Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([O:11]COCCOC)=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[C:7]([C:22]([NH:24][NH2:25])=[O:23])[N:6]=1)([CH3:4])[CH3:3].[OH-].[K+].[C:28](=[S:30])=S>CO>[CH3:4][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:18]([CH3:20])([CH3:19])[CH3:21])[N:8]=[C:7]([C:22]2[O:23][C:28](=[S:30])[NH:25][N:24]=2)[N:6]=1)([CH3:1])[CH3:3]
Reactant: COCCOCOc1c(C(C)(C)C)nc(C(=O)NN)nc1C(C)(C)C
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1nc(-c2n[nH]c(=S)o2)nc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.9 %

Procedure:
4,6-Bis(1,1-dimethylethyl)-5-[(2-methoxyethoxy)methoxy]-2-pyrimidine carboxylic acid hydrazide (0.9 g, 2.5 moles), KOH (0.16 g, 2.8 moles), and carbon disulfide (0.44 g, 5.8 mmoles) are dissolved in 20 mL of MeOH. The reaction mixture is warmed to reflux under argon for 24 hours. It is cooled to room temperature, quenched with 150 mL of 10% HOAc/H2O, and extracted with ether (3×100 mL). The ether extract is washed with brine (3×100 mL) and evaporated. The oil remaining is taken up in 20 mL of TFA and stirred at room temperature for 30 minutes. The TFA is evaporated on the rotovap, and the oil is partitioned between 100 mL of ether and 100 mL of H2O. The pH of the water layer is adjusted to 5 by the addition of saturated sodium bicarbonate. The layers are separated and the organic layer is washed with 50 mL of brine. Drying over MgSO4 and evaporation of solvent gives a yellow oil. Flash chromatography in 50% Et2O/hexane followed by two recrystallizations from Et2O/hexane gives 0.16 g (20%) of 5-[ 4,6-bis (1,1-dimethylethyl) -5-hydroxy-2-pyrimidinyl ]-1,3,4-oxadiazole-2(3H )-thione, 234°-236° C. dec. Analysis for C14H20N4O2S: Calcd.: C, 54.52; H, 6.54; N, 18.17; S, 10.40. Found: C, 54.46; H, 6.40; N, 18.38; S, 10.53.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([OH:17])=[O:16])=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:18][C:19]1[O:20][CH:21]=[CH:22][CH:23]=1)[CH2:4][CH3:5])[CH3:2]>C(O)C.[Pt]=O>[CH2:1]([CH:3]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([OH:17])=[O:16])=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][O:20]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)n1c(Cc2ccco2)nc2cc(C(=O)O)ccc21
Agent: O=[Pt]
Solvent: CCO
Product: CCC(CC)n1c(CC2CCCO2)nc2cc(C(=O)O)ccc21
Yield: 15.6 %

Procedure:
A solution of 348 mg of 1-(1-ethyl-propyl)-2-furan-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid in 5 ml of ethanol was hydrogenated at 5 bar for 24 h in the presence of 10 mg platinum oxide. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. The resulting residue was purified by HPLC to obtain 55 mg (17%) of 1-(1-Ethyl-propyl)-2-(tetrahydro-furan-2-ylmethyl)-1H-benzoimidazole-5-carboxylic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH3:14])=[O:12])[S:10][C:3]=12.[CH3:20][NH:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([OH:33])=[CH:30][CH:31]=2)[N:26]([CH3:34])[C:25]=1[CH3:35])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:18][N:17]([CH3:19])[CH2:16][CH2:15][N:13]([CH3:14])[C:11]([C:9]1[S:10][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[O:33][C:29]2[CH:28]=[C:27]3[C:32]([C:24]([C:22]([NH:21][CH3:20])=[O:23])=[C:25]([CH3:35])[N:26]3[CH3:34])=[CH:31][CH:30]=2)[CH:8]=1)=[O:12]
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Reactant: CN(C)CCN(C)C(=O)c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(C(=O)N(C)CCN(C)C)sc34)ccc12
Yield: 14.9 %

