Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@:2]12[CH2:21][CH2:20][C@@:19]3([CH3:22])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[C:16](=[O:18])[CH3:17])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:24])[CH2:4][CH2:5][C:6](=[O:23])[CH:7]=1.O.C(OCC)(=O)C>S(=O)(=O)(O)O>[CH3:17][C:16](=[O:18])[C@@H:15]1[C@:19]2([CH3:22])[C@H:12]([C@H:11]3[C:2](=[CH:21][CH2:20]2)[C@:3]2([CH3:24])[C:8](=[CH:7][C:6](=[O:23])[CH2:5][CH2:4]2)[CH2:9][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(O)CC[C@]12C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]12C

Procedure:
A solution of 9α-hydroxypregn-4-ene-3,20-dione (218 mg) in 70% (v/v) aqueous sulfuric acid was stirred at room temperature for 1 hour after which the reaction mixture was added dropwise to a stirred mixture of water (5 ml) and ethyl acetate (5 ml). The organic layer was washed with a 5% aqueous potassium carbonate solution, then with water to neutral pH, dried (MgSO4) and concentrated under reduced pressure. The crude product (149 mg), still containing some starting material, was purified by chromatography (silica gel, toluene/acetone 3/1) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([S:7][C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:21][CH3:22])=[C:15]([C:18]([NH2:20])=[O:19])[CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[CH3:22][O:21][C:14]1[CH:13]=[C:12]2[C:17]([C:8]([S:7][C:5]3[S:6][C:2]([NH:1][C:30]([NH:29][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:31])=[CH:3][CH:4]=3)=[CH:9][CH:10]=[N:11]2)=[CH:16][C:15]=1[C:18]([NH2:20])=[O:19]
Reactant: COc1cc2nccc(Sc3ccc(N)s3)c2cc1C(N)=O
Reactant: O=C=Nc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc2nccc(Sc3ccc(NC(=O)Nc4ccccc4)s3)c2cc1C(N)=O
Yield: 37.3 %

Procedure:
4-(5-Aminothiophen-2-ylsulfanyl)-7-methoxyquinoline-6-carboxamide (49.0 mg, 0.150 mmol) and phenylisocyanate (19.6 mg, 0.165 mmol) were stirred in dimethylformamide (1 ml) at room temperature for 2 hours. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was suspended in ethyl acetate and diluted with hexane, and then the crystals were filtered out, washed with hexane and blow-dried to obtain the title compound (25.0 mg, 0.056 mmol, 37%) as light yellow crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH:3]=O.O.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[OH:17].CNC>CO>[CH3:9][C:10]1[CH:15]=[C:14]([CH2:3][C:2]([CH3:1])([CH3:7])[CH:5]=[O:6])[CH:13]=[C:12]([CH3:16])[C:11]=1[OH:17]
Reactant: Cc1cccc(C)c1O
Reactant: CC(C)(C=O)CO
Agent: CNC
Solvent: O
Solvent: CO
Product: Cc1cc(CC(C)(C)C=O)cc(C)c1O
Yield: 91 %

Procedure:
125 g (1 mol) of 80% strength aqueous 2,2-dimethyl-3-hydroxypropanal (crude mixture from the synthesis, reduced to a water content of 20% by distillation), 109 g (0.9 mol) of 2,6-dimethylphenol, 12 g (0.11 mol) of 40% strength aqueous dimethylamine and 700 g of methanol are reacted in a stirred autoclave at 180° C. and under the autogenous pressure of 20-30 bar for 10 h. Workup of the reaction mixture by distillation yields 168 g (91%) of 3-(3,5-dimethyl-4-hydroxyphenyl)-2,2-dimethylpropanal (boiling point 140°-142° C.; melting point 72°-73° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[CH3:12][S:13][C:14](SC)=[CH:15][N+:16]([O-:18])=[O:17]>C(O)(C)C>[N+:16]([CH:15]=[C:14]([S:13][CH3:12])[NH:11][CH2:10][CH2:9][S:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([O-:18])=[O:17]
Reactant: NCCSCc1ccccn1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CC(C)O
Product: CSC(=C[N+](=O)[O-])NCCSCc1ccccn1

