate under reduced pressure. ESI mass spectrum: [M+H]+=338; Retention time HPLC: 0.95 min (Z002_005).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH2:18][CH:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][N:15]=3)=[CH:10][CH:9]=2)=[CH:4][CH2:3]1.CC1(C)[O:31][C@H:30]([C:32](Cl)=O)[CH2:29][O:28]1>>[OH:31][C@H:30]([CH2:29][OH:28])[CH2:32][N:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH2:18][CH:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][N:15]=3)=[CH:10][CH:9]=2)=[CH:4][CH2:3]1
Reactant: CC1(C)OC[C@@H](C(=O)Cl)O1
Reactant: C1=C(c2ccc(C3=NOC(COc4ccon4)C3)cc2)CCNC1
Agent: Cl
Product: OC[C@@H](O)CN1CC=C(c2ccc(C3=NOC(COc4ccon4)C3)cc2)CC1

Procedure:
(5RS)-3-(4-(1,2,5,6-Tetrahydropyrid-4-yl)phenyl)-5-isoxazol-3-yloxymethyl-4,5-dihydro-isoxazole hydrochloride (300 mg, 0.83 mM) was treated with (4S)-2,2-dimethyl-1,3-dioxolan-4-ylcarbonyl chloride under essentially the conditions of Example 2. Crude product was chromatographed on a 20 g silica Mega Bond Elut® column, eluting with 5% methanol in dichloromethane. Relevant fractions were combined to give the desired product (43 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2occc2n1
Solvent: CO
Product: Clc1nc(N2CCOCC2)c2occc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
2,4-Dichlorofuro[3,2-d]pyrimidine 37 (23 mg, 1.0 eq) was suspended in methanol (1.7 ml) and treated with morpholine (0.09 ml, 4.0 eq). Reaction mixture was stirred at room temperature for 2 h, before being quenched with saturated aq. NaHCO3. Mixture was extracted with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated to yield 2-chloro-4-morpholinofuro[3,2-d]pyrimidine 38 (14 mg, 48%) which was used in the next reaction without further purification.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[CH2:17]([OH:20])[CH:18]=[CH2:19]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl[Pd]Cl.CN(C=O)C>[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:19][CH2:18][CH:17]=[O:20])=[CH:3][CH:4]=1)(=[O:11])[CH3:10]
Reactant: C=CCO
Reactant: CC(=O)Nc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(CCC=O)cc1
Reaction time: 0.17 h
Yield: 23.9 %

Procedure:
To a mixture of N-(4-Iodophenyl)acetamide (10.8 g, 42 mmol, 1.0 equiv) and DMF (50.0 ml) were added tetrabutylammonium chloride (11.7 g, 42 mmol, 1.0 equiv), NaHCO3 (8.7 g, 105 mmol), and allyl alcohol (4.2 ml, 63 mmol, 1.5 equiv) and the mixture was stirred for 10 min. To the resulting mixture PdCl2 (1.21 g, 9.6 mmol, 0.23 equiv) was added and the mixture was stirred under nitrogen for 45 h. The resulting mixture was extracted with EtOAc (3×100 ml). The combined extracts were washed with 5% HCl, brine, dried over MgSO4 and concentrated under vacuum. The residue was purified by column chromatography (EtOAc:hexane 70:30) to give 3-(4′-Acetamidophenyl)-1-propanal (1.92 g, 23.1%) which was used as such in the next step.