Procedure:
This material was prepared by the reaction of 7-chloro-N-[2-(dimethylamino)ethyl]-N-methylthieno[3,2-b]pyridine-2-carboxamide 29a (0.167 g, 0.56 mmole) with 6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e (0.123 g, 0.56 mmole) and Cs2CO3 (0.182 g, 0.56 mmole) in a manner as previously described for example 1 to give a yellow solid (0.040 g, 13%). 1H NMR (400 MHz, CD3OD) δ 8.71 (1H, d, J=6.8 Hz), 8.06 (1H, s), 7.83 (1H, d, J=8.6 Hz), 7.46 (1H, d, J=2.0 Hz), 7.09 (1H, d, J=6.8 Hz), 7.05 (1H, dd, J=2.0, 8.6 Hz), 3.90 (2H, t, J=5.8 Hz), 3.64 (3H, s), 3.42 (2H, t, J=5.8 Hz), 3.23 (6H, s), 2.93 (3H, s), 2.88 (3H, s), 2.58 (3H, s). HRMS (MH+): Calcd: 480.2090. Found: 480.2069.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>CN(C)C=O>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:23])[NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: O=C=Nc1ccccc1F
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccccc2F)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 5 g of ethyl 2-aminothiazol-4-ylglyoxylate, 4.87 g of o-fluorophenyl isocyanate and 30 ml of dimethylformamide. The resulting product was a pale yellow powder having the following physical properties.
Reaction SMILES: [CH2:1]([S:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:26]=[CH:27][CH:28]=[CH:29][C:7]=2[N:6]=1)[CH3:2].[OH:30]O>C(O)(=O)C>[CH2:1]([S:3]([CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:26]=[CH:27][CH:28]=[CH:29][C:7]=2[N:6]=1)=[O:30])[CH3:2]
Reactant: OO
Reactant: CCSCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Solvent: CC(=O)O
Product: CCS(=O)Cc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reaction time: 24 h

Procedure:
2.01 g (5.0 mmol) of 4'-[(2-ethylthiomethyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid are dissolved in 25 ml of glacial acetic acid and treated with 0.51 ml of 30% strength hydrogen peroxide. The solution is allowed to stand for 24 hours at ambient temperature and is then evaporated to dryness. The residue is purified over a silica gel column (grain size: 40-63 μm, eluting agent: methylene chloride/ethanol/glacial acetic acid=50/1/0.15). The homogeneous fractions are combined, the solvents, are distilled off, the residue is dissolved in methylene chloride and washed three times using water. The organic phase is dried using magnesium sulphate and evaporated to dryness. The crystalline residue is mixed with diethylether, the mixture is filtered under suction and the crystals are dried at 75° C. in vacuum.
Reaction SMILES: [NH4+:1].[OH-].Cl[C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=[C:6]([S:15][CH3:16])[N:5]=1>CCO>[NH2:1][C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=[C:6]([S:15][CH3:16])[N:5]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cnc(SC)nc1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
140 ml of a 20% NH4OH solution was added to a suspension of 50.7 g of ethyl 4-chloro-2-(methylthio)pyrimidin-5-carboxylate in 400 ml of EtOH over 20 minutes, keeping the temperature at about 20° C. After stirring for 20 hours at ambient temperature, the reaction medium was concentrated under vacuum almost to dryness, then the residue was taken up in 350 ml of water, stirred for 20 minutes, filtered, and washed with 3×60 ml of water then vacuum dried in the presence of P2O5. A white solid was obtained: MP=134-135° C., m=39.9 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([NH2:13])=[C:9]([NH2:12])[CH:10]=2)[NH:5][C:4](=[O:14])[CH2:3]1.Cl.[C:17](Cl)(Cl)=[O:18]>>[CH3:1][C:2]1([CH3:15])[C:11]2[CH:10]=[C:9]3[NH:12][C:17]([OH:18])=[N:13][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:14])[CH2:3]1
Reactant: O=C(Cl)Cl
Reactant: CC1(C)CC(=O)Nc2cc(N)c(N)cc21
Agent: Cl
Product: CC1(C)CC(=O)Nc2cc3nc(O)[nH]c3cc21