Procedure:
A solution of 2-[(2-pyridyl)methylthio]ethylamine (from the dihydrobromide, 20.0 g; 60.6 mmoles) [prepared according to the procedure described in Belgian Pat. No. 779,775] and 1,1-bis(methylthio)-2-nitroethylene [prepared according to the procedure described in Chem. Ber., 100, 591 (1967) or Acta Chem. Scand., 21, 2797 (1967)] (10.0 g; 60.6 mmoles) in isopropyl alcohol (175 ml) was stirred at ambient temperature under a positive pressure of nitrogen for 16 hours then at reflux temperature for 2 hours to complete the reaction. The mixture was cooled in an ice-water bath and the product collected by filtration. Recrystallization from isopropyl alcohol with activated carbon treatment gave 1-nitro-2-methylthio-2-{2-[(2-pyridyl)methylthio]ethylamino}ethylene; mp 97°-99°.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH:6][C:7]1(O)[C:12](=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:11][S:10](=[O:23])(=[O:22])[CH2:9][C:8]1=[CH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1>CCCCO.CS(C)=O>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH:24]2[N:3]3[CH2:4][CH2:5][S:1][C:2]3=[N:6][C:7]3[C:12](=[CH:13][C:14]4[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=4)[CH2:11][S:10](=[O:22])(=[O:23])[CH2:9][C:8]2=3)=[CH:26][CH:27]=1
Reactant: COc1ccc(C=C2CS(=O)(=O)CC(=Cc3ccc(OC)cc3)C2(O)NC2=NCCS2)cc1
Solvent: CS(C)=O
Solvent: CCCCO
Product: COc1ccc(C=C2CS(=O)(=O)CC3=C2N=C2SCCN2C3c2ccc(OC)cc2)cc1

Procedure:
A suspension of 4-[(4,5-dihydro-2-thiazolyl)amino]-tetrahydro-3,5-bis[(4-methoxyphenyl)methylene]thiopyran-4-ol-1,1-dioxide (6.0 g, 0.012 mole) in 75 ml of n-BuOH and 25 ml of DMSO is stirred and heated at reflux for 1 hour. The volume of the resulting solution is reduced by approximately one-half using a Dean-Stark trap. After cooling, the yield of yellow product is 4.7 g, m.p. 235°-240°. Crystallization from 25 ml of DMF gives 4.0 g (69%) of cream colored product, m.p. 243°-245°.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:34])[CH2:15][CH2:16][C:17]2[CH:18]=[N:19][N:20]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:9][CH:8]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[C:28]1([N:20]2[C:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:17]([CH2:16][CH2:15][C:14]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:4]([OH:5])=[O:3])=[CH:12][CH:11]=3)=[O:34])[CH:18]=[N:19]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)CCc2cnn(-c3ccccc3)c2-c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccc(NC(=O)CCc2cnn(-c3ccccc3)c2-c2ccccc2)cc1
Yield: 94 %

Procedure:
A mixture of N-[4-(ethoxycarbonylmethyl)phenyl]-3-(1,5-diphenyl-1H-pyrazol-4-yl)propionamide (0.76 g), a 1N aqueous sodium hydroxide solution (5 ml) and ethanol (5 ml) was stirred at 50° C. for 3 hrs. The reaction mixture was poured into a 1N aqueous hydrochloric acid solution and the precipitated crystals were collected by filtration, washed with water and dried to give (4-{[3-(1,5-diphenyl-1H-pyrazol-4-yl)propanoyl]amino}phenyl)acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[CH:4]=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1c(Cl)cccc1Oc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1c(Cl)cccc1Oc1ccccc1
Yield: 94 %

Procedure:
19.0 g (77.67 mmol) of 2-chloro-6-phenoxybenzaldehyde in approximately 40 ml of tetrahydrofuran are added dropwise at room temperature in the course of 30 minutes to a suspension of 4.42 g (116.5 mmol) of lithium aluminium hydride in approximately 150 ml of tetrahydrofuran. The mixture is then heated under reflux for 4 hours, cooled and hydrolysed with 4.4 ml of water, 4.4 ml of 4N sodium hydroxide and 13.2 ml of water. The reaction mixture is boiled under reflux for 30 minutes, cooled and filtered, and the suction filter residue is 3× taken up in ethyl acetate, boiled under reflux for 15 minutes and filtered. The combined filtrates are concentrated. 17.97 g (76.57 mmol)=94% of crude (2-chloro-6-phenoxy-phenyl)-methanol are obtained in the form of a yellow oil; TLC (silica gel; ethyl acetate/hexane=1:1; UV): Rf =0.68; 1H-NMR (CDCl3, 200 MHz): 4.90 (s, 2H); 6.76-7.40 (m, 8H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12](I)[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2].C([Mg]Br)C.[CH3:20][CH2:21][C:22](=[O:25])[CH2:23][CH3:24]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([C:22]([CH2:23][CH3:24])([OH:25])[CH2:21][CH3:20])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(I)cc2s1
Reactant: CCC(=O)CC
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(C(O)(CC)CC)cc2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25 %

