Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:30]=[CH:29][C:17]([C:18]([O:20][C:21]2[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=2)=[O:19])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH2:31]>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[CH2:1]([O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]([OH:31])=[O:26])=[CH:23][CH:22]=2)=[O:19])=[CH:29][CH:30]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Reactant: O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)O)cc2)cc1
Reaction time: 20 h
Yield: 83 %

Procedure:
The 4-(4-n-dodecoxybenzoyloxy)-benzaldehyde produced in step A4 (17.4 g) was dissolved in acetic acid (60 ml) and treated with a solution of chromium trioxide (12.7 g) dissolved in 50% acetic acid added dropwise over 20 minutes at 40° C. After stirring at 45°-50° for 20 hours, water (150 ml) was added and the mixture stirred for 3 hours. The product separated and was recrystallized from acetic acid (55 ml) to give 4-(4-n-dodecoxybenzoyloxy)-benzoic acid (15 g, 83% theory).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CC(O)C.C(C1C=CC=CC=1)(=O)C>[CH:1]([OH:8])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)c1ccccc1
Solvent: CC(C)O
Product: OC(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
1.8 g of benzophenone (10 mmol) and 45 ml of 2-propanol are introduced into a 100 ml flask under argon atmosphere. The system is heated under reflux. 2.5 ml of a 0.1 M solution of NaOH in 2-propanol and 2 ml of a 2-propanol solution containing the catalyst (10) (1.8 mg, 0.0025 mmol) are added. The molar ratios of benzophenone/catalyst/NaOH are equal to 4000/1/100. 1H NMR analysis of the mixture shows that the reaction is complete after 30 minutes. By evaporating the solvent, a colourless residue is obtained which is extracted with 30 ml of diethyl ether. This solution is then passed through a silica filled column to remove the catalyst and sodium hydroxide. The filtrate is dried by adding Na2SO4 and, after filtering and removal of the solvent, the benzhydrol is recovered and then dried under reduced pressure (10−2 mmHg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([NH:21][CH2:22][C:23]([O:25]CC)=[O:24])[C:11]=3[C:12](=[O:14])[CH:13]=2)=[CH:4][C:3]=1[F:28].[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([NH:21][CH2:22][C:23]([OH:25])=[O:24])[C:11]=3[C:12](=[O:14])[CH:13]=2)=[CH:4][C:3]=1[F:28]
Reactant: CCOC(=O)CNc1c(F)cc(F)c2oc(-c3ccc(N)c(F)c3)cc(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(-c2cc(=O)c3c(NCC(=O)O)c(F)cc(F)c3o2)cc1F
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 52.2 %

Procedure:
305 mg (0.779 mmol) of the above 2-(4-amino-3-fluorophenyl)-5-ethoxycarbonylmethylamino-6,8-difluoro-4H-1-benzopyran-4-one was dissolved in 20 mL of ethanol, a 2N aqueous solution of sodium hydroxide was added and the mixture was stirred at 50° C. for 40 minutes. The reaction solution was cooled on ice and the crystals were collected by filtration. The crystals were suspended in water, the suspension was adjusted to pH 2 by addition of hydrochloric acid thereto, and the crystals were collected by filtration again and purified by silica gel column chromatography (chloroform:methanol:acetic acid=90:10:1) to give 148 mg of Compound 140 (yield: 52%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]2)[NH:11][C:10]3=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]2)[N:11]=[C:10]3[N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(N4CCCCC4)cc3c(=O)[nH]2)c1
Reactant: C1CCNC1
Product: O=C(O)c1cnn(-c2nc(N3CCCC3)c3cc(N4CCCCC4)ccc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(piperidin-1-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and pyrrolidine in step E. MS (ESI/CI): predicted mass O21H24N6O2, 392.2.
Reaction SMILES: [Mg].C(Br)C.[O:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[O:11][CH2:12][C:13]#[CH:14].Br[CH2:16]/[CH:17]=[CH:18]/[CH2:19][CH2:20][CH3:21]>O1CCCC1.Cl>[O:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[O:11][CH2:12][C:13]#[C:14][CH2:16]/[CH:17]=[CH:18]/[CH2:19][CH2:20][CH3:21]
Reactant: CCC/C=C/CBr
Reactant: C#CCOC1CCCCO1
Agent: Cl
Agent: [Mg]
Solvent: CCBr
Solvent: C1CCOC1
Product: CCC/C=C/CC#CCOC1CCCCO1
Yield: 73.3 %

