Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl:23]N1C(=O)CCC1=O>ClCCCl>[Cl:23][C:21]1[CH:22]=[C:16]([S:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:15])=[O:14])[CH:17]=[CH:18][C:19]=1[NH2:20]
Reactant: CCCCCCCCCCCCS(=O)(=O)c1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCCl
Product: CCCCCCCCCCCCS(=O)(=O)c1ccc(N)c(Cl)c1
Reaction time: 0.75 h
Yield: 173 %

Procedure:
A stirred mixture of 4-dodecylsulfonylaniline (519.6 g 1.6 moles), 1,2-dichloroethane (2.5 liters) and N-chlorosuccinimide (110 g 0.825 moles) was heated under reflux for 45 minutes. A further 60 g (0.45 moles) of N-chlorosuccinimide was added and heating was continued for 45 minutes. A further 53 g of N-chlorosuccinimide (0.40 moles) was added and heating was maintained for another hour. The total amount of N-chlorosuccinimide was used 223 g (1.67 moles). TLC showed no starting material. The solvent was removed on the rotovapor and the residue was dissolved in ethyl acetate (2 liters). The solution was washed with 3×15 liters of hot water, then it was dried over magnesium sulfate and the solvent was removed. The product was recrystalized twice from petroleum ether (bp 60°-80° C.) containing a little ethyl acetate to give 513.6 g (89%) of pure material.
Reaction SMILES: ClCC(=O)C.Cl[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]>>[C:10]1([C:8]([CH3:7])=[O:9])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(CCl)c1ccccc1
Agent: CC(=O)CCl
Product: CC(=O)c1ccccc1

Procedure:
The procedure for Cpd. 1 is used for Cpd. 4 with minor changes. Instead of chloroacetone, α-chloroacetophenone is used.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9]1([CH:16]([OH:18])O)[C:10](C)=[CH:11][CH:12]=[CH:13][CH:14]=1.CS(O)(=O)=O.C[C:25](C)=[O:26]>O>[CH:5]1[C:6]([OH:7])=[CH:1][CH:2]=[C:3]([CH3:8])[CH:4]=1.[OH:18][CH2:16][C:9]1[CH:14]=[CH:13][C:12]([CH2:25][OH:26])=[CH:11][CH:10]=1
Reactant: Cc1ccccc1C(O)O
Reactant: CC(C)=O
Agent: CS(=O)(=O)O
Agent: Cc1ccc(O)cc1
Solvent: O
Product: OCc1ccc(CO)cc1
Reaction time: 2 h

Procedure:
p-Cresol in an amount of 38.4 g (0.36 mole) and 35.0 g (0.25 mole) of xylene-α,α-diol were dissolved with heating, followed by addition of 0.15 g of methanesulfonic acid at 90° to 100° C. The reaction was carried out at 90° to 100° C. for 2 hours with stirring. After cooling, 100 ml of acetone was poured into the reaction solution. After dissolving, the reaction solution was poured into 2000 ml of water and stirred. After allowed to stand, a supernatant was removed by decantation. The residue was dissolved in 100 ml of acetone, followed by pouring into 2000 ml of water and stirring. After allowed to stand, a supernatant was removed by decantation. The residue was dried under reduced pressure to give 65.0 g of pale yellowish powdered crystals of p-cresol/1,4-dihydroxymethylbenzene polycondensate. Mw was about 6,700 and the degree of dispersion was 3.50 (GPC method, polystyrene standard).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.Cl.[NH2:17][CH2:18][C:19]1([NH2:25])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(N(CC)CC)C>O1CCOCC1.O>[NH2:25][C:19]1([CH2:18][NH:17][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: NCC1(N)CCOCC1
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: NC1(CNc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CCOCC1
Temperature: 110 °C

Procedure:
A mixture of 4-chloro-3-nitrobenzenesulfonamide, 4-(aminomethyl)tetrahydro-2H-pyran-4-amine bis-hydrochloric acid salt and triethylamine in dioxane (10 mL) was heated at 110° C. overnight. After cooling, the reaction mixture was diluted with water (10 mL), and the solid was filtered to give the title compound.
Reaction SMILES: Cl[C:2]1C2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1C=O.O[CH:21]1[CH2:26]S[CH:24]([OH:27])[CH2:23][S:22]1.C(N(CC)CC)C.O>N1C=CC=CC=1>[C:12]1([CH:4]2[C:3]3[CH:2]=[C:23]([CH:24]=[O:27])[S:22][C:21]=3[C:26]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:5]2)[CH:13]=[CH:14][CH2:15][CH2:16][CH:17]=1
Reactant: OC1CSC(O)CS1
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: O
Product: O=Cc1cc2c(s1)-c1ccccc1OC2C1=CCCC=C1
Reaction time: 8 h