Procedure:
To a stirred solution of 6-iodo-benzo[b]thiophene-2-carboxylic acid ethyl ester (2.95 g, 8.88 mmol) in THF (60 mL) at −78° C. is added ethylmagnesium bromide (4.45 mL, 3.0 M). The reaction mixture is stirred for 15 min, and 3-pentanone (3.0 mL) is added. The mixture is allowed to warm to RT and stirred for 30 min. The reaction is quenched with HCl (15 mL, 1.0 M) and extracted with EtOAc (2×50 mL). The organic layer is dried over Na2SO4, concentrated, and purified by silica gel column chromatography to give the title compound (0.65 g, 25%).
Reaction SMILES: Cl.[CH:2]12[O:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][NH:4][CH2:3]2.[Cl:10][C:11]1[N:16]=[C:15](Cl)[N:14]=[C:13]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[N:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.CC(C)=O>[CH:6]12[O:9][CH:2]([CH2:8][CH2:7]1)[CH2:3][N:4]([C:15]1[N:16]=[C:11]([Cl:10])[N:12]=[C:13]([N:18]3[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]3)[N:14]=1)[CH2:5]2
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc(Cl)n2)CC1
Reactant: C1CC2CNCC1O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc(N3CC4CCC(C3)O4)n2)CC1
Temperature: 72.5 °C
Reaction time: 2 h

Procedure:
To a solution of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (0.49 g, 3.3 mmol) in water (18 mL) was added a suspension of tert-butyl 4-(4,6-dichloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate (1.0 g, 3.0 mmol) in acetone (about 10 mL). The suspension was stirred magnetically while solid sodium carbonate (0.70 g, 6.6 mmol) was added in a single portion. The mixture was stirred for two hours while heating in a 70-75° C. in an oil bath. After allowing the mixture to cool to room temperature, the title compound was removed by filtration, washed with water, and dried under vacuum.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[NH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)N>>[C:14]1([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Reactant: NNc1ccccn1
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1ccccn1
Yield: 64 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and 2-hydrazinopyridine according to the method described for Example 1 in 64% yield. MS: M=316.1 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([OH:37])[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:37][CH2:39][CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCN1CCOCC1
Reactant: CC(C)c1cc(C(=O)N2Cc3ccc(O)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(=O)N2Cc3ccc(OCCCN4CCOCC4)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 90 °C
Yield: 72.6 %

Procedure:
A mixture of (2,4-bis-benzyloxy-5-isopropyl-phenyl)-(5-hydroxy-1,3-dihydro-isoindol-2-yl)-methanone (100 mg, 0.2 mmol), 4-(3-chloropropyl)morpholine (82 mg, 0.5 mmol) and K2CO3 (104 mg, 0.75 mmol) in DMF (5 ml) was heated at 90° C. for 16 hours. The reaction mixture was diluted with EtOAc and filtered. The filtrate was reduced in vacuo and purified by flash column chromatography, eluting with 0-100% P.E./EtOAc then 0-10% MeOH/EtOAc to give the title compound as a colourless gel (90.1 mg). MS: [M+H]+ 621.
Reaction SMILES: CCCCN1C=[N+](C)C=C1.[CH:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:17]=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[Ni+2]>[CH2:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[CH2:17]=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: c1ccccc1
Agent: [Ni+2]
Agent: CCCCn1cc[n+](C)c1
Agent: O=S(=O)(NS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: C=CCCCCCC
Product: CCCCCCCCc1ccccc1