Procedure:
To a solution of magnesium metal (8.6 g) in dry tetrahydrofuran (100 ml) was added dropwise ethyl bromide (39 g) in a nitrogen atmosphere at ambient temperature. After the mixture was stirred for an hour at the same temperature, to the mixture was added dropwise a solution of 3-(2-tetrahydropyranyloxy)-1-propyne (50 g) in dry tetrahydrofuran (75 ml) and cuprous cyanide (20 mg). The reaction mixture was stirred for 30 minutes at ambient temperature. To the mixture was added with stirring a solution of 1-bromo-trans-2-hexene (58 g) in dry tetrahydrofuran (75 ml) under ice-cooling. The reaction mixture was stirred for 30 minutes at ambient temperature and concentrated under reduced pressure to give a residue, which was dissolved in diluted hydrochloric acid and extracted with ether. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a yellowish oily residue, which was distilled under reduced pressure to give colorless oily 1-(2-tetrahydropyranyloxy)-trans-5-nonen-2-yne (58 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([SH:13])[N:10]=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14](Br)[CH:15]=[CH2:16]>>[CH2:16]([S:13][C:9]1[N:10]=[N:11][CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)[CH:15]=[CH2:14]
Reactant: Sc1nncc(-c2ccccc2)n1
Reactant: C=CCBr
Product: C=CCSc1nncc(-c2ccccc2)n1

Procedure:
3-(Allylthio)-5-phenyl-1,2,4-triazine (compound A) is prepared from 5-phenyl-1,2,4-triazine-3-thiol and allyl bromide according to the following synthetic scheme;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[O:5][CH2:6][C:7](=O)[CH3:8].Cl>C(O)C>[NH2:1][C:2]1[C:12]([Cl:13])=[CH:11][C:10]2[C:7]([CH3:8])=[CH:6][O:5][C:4]=2[CH:3]=1
Reactant: CC(=O)COc1ccc(Cl)c(N)c1
Agent: Cl
Solvent: CCO
Product: Cc1coc2cc(N)c(Cl)cc12

Procedure:
A mixture of 11.4 g (57 mmole) of 1-(3-amino-4-chlorophenoxy)-2-propanone, 10 ml of concentrated hydrochloric acid and 150 ml of ethanol is boiled under reflux for 14 hours and subsequently concentrated by evaporation in vacuo. Ice-water is added to the residue and the whole is rendered alkaline with 3N sodium hydroxide solution and extracted with ether. The crude product obtained after drying and concentration by evaporation of the organic phase is chromatographed over silica gel with petroleum ether/methylene chloride. Recrystallisation of the pure fractions from ether/petroleum ether yields 6-amino-5-chloro-3-methylbenzofuran having a melting point of 73°-75°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:25][CH2:26][CH:27]=[C:28]([Cl:30])[Cl:29])[CH:5]=[C:6]([Cl:24])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1C(=O)C2=CC=CC=C2C1=O.O.NN.Cl.[OH-].[K+]>C(O)C.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:25][CH2:26][CH:27]=[C:28]([Cl:30])[Cl:29])[CH:5]=[C:6]([Cl:24])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13]
Reactant: O=C1c2ccccc2C(=O)N1CCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: NCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Yield: 70.6 %