Procedure:
2 g. (9.7 mmole) 4,4-dimethyl-6,7-diamino-1,2,3,4-tetrahydroquinolin-2-one (see Example 13 a)) were dissolved in 50 ml. 2N hydrochloric acid and phosgene passed in for 1 hour. The evaporation residue was recrystallised from methanol to give 1.6 g. (72% of theory) of the title compound; m.p. >300° C.
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][C:10]#[C:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[OH:23])(=[O:3])[CH3:2].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])[CH:25]=1>>[C:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][C:10]#[C:11][CH2:12][CH2:13][CH2:14][C:15]([NH:34][CH2:33][CH2:32][CH2:31][CH2:30][C:26]2[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=2)=[O:17])=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[OH:23])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCC#CCCCC(=O)O)ccc(C(C)=O)c1O
Reactant: NCCCCc1cccnc1
Product: CCCc1c(OCC#CCCCC(=O)NCCCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
7-(4-Acetyl-3-hydroxy-2-propylphenoxy)-5-heptynoic acid was allowed to react with 3-pyridine butanamine according to procedure A and the product was purified by HPLC to give 7-(4-acetyl-3-hydroxy-2-propylphenoxy)-N-[4-(3-pyridinyl)butyl]-5-heptynamide, the title compound, mp 77°-80° (from ethyl acetate-hexane) in 53% yield.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[C:6]([CH2:14][CH:15]=[CH2:16])[C:5]=1[OH:17])(=[O:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[C:6]([CH2:14][CH2:15][CH3:16])[C:5]=1[OH:17])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: C=CCc1c(O)c(C(C)=O)cc2c1CCCC2
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(O)c(C(C)=O)cc2c1CCCC2
Yield: 82.8 %

Procedure:
5% Palladium/carbon catalyst (9 g) was added to a solution of the product of step (b) (115 g) in ethanol (500 ml). The mixture was shaken with hydrogen at an overpressure of 4 to 5 psi at room temperature for 1 hour. The catalyst was removed by filtration and the filtrate concentrated and cooled. The precipitated solid was filtered off and dried to give 7-acetyl-6-hydroxy-5-propyl-1,2,3,4-tetrahydronaphthalene (96 g), mp 52°-53°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][N:6]1[C:13]([NH:14][NH2:15])=[CH:12][C:10](=[O:11])[N:9]([CH2:16][CH2:17][CH3:18])[C:7]1=[O:8].[CH3:22][N:23]=[C:24]=S.CO>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][N:6]1[C:13]2[NH:14][N:15]=[C:22]([NH:23][CH3:24])[C:12]=2[C:10](=[O:11])[N:9]([CH2:16][CH2:17][CH3:18])[C:7]1=[O:8]
Reactant: CN=C=S
Reactant: CCCn1c(=O)cc(NN)n(Cc2cccc(Cl)c2)c1=O
Solvent: CN(C)C=O
Solvent: CO
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2cccc(Cl)c2)c1=O

Procedure:
A solution of 1-(3-chlorobenzyl)-6-hydrazino-3-propyluracil (3.0 g, 9.6 mM) and methyl isothiocyanate (2.2 ml, 32 mM) in DMF (30 ml) was heated at 120° C. for 27 hours. To the solution was added 50% methanol (10 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/methanol afforded colorless crystals (1.22 g, 36%), m.p. 263°-265° C.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[NH:19]1[C@@H:23]([C:24](O)=[O:25])[CH2:22][CH2:21][C:20]1=[O:27].C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(#N)C>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:24]([C@@H:23]2[NH:19][C:20](=[O:27])[CH2:21][CH2:22]2)=[O:25])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C1CC[C@H](C(=O)O)N1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)[C@H]2CCC(=O)N2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (0.30 g, 1.03 mmol), (R)-(+)-2-pyrrolidone-5-carboxylic acid (0.15 g, 1.13 mmol), triethylamine (0.23 g, 2.26 mmol), EDCI (0.22 g, 1.13 mmol) and HOBt (0.17 g, 1.13 mmol) in acetonitrile (10 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and 10% sodium hydrogen carbonate solution. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting light pink solid was triturated with hexane to afford the title compound (0.32 g, 94%) as a light pink solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:14]=1
Reactant: CCOC(=O)CC(=O)CCc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)CCc1ccc(O)cc1
Reaction time: 8 h
Yield: 100 %