Procedure:
Nickel(II) bis-triflimide (0.06 g, 0.1 mmol) was dissolved in [bmim] [NTf2] (1.0 g) in a round-bottomed flask equipped with a magnetic stirrer and reflux condenser. Benzene (3.90 g, 50 mmol) and oct-1-ene (1.12 g, 10 mmol) were added. The mixture was heated under reflux for 18 hours and was analysed by gas chromatographic analysis as in previous examples. The oct-1-ene peak disappeared and three isomers of octylbenzene were formed (70%, 20:26:54 2- to 3- to 4-isomer ratio) as well as octene dimer (30%). The less dense product phase was decanted from the ionic/catalyst phase and purified by Kugelrohr distillation. The ionic liquid and catalyst were prepared for reuse by heating at 60° C. under vacuum for 1 hour. The ionic liquid and catalyst were used for further reactions of benzene with oct-1-ene without loss of activity. This is an alkylation of benzene with an alkene using a metal bis-triflimide catalyst. Benzene and oct-1-ene react in the presence of 1% nickel(II) bis-triflimide in [bmim] [NTf2] to form three isomers of octyl benzene and a small amount of hexadecene (unknown isomeric distribution). This reaction shown below:
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)[CH2:5][CH3:6])[CH3:3].C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl>[ClH:20].[CH2:2]([N:4]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([Cl:1])=[O:13])=[CH:15][CH:16]=1)[CH2:5][CH3:6])[CH3:3]
Reactant: CCN(CC)Cc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)Cc1ccc(C(=O)Cl)cc1
Temperature: 25 °C

Procedure:
To a well-stirred suspension consisting of 1.34 g. (5.0 mmole) of 4-(N,N-diethylaminomethyl)benzoic acid hydrochloride (the product of Preparation G) in 25 ml. of methylene chloride under a nitrogen atmosphere, there was added over a five-minute period a solution consisting of 1.5 g. (0.0118 mole) of oxalyl chloride dissolved in 5 ml. of methylene chloride. The resulting reaction mixture was refluxed for a period of 17 hours and then cooled to room temperature (~20° C.). The colorless solution so obtained was evaporated under reduced pressure, and the resulting residue was washed twice with methylene chloride and then stripped free of solvent to give a white solid product. In this way, there was readily obtained substantially pure 4-(N,N-diethylaminomethyl)benzoyl chloride hydrochloride, which was used in the next reaction step without any further purification being necessary. The yield of product was assumed to be quantitative.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:25][OH:26])[N:7]([CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[C:8]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16]C)[CH:11]=1)([CH3:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[OH:26][CH2:25][C:6]1[N:7]([CH2:18][C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)[C:8]([S:9][C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=1
Reactant: COc1cccc(Sc2c(C(C)C)nc(CO)n2Cc2ccncc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1nc(CO)n(Cc2ccncc2)c1Sc1cccc(O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a solution of alcohol 38 (56 mg, 0.15 mmol) in CH2Cl2 (2 mL) was added 1M BBr3 in CH2Cl2 at 0° C. See Scheme 22 (FIG. 24). After the reaction mixture was stirred for 1 h at 0° C., the mixture was partitioned between CH2Cl2 and sat. NaHCO3. The aqueous phase was neutralized with solid NaHCO3 and extracted with CH2Cl2 and EtOAc. The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude product was chromatographed on silica gel (eluting 5-10% MeOH/CH2Cl2) to give 3-(2-hydroxymethyl-5-isopropyl-3-pyridin-4-ylmethyl-3H-imidazol-4-ylsulfanyl)-phenol 39 (43 mg, 81%) as a colorless solid.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH:24]O.[OH-].[Na+].Cl>C(O)C>[OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]([NH2:17])=[O:24])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: OO
Reactant: CCCCCC(O)c1cccc(OCc2cccc(C#N)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCC(O)c1cccc(OCc2cccc(C(N)=O)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3[[3-(1-hydroxyhexyl)phenoxy]methyl]benzonitrile (5.0 g.), 30% hydrogen peroxide (6.6 ml), ethanol (9 ml) and 6N sodium hydroxide (0.7 ml) was stirred at room temperature for one hour. The reaction was then heated to 50° C. for three hours. The solution was neutralized with 5% aqueous hydrochloric acid and extracted with chloroform. The organic extract was dried (MgSO4) and concentrated to a solid. The solid was recrystallized from ethyl acetate giving 3.4 g (63%) yield) of solid, m.p. 97°-98° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>CN(C)C=O>[CH2:20]([O:19][C:17]([CH2:16][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: O=C(CBr)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)cc(OCC(=O)OCc2ccccc2)c1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
To a mixture of methyl 3,5-dihydroxybenzoate (20 g) in N,N-dimethylformamide (200 ml) was added sodium hydride (60% in mineral oil, 5.23 g) slowly at 10° C. After stirring at 10° C. for 30 minutes, benzyl bromoacetate (20.7 ml) was added dropwise to the mixture over 10 minutes. The reaction mixture was stirred at room temperature overnight and then evaporated in vacuo. Ethyl acetate (400 ml) and water (100 ml) was added to the residue and the mixture was adjusted to pH 5 with hydrochloric acid. Two layers were separated and the organic layer was washed successively with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (20:1). The fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-benzyloxycarbonylmethoxy-5-hydroxybenzoate (12.92 g).
Reaction SMILES: [CH2:1]([O:17][C:18]1[N:23]=[C:22]([O:24]CCCCCCCCCCCCCCCC)[C:21]([F:41])=[CH:20][N:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>[OH-].[K+].C(O)C>[CH2:1]([O:17][C:18]1[NH:23][C:22](=[O:24])[C:21]([F:41])=[CH:20][N:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOc1ncc(F)c(OCCCCCCCCCCCCCCCC)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCOc1ncc(F)c(=O)[nH]1
Yield: 73 %