Procedure:
A mixture of 14.5 g of 3,5-dichloro-4-(4-phthalimidobutyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene, 1.73 ml of hydrazine monohydrate and 100 ml of ethanol was heated under reflux for 4 hours. The reaction mixture was made weak acidic by the addition of concentrated hydrochloric acid and further heated under reflux for 1 hour. The temperature of the reaction mixture was decreased to room temperature, after which the deposited solid was collected by filtration and the filtrate was concentrated to give a residue. To the residue was added a solution of 2.1 g of potassium hydroxide dissolved in 100 ml of ethanol, after which the deposited solid was collected by filtration and the filtrate was concentrated to give a residue. To the residue was added 100 ml of diethyl ether for dissolution, and the solution was dried over anhydrous magnesium sulfate and then concentrated, which afforded 7.51 g of 3,5-dichloro-4-(4-aminobutyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (71% yield), nD23.5 1.5672.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][N:22]=1>C1COCC1>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:21]2[N:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)[CH2:3]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC1(C)CCCC(O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CCCC(Oc2ccc(C#N)cn2)C1
Temperature: -78 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
Dissolve 3,3-dimethylcyclohexanol (6 g, 47 mmoles) in anhydrous THF (70 mL) under nitrogen atmosphere and cool at −78° C. Add sodium bis(trimethylsilyl)amide (23.4 mL, 47 mmol, 2M solution in THF) to this solution and stir at −78° C. for 30 min before raising to room temperature. Cool down again to −78° C. and add a solution of 2-chloro-5-cyanopyridine (7.1 g, 51.7 mmoles) in anhydrous THF (20 mL) and stir overnight while warming to room temperature. Add saturated aqueous NaHCO3 (100 mL) and extract the aqueous layer with DCM (3×100 mL). Wash the combined organic extracts with brine (200 mL). Dry over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with cyclohexane/EtOAc (1:0 to 9:1 gradient) to afford the desired intermediate as a solid (9.14 g, 84%). MS (ES+) m/z: 231.1 (M+H)+.
Reaction SMILES: C[N:2]([CH:21]1[CH:28]2[CH2:29][C:24]3([C:31](O)=[O:32])[CH2:25][CH:26]([CH2:30][CH:22]1[CH2:23]3)[CH2:27]2)[C:3](=[O:20])[C:4]([N:7]([CH2:18][CH3:19])[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])(=[O:10])=[O:9])([CH3:6])[CH3:5].C[CH2:35][N:36]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[OH-]>C(Cl)Cl.O>[CH3:35][NH:36][C:31]([C:24]12[CH2:29][CH:28]3[CH2:27][CH:26]([CH2:30][CH:22]([CH:21]3[NH:2][C:3](=[O:20])[C:4]([N:7]([CH2:18][CH3:19])[S:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])(=[O:9])=[O:10])([CH3:6])[CH3:5])[CH2:23]1)[CH2:25]2)=[O:32]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCN(C(C)(C)C(=O)N(C)C1C2CC3CC1CC(C(=O)O)(C3)C2)S(=O)(=O)c1ccccc1C
Agent: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCN(C(C)(C)C(=O)NC1C2CC3CC1CC(C(=O)NC)(C3)C2)S(=O)(=O)c1ccccc1C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
N-methyl-4-(2-(N-ethyl-2-methylphenylsulfonamido)-2-methylpropanamido)adamantane-1-carboxylic acid (380 mg, 0.82 mmol) was dissolved in CH2Cl2 (10 ml), and added with EDCI (314 mg, 1.64 mmol) and HOBT (222 mg, 1.64 mmol), followed by stirring for 30 minutes. 30% NH4OH aqueous solution (5 ml) was added thereto, followed by stirring at room temperature for 12 hours. The resultant solution was added with H2O, extracted with CH2Cl2 (×3), dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed. The resultant mixture was purified with column chromatography so as to obtain N-methyl-4-(2-(N-ethyl-2-methylphenylsulfonamido)-2-methylpropanamido)adamantane-1-carboxamide (296 mg, 0.64 mmol, 78%).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:8]=1[CH3:14])=[O:5].Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1>[Br:13][C:9]1[C:8]([CH3:14])=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:18][CH:17]=[C:16]([F:19])[CH:15]=3)[NH:1][C:21]2=[O:23])[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1c(Br)cccc1NC(=O)c1cc(F)ccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1-n1c(=O)[nH]c2ccc(F)cc2c1=O
Yield: 87.7 %

Procedure:
A solution of 2-amino-N-(3-bromo-2-methylphenyl)-5-fluorobenzamide (0.893 g, 2.76 mmol) and triphosgene (0.984 g, 3.32 mmol) in THF (30 mL) was stirred at room temperature for 2 h. The mixture was carefully treated with saturated aqueous NaHCO3 and stirred until gas evolution ceased. The mixture was extracted twice with DCM. The combined organic phases were washed with water, dried and concentrated. The residue was triturated with DCM to give a white solid, isolated by filtration. The filtrate was concentrated and subjected to column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (gradient from 0-80%), to provide additional solid. The two solids were combined to provide 3-(3-bromo-2-methylphenyl)-6-fluoroquinazoline-2,4(1H,3H)-dione as a white solid (845 mg, 87% yield). Mass spectrum m/z 349, 351 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:15]([NH2:17])=[O:16])=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=1.C1(C)C=CC=CC=1.CO[CH:27](OC)[N:28]([CH3:30])[CH3:29]>>[Br:1][C:2]1[S:3][C:4]([C:15](/[N:17]=[CH:27]\[N:28]([CH3:30])[CH3:29])=[O:16])=[C:5]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[N:6]=1
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1sc(Br)nc1Cc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CN(C)/C=N\C(=O)c1sc(Br)nc1Cc1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
In a 250 mL round bottomed flask were placed 2-bromo-4-(4-chlorobenzyl)-1,3-thiazole-5-carboxamide (0.66 g, 2.0 mmol) and toluene (30 mL, 300 mmol). The mixture was turned into a suspension by ultrasonication. To the suspension was added 1,1-dimethoxy-N,N-dimethylmethanamine (80 uL, 6.0 mmol) and the mixture was stirred for 2 h at 50° C. The mixture was allowed to cool to rt then was concentrated under reduced pressure. The residue was used in the next step without further purification. LC/MS (FA) ES+ 388.
Reaction SMILES: [C:1]([C:4]([C:21]([O:23][CH3:24])=[O:22])([CH2:16][C:17]#[C:18][CH2:19][CH3:20])[CH:5]([CH:11](OC)[O:12]C)[CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:1]([C:4]([C:21]([O:23][CH3:24])=[O:22])([CH2:16][C:17]#[C:18][CH2:19][CH3:20])[CH:5]([CH:11]=[O:12])[CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: CCC#CCC(C(C)=O)(C(=O)OC)C(CC(=O)OC)C(OC)OC
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Product: CCC#CCC(C(C)=O)(C(=O)OC)C(C=O)CC(=O)OC
Reaction time: 12 h