Procedure:
To a suspension of 4.2 g 4-chloro-3-formyl-flav-3-ene in 10 ml pyridine is added a solution of 2.6 g 2,5-dihydroxy-1,4-dithian and 2.2 g triethylamine in 11 ml pyridine. After overnight stirring one adds slowly 100 ml water and the precipitate is collected, washed with water, dried, and crystallized in absolute ethanol. Pure 4H-4-phenyl-thieno[3,2-c][1]benzopyran-2-carboxaldehyde is obtained; m.p. 117°-118° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:15][C@H:14]3[N:11]([C:12](=[O:26])[C@@H:13]3[C@H:16]([O:18][Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH3:17])[C:10]=2[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])[CH:6]=[CH:7][CH:8]=1.C(N(CC)C(C)C)(C)C.[CH3:42][N:43]=[C:44]=[O:45]>ClCCl>[CH3:42][NH:43][C:44]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:15][C@H:14]3[N:11]([C:12](=[O:26])[C@@H:13]3[C@H:16]([O:18][Si:19]([CH2:20][CH3:21])([CH2:24][CH3:25])[CH2:22][CH3:23])[CH3:17])[C:10]=2[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])[CH:6]=[CH:7][CH:8]=1)=[O:45]
Reactant: CN=C=O
Reactant: C=CCOC(=O)C1=C(c2cccc(CO)c2)C[C@@H]2[C@@H]([C@@H](C)O[Si](CC)(CC)CC)C(=O)N12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)C1=C(c2cccc(COC(=O)NC)c2)C[C@@H]2[C@@H]([C@@H](C)O[Si](CC)(CC)CC)C(=O)N12
Reaction time: 24 h
Yield: 43.4 %

Procedure:
Allyl (5R,6S)-3-[3-(hydroxymethyl)phenyl]-7-oxo-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (250 mg) prepared in the above step, was dissolved in dichloromethane (10 ml), and thereto were added N,N-diisopropylethylamine (14 mg) and methyl isocyanate (276 mg). The mixture was stirred for 1 day, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform) to give allyl (5R,6S)-3-[3-({[(methylamino)carbonyl]oxy}methyl)phenyl]-7-oxo-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (122 mg).
Reaction SMILES: NCCC1N=CN([C:9](C2C=CC=CC=2)(C2C=CC=CC=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)C=1.[C:28]1([C:34]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[N:35]2[CH:39]=[C:38]([CH2:40][CH2:41][NH:42][S:43]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])(=[O:45])=[O:44])[N:37]=[CH:36]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(Br)C1C=CC=CC=1>>[C:60]1([C:34]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[N:35]2[CH:39]=[C:38]([CH2:40][CH2:41][NH:42][S:43]([N:46]([C:47]([O:49][C:50]([CH3:53])([CH3:51])[CH3:52])=[O:48])[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:45])=[O:44])[N:37]=[CH:36]2)[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: BrCc1ccccc1
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)S(=O)(=O)NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
4-(2-Aminoethyl)-1-(triphenylmethyl)-imidazole (Example 17 step b) was converted to N-2-[1-(triphenylmethyl)imidazol-4-yl]ethyl-N'-tert-butoxycarbonyl-sulfamide according to the procedure of Example 12 step a. The subsequent alkylation with benzyl bromide was performed essentially as Example 12 step b and gave N-[2-(1-(triphenylmethyl)imidazol-4-yl)ethyl]-N'-tert-butoxycarbonyl-N'-phenylmethyl-sulfamide. The final deprotection was carried out in the manner of Example 17 step b and the title compound (Rf 0.21; 1:10:90 ammonia(880)/methanol/dichloromethane) was isolated as a colourless oil: 1H NMR (300 Hz, d6 -DMSO) 7.50(1H, s), 7.30(6H, m), 6.95(1H, t), 6.78(1H, s), 3.96(2H, s), 3.03(2H, dd), 2.65(2H, t). The maleate salt was prepared by lyophilysis of an equimolar solution of the product and maleic acid in water/dioxan. Found: C 48.05, H 5.10, N 13.87%; C16H2ON4O6S requires: C 48.48, H 5.09 N 14.13%.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.C(O)C.C(#N)C.C([O-])(=O)C.[Ca+2:43].C([O-])(=O)C>CCCCCCC.O>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[Ca:43]
Reactant: [Ca+2]
Agent: CC(=O)[O-]
Agent: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Solvent: CCCCCCC
Solvent: CCO
Solvent: O
Product: [Ca]
Temperature: 67.5 °C
Reaction time: 6 h

Procedure:
Raltegravir (10 gm), ethanol (60 ml), acetonitrile (40 ml), water (2 ml) and calcium acetate (4 gm) were added at 25 to 30° C. The contents were heated to 65 to 70° C. and distilled off solvent completely under vacuum at 45° C. to obtain residue. To the residue was added n-heptane (50 ml) and again distilled to obtain residue. n-Heptane (100 ml) was added to the residue and stirred for 6 hours at room temperature. The solid obtained was collected by filtration and dried to obtain 10.2 gm of raltegravir calcium.
Reaction SMILES: Br[C:2]1[C:3]([N:25]2[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]2)=[N:4][CH:5]=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=1)=[O:8].[F:31][C:32]1[CH:33]=[N:34][CH:35]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:37]=1>>[F:31][C:32]1[CH:37]=[C:36]([C:2]2[C:3]([N:25]3[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:23])([F:22])[C:18]([F:20])([F:21])[F:19])=[CH:14][CH:15]=3)=[O:8])[CH:24]=2)[CH:35]=[N:34][CH:33]=1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 185 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethoxy)phenyl)nicotinamide (Stage 220.1) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford an off-white foam. HPLC (Condition 4) tR=5.58 min, UPLC-MS (Condition 3) tR=1.07 min, m/z=513.4 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.76 (m, 1H) 1.78-1.89 (m, 1H) 2.86 (d, J=11.34 Hz, 1H) 3.13-3.26 (m, 2H) 3.33-3.43 (m, 1H) 4.19 (br. s, 1H) 4.85 (d, J=3.13 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.76-7.90 (m, 3H) 8.03-8.09 (m, 1H) 8.49