Procedure:
2.0 g of 10% Pd/C is added, at ambient temperature, to a solution of the protected phenol 3 (23.74 g, 0.07 mol) in 320 mL of AcOEt. The reaction medium is stirred overnight under an atmosphere of H2 then it is filtered on Celite®, washed with AcOEt. The filtrate is then concentrated under vacuum in order to produce the expected product 4 (17.02 g, 0.07 mol, 99%) in the form of a colourless oil. The crude product is used in the following stage without other purification.
Reaction SMILES: C[O:2][C:3](=[O:49])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:14]=[C:13](OCCOCCOCCOCC)[CH:12]=1)[CH2:6][C:7]([O:9]C)=[O:8].[OH-].[Na+].C(CN(C1C=C(OCCCCCCCCCCCCOC2C=CC=CC=2)C=[C:63]([O:87][CH2:88][CH2:89][O:90][CH2:91][CH2:92][O:93][CH2:94][CH2:95][O:96]CC)[CH:62]=1)CC(O)=O)(O)=O>CO.O1CCOCC1>[C:7]([CH2:6][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:14]=[CH:13][C:12]=1[O:96][CH2:95][CH2:94][O:93][CH2:92][CH2:91][O:90][CH2:89][CH2:88][O:87][CH2:63][CH3:62])[CH2:4][C:3]([OH:2])=[O:49])([OH:9])=[O:8]
Reactant: CCOCCOCCOCCOc1cc(OCCCCCCCCCCCCOc2ccccc2)cc(N(CC(=O)O)CC(=O)O)c1
Reactant: CCOCCOCCOCCOc1cc(OCCCCCCCCCCCCOc2ccccc2)cc(N(CC(=O)OC)CC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCOCCOCCOCCOc1ccc(OCCCCCCCCCCCCOc2ccccc2)cc1N(CC(=O)O)CC(=O)O
Yield: 85 %

Procedure:
A solution of 1.15 g (1.67 mmol) of N-[3-[2-[2-(2-ethoxyethoxy)ethoxy]ethoxy]-5-[(12-phenoxydodecyl)oxy]phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester and 1.4 ml (8.4 mmol) of 6 N NaOH in 50 ml of methanol and 10 ml of dioxane was stirred at reflux under argon for 19 hours. After the usual workup the product was crystallized from acetone-hexane to give 0.94 g (85% yield), mp 58°-61°, of N-(carboxymethyl)-N-[3-[2-[2-(2-ethoxyethoxy)-ethoxy]ethoxy]-5-[(12-phenoxydodecyl)oxy]phenyl]glycine.
Reaction SMILES: C([N:11]1[CH2:34][CH2:33][N:14]2[C:15]3[C:20]([NH:21][C:22](=[O:23])[CH:13]2[CH2:12]1)=[CH:19][C:18]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[CH3:32])=[CH:17][CH:16]=3)(OCC1C=CC=CC=1)=O.C1CCCCC=1>C(O)C.[Pd]>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[N:14]2[CH2:33][CH2:34][NH:11][CH2:12][CH:13]2[C:22](=[O:23])[NH:21]3)=[C:25]([CH3:32])[CH:26]=1
Reactant: COc1ccc(-c2ccc3c(c2)NC(=O)C2CN(C(=O)OCc4ccccc4)CCN32)c(C)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: COc1ccc(-c2ccc3c(c2)NC(=O)C2CNCCN32)c(C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 24.4 %