Procedure:
Methyl 4-acetyl-4-methoxycarbonyl-3-dimethoxymethyl-6-nonynoate (530 mg) is dissolved in 20 ml of tetrahydrofuran, and 25 ml of 1% aqueous solution of perchloric acid is added to the solution. The mixture is stirred at 26° to 28° C. for 12 hours. Subsequently the reaction mixture is neutralized with sodium bicarbonate and concentrated in a vacuum. The residue is extracted with ethyl acetate. The extract is dried and then concentrated to give methyl 4-acetyl-4-methoxycarbonyl-3-formyl-6-nonynoate (compound (8), R1 =R2 =CH3) in a yield of 98.3%.
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[CH:27]=[CH:26][C:16]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])=[O:18])=[C:15]([Cl:28])[CH:14]=1)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)C(F)(F)F>[Cl:28][C:15]1[CH:14]=[C:13]([NH:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[OH:5])[CH:27]=[CH:26][C:16]=1[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25])=[O:18]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2OC(C)(C)C)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCC(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2O)cc1Cl
Temperature: -5 °C
Reaction time: 1 h

Procedure:
A solution of 4-(2-tert-butoxy-phenylamino)-2-chloro-2′-methylbenzophenone (Compound 107) (1.33 g, 3.4 mmol) in a mixture of CH2Cl2 (5 ml) and trifluoroethanol (20 ml) was cooled to −5° C. under argron. Trifluoroacetic acid (423 mg, 3.7 mmol) was added dropwise and the reaction mixture was allowed to come to room temperature over 1 h. After 23 h at room temperature the reaction mixture was poured into saturated NaHCO3 and then extracted with EtOAc and CH2Cl2. The organic phases was collected, dried (MgSO4), filtered, and concentrated in vacuo to give the crude product. This was further purified by flash chromatography using EtOAc/pentane 1:4 as eluant.
Reaction SMILES: O(CCSCC1C=CC(C2C=CC=C(C(O)=O)C=2)=CC=1)C1C=CC=CC=1.C([O:29][C:30]([C:32]1[C:33]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][S:45][CH2:46][CH2:47][O:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:39]=2)=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:31])C.[OH-].[Li+]>C1COCC1>[O:48]([CH2:47][CH2:46][S:45][CH2:44][C:40]1[CH:39]=[C:38]([C:33]2[C:32]([C:30]([OH:31])=[O:29])=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:43]=[CH:42][CH:41]=1)[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: CCOC(=O)c1ccccc1-c1cccc(CSCCOc2ccccc2)c1
Agent: O=C(O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1-c1cccc(CSCCOc2ccccc2)c1
Yield: 99 %

Procedure:
3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid. 3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester (2.1 g, 5.35 mmol, 1 eq.) in 30% aqueous THF was treated with lithium hydroxide (0.38 g, 16.05 mmol, 3 eq.). When complete, the reaction was worked up as described leaving 3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (1.94, 99% yield) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:38])=[C:14]([CH:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([Br:31])=[CH:27][CH:28]=4)[NH:23][C:22]=3[CH:21]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[NH:20][CH:19]2[CH3:37])[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:38])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([Br:31])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:20][C:19]=2[CH3:37])[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1NC(C)C(c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(Br)ccc21
Agent: [Pd]
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C)c(-c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(Br)ccc12
Yield: 32 %