Procedure:
A 2.9 g portion of the 2,4-di-(n-hexadecyloxy)-5-fluoropyrimidine is dissolved in a mixture of 5 ml of 2N aqueous potassium hydroxide solution and 25 ml of ethanol, and the solution is refluxed for 4 hours. The ethanol is distilled off from the resulting reaction mixture, and 50 ml of ether is added to the residue to remove ether-soluble substances. Dilute hydrochloric acid is added to the remaining mass to adjust the pH to 4-5 and to separate out crystals, which are recrystallized from ethanol to give 1.3 g of white crystalline 2-n-hexadecyloxy-5-fluoropyrimidin-4-one in a yield of 73.0%, m.p. 97°-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][C:8](N)=[CH:7]2.N([O-])=O.[Na+].C(=O)(O)[O-].[Na+].[ClH:22]>>[Cl:22][C:8]1[N:9]=[CH:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[Cl:1]
Reactant: Nc1cc2cccc(Cl)c2cn1
Reactant: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Product: Clc1cc2cccc(Cl)c2cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
8-Chloroisoquinolin-3-amine (724 mg, 4.05 mmol) was suspended in 10 M HCl and cooled to 0° C. Sodium nitrite (336 mg, 4.86 mmol) was added in portions over 10 minutes. The reaction mixture was stirred for 2 hours, slowly warming to room temperature over an additional 1 hour. After 3 hours, the mixture was poured cautiously into saturated sodium bicarbonate solution, and extracted into ethyl acetate. The organic extract was washed with brine, dried (Na2SO4) and concentrated. Flash chromatography on silica, eluting with dichloromethane, gave the title compound as a white solid (362 mg, 1.83 mmol, 45%). 1H NMR (d6-DMSO, 400 MHz) δ 9.40 (br t, 1H, J=0.8 Hz), 8.20 (br s, 1H), 8.00-7.98 (m, 1H), 7.88-7.81 (m, 2H). LCMS (3) Rt=2.49 min; m/z (ESI+) 198 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([C:23]2[C:24]([O:35]C)=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:26]=[CH:27][CH:28]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)O)=[CH:13][CH:12]=[CH:11][C:10]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)C1C=CC=CC=1>C(#N)C>[CH3:1][O:8][C:9]1[C:14]([CH:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:24]=2[OH:35])=[CH:13][CH:12]=[CH:11][C:10]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COc1c(-c2ccccc2)cccc1C(O)(c1ccccc1)c1cccc(-c2ccccc2)c1OCc1ccccc1
Solvent: CC#N
Product: COc1c(-c2ccccc2)cccc1C(c1ccccc1)c1cccc(-c2ccccc2)c1O
Yield: 38.9 %

Procedure:
A solution of crude 8 (2.2 g) in acetonitrile (50 mL) was treated with 50% aqueous hypophsophorous acid (22 mL) and stirred at reflux overnight. After cooling, the acetonitrile was removed on a rotary evaporator. The residue was taken in ethyl acetate (150 mL) and washed with water (2×100 mL), saturated sodium bicarbonate (100 mL) and water (100 mL). The organic layer was dried over sodium sulfate and stripped. The residue was chromatographed on silica (60 g) with 0.5% ethyl acetate in hexane (3 L). The relevant fractions were stripped and the residue was triturated with a little ethanol. The solid was collected by filtration, washed with cold ethanol and dried in a vacuum oven at 65° C. to produce pure B2 (0.69 g, 37% over 2 steps).