Procedure:
Deprotection procedure: To a solution of 3-carbobenzyloxy-8-(4-methoxy-2-methylpheny)-2,3,4, 4a-tetrahydro-1H-pyrazino [1,2-a]quinoxalin-5(6H) -one (0.38 mmol) in 6 ml absolute ethanol was added 10% Pd/C (150 mg) and excess cyclohexene (3 ml). The black reaction mixture was heated to reflux. After 5 h, the mixture was cooled to rt and filtered through a pad of celite, washing heavily with methanol. The filtrate was concentrated to a colorless residue. The crude material was purified by radial PLC (1 mm plate, load and elute with methanol) to give the title compound as a colorless oil (30 mg, 24%). 1H NMR (CDCl3, 300 MHz) δ7.12 (d, J=8.1 Hz, 1H), 6.95 (dd, J=8.5, 1.9 Hz, 1H), 6.76-6.82 (m, 3H), 6.67 (d, J=1.8 Hz, 1H), 3.83 (s, 3H), 3.53-3.67 (m, 3H), 3.18 (m, 1H), 2.79-3.01 (m, 3H), 2.26 (s, 3H) ppm. MS (ESI) m/z=324.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([O:13]C)=[O:12])[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>CO.O>[CH3:1][N:2]([CH3:15])[C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)N(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)C(=O)[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl trans-4-[(dimethylamino)carbonyl]cyclohexane-carboxylate (20.0 g) obtained in Reference Example 80(1) is dissolved in methanol (100 ml), and thereto is added a solution of sodium hydroxide (7.50 g) in water (40 ml). The mixture is then stirred at room temperature for 18 hours. The reaction solution is concentrated under reduced pressure, and the residue is diluted with ice-water and washed with diethyl ether. The resulting aqueous layer is acidified with 10% hydrochloric acid and extracted twice with chloroform. The organic layer is washed with saturated brine and dried over sodium sulfate. The solvent is concentrated under reduced pressure. The resulting residue is suspended in n-hexane and collected by filtration to give the title compound (15.7 g).
Reaction SMILES: Br[C:2]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][C:3]=1[O:4][C@@H:5]([CH3:9])[C:6]([OH:8])=[O:7].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1B(O)O>>[Cl:16][C:17]1[CH:18]=[C:19]([Cl:23])[CH:20]=[CH:21][C:22]=1[C:2]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][C:3]=1[O:4][C@@H:5]([CH3:9])[C:6]([OH:8])=[O:7]
Reactant: C[C@H](Oc1ccc(C#N)cc1Br)C(=O)O
Reactant: OB(O)c1c(Cl)cccc1Cl
Product: C[C@H](Oc1ccc(C#N)cc1-c1ccc(Cl)cc1Cl)C(=O)O

Procedure:
The title compound was prepared by the method of example 16 step (iii) using the product from step (i) and 2,6-dichlorophenylboronic acid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]>[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C(O)CCCCCCCCC=Cc1ccco1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Product: O=C(O)CCCCCCCCCCc1ccco1
Yield: 89.6 %

Procedure:
This compound was synthesized from 11-(2-furyl)-10-undecenoic acid (1.25 g, 5 mmol) by a hydrogenation reaction using Pd/BaSO4 (125 mg). Crystallization (petroleum ether) afforded the product (1.13 g, 90%) as white crystals (mp 40-41° C.); IR: 3450-2500, 1720 cm-1 ; 1H-NMR: 1.30 (m, 12H), 1.65 (m, 4H), 2.34 (t, 2H), 2.60 (t, 2H), 5.95 (d, 1H), 6.28 (d, 1H), 7.30 (s, 1H), 10.10 (bs, 1H). Anal. Calcd. for C15H24O3 : C, 71.39, H, 9.58%; Found: C, 71.21, H, 9.63%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:21][C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][C:27]([F:40])=[CH:26][CH:25]=4)[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([F:17])[C:14]([O:18]C)=[C:13]([F:20])[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:21][C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][C:27]([F:40])=[CH:26][CH:25]=4)[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([F:20])[C:14]([OH:18])=[C:15]([F:17])[CH:16]=3)[C:3]=12
Reactant: COc1c(F)cc(-c2nn(Cc3oc4ccc(F)cc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1cc(F)c(O)c(F)c1)nn2Cc1oc2ccc(F)cc2c(=O)c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 22.9 %