Procedure:
A solution of ethyl 4-(3-(((benzyloxy)carbonyl)amino)-2-methylphenyl)-7-bromo-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylate (4.68 g, 8.12 mmol) and 10% palladium on carbon (2.59 g, 2.44 mmol) in xylene (130 mL) was heated at 120° C. overnight. The reaction mixture was diluted with ethyl acetate and filtered through a pad of CELITE®. The CELITE® pad was washed well with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane (20%-35%-50%) to give ethyl 4-(3-(((benzyloxy)carbonyl)amino)-2-methylphenyl)-7-bromo-3-methyl-9H-pyrido[3,4-b]indole-1-carboxylate (1.49 g, 2.60 mmol, 32% yield) as a burgundy solid. LC/MS M+1=572.2 and 574.2.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:7]([OH:15])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4].F[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[CH2:1]([C:5]1[C:6]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[C:7]([O:15][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2ccccc2c(O)c1-c1ccc(OC)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCCCc1cc2ccccc2c(Oc2ccc(C=O)cc2)c1-c1ccc(OC)cc1
Yield: 69 %

Procedure:
3-Butyl-2-[4-(methyloxy)phenyl]-1-naphthalenol (160) (0.25 g, 0.82 mmol) and 4-fluorobenzaldehyde was heated with Cs2CO3 in DMSO at 100° C. to give 0.23 g (69%) of compound 161 as a light brown viscous oil. 1H NMR (400 MHz, CDCl3): δ 0.80 (t, J=7.3 Hz, 3H), 1.20-1.30 (m, 2H), 1.40-1.50 (m, 2H), 2.60 (t, J=7.8 Hz, 2H), 3.78 (s, 3H), 6.71 (d, J=8.8 Hz, 2H), 6.79 (d, J=8.6 Hz, 2H), 7.05 (d, J=8.7 Hz, 2H), 7.39 (t, J=7.4 Hz, 1H), 7.50 (t, J=7.5 Hz, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.70 (s, 1H), 7.77 (d, J=8.2 Hz, 1H), 7.87 (d, J=8.1 Hz, 1H), 9.81 (s, 1H). LCMS (ESI): m/z 411 (M+H)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:15][N:16]([C:23](=[O:52])[CH2:24][CH2:25][CH2:26][CH2:27][N:28]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:29](=[O:43])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1.C(Cl)Cl>[CH2:8]([O:15][N:16]([C:23](=[O:52])[CH2:24][CH2:25][CH2:26][CH2:27][N:28]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:29](=[O:43])[CH2:30][CH2:31][CH2:32][CH2:33][N:34]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:1](=[O:3])[CH3:2])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N#CCCCCN(OCc1ccccc1)C(=O)CCCCN(OCc1ccccc1)C(=O)CCCCNOCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(CCCCC(=O)N(CCCCC(=O)N(CCCCC#N)OCc1ccccc1)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
Acetic anhydride (8 mL) was slowly added to a solution of (8) (1.25 g, 2.03 mmol) in pyridine (50 mL) and CH2Cl2 (30 mL) which had been cooled to 0° C. Stirring was continued at 0° C. for 30 minutes and then at room temperature overnight. Solvents were removed under high vacuum, and the residue was dissolved in CHCl3 (120 mL), followed by washing with 0.5N HCl (2×40 mL) and saturated NaHCO3 (2×40 mL). After solvent removal, the crude oil was purified by silica gel column chromatography, eluting with 3:1 EtOAc/hexane, to furnish 0.8 g (60%) of (9) as an oil: NMR δ 1.40-1.80 (m, 12H), 2.05 (s, 3H), 2.20-2.50 (m, 6H), 3.40-3.73 (m, 6H), 4.75 (s, 6H), 7.32 (s, 15H). Anal. (C38H 48 N4O6) C, H, N.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[N:7]1[CH:12]=[CH:11][CH:10]=[N:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+].C(O)CCC>O>[C:5]([CH2:4][CH2:3][CH2:2][N:16]1[CH2:17][CH2:18][N:13]([C:8]2[N:9]=[CH:10][CH:11]=[CH:12][N:7]=2)[CH2:14][CH2:15]1)#[N:6]
Reactant: N#CCCCCl
Reactant: c1cnc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Product: N#CCCCN1CCN(c2ncccn2)CC1

Procedure:
A mixture of 4-chlorobutyronitrile (3.3 g; 0.032 mol), 1-(2-pyrimidinyl)piperazine (3.3 g; 0.032 mol), sodium carbonate (6.4 g; 0.0608 mol) and n-butanol (50 ml) was heated under reflux for 19 hours. After completion of the reaction, the resultant mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography to give 1-(3-cyanopropyl)-4-(2-pyrimidinyl)-piperazine. M.P., 56°-57° C.