Procedure:
To a solution of example 127 (0.099 g, 0.180 mmoles) in dichloromethane (10 ml), BBr3 (1M in dichloromethane, 0.99 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated to afford the title compound as brown solid (0.022 g, 23% yield). MP: 274-278° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 10.20(s, 1H), δ 8.18(s, 1H), 7.72-7.60(m, 4H), 7.38(m, 1H), 7.20 (d, J=8.7 Hz, 2H), 7.17-7.10(m, 4H), 5.51(s, 2H). Mass: 534.06(M++1).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.N1(O)CCCC[CH2:13]1.C=O.[OH-].[K+]>C(O)=O>[CH3:13][N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: ON1CCCCC1
Agent: C=O
Agent: [K+]
Agent: [OH-]
Solvent: O=CO
Product: CN1C(C)(C)CC(O)CC1(C)C
Yield: 91 %

Procedure:
1,2,2,6,6-pentamethy-4-piperidinol was synthesized upon reductive-amination of 2,2,6,6-tetramethy-4-piperidinol. A mixture of 2,2,6,6-tetramethyl]-piperidinol (3.55 g, 0.02 M), 37% formalin (3.3 mL) and 1 mL formic acid was heated under a reflux condensor on the steam bath for 5 h. The reaction mixture was made basic with (1.0 M) potassium hydroxide solution and the product was extracted with ether (5×50 mL). The combined extract was washed with saturated solution of potassium carbonate (2×20 mL) and dried over anhydrous magnesium sulfate and finally the solvent was evaporated under vacuum. The residue was then sublimed at 0.05 mm, bath temperature 85° C. The white sublimate weighed 3.5 g to give 91% yield, mp=72-74° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7](=[O:18])[CH2:6][CH2:5][CH2:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][CH:2]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7](=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CC1=CCCCC(=O)OCCCCCCCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1CCCCCCCCCOC(=O)CCCC1
Yield: 92.9 %

Procedure:
28 g (0.11 mol) of 7-methyloxacyclohexadec-6-en-2-one were dissolved in 200 ml of ethyl acetate and hydrogenated in the presence of 2 g of 5% palladium-on-carbon under 150 mbar of hydrogen. The mixture was filtered over Celite, concentrated and distilled in a bulb-tube. 26 g (92%) of 7-methyloxacyclohexadecan-2-one were obtained having the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[OH:11][C:12]1[C:13]([O:20][CH2:21][CH2:22][CH3:23])=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C:12]2[CH:19]=[CH:18][CH:17]=[C:14]([CH:15]=[O:16])[C:13]=2[O:20][CH2:21][CH2:22][CH3:23])[CH:3]=1
Reactant: CCCOc1c(O)cccc1C=O
Reactant: N#Cc1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1c(C=O)cccc1Oc1cc(Cl)ccc1C#N
Yield: 99.3 %

Procedure:
4-Chloro-2-fluorobenzonitrile (0.35 g, 2.2 mmol), 3-hydroxy-2-propoxybenzaldehyde (0.40 g, 2.2 mmol) and cesium carbonate (0.72 g, 2.2 mmol) were heated with stirring in dry DMF (4 mL) at 50° C. for 19 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with 1N sodium hydroxide solution (2×), water (1×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(3-formyl-2-propoxyphenoxy)-benzonitrile (0.69 g, 98%) as a brown oil, which was used without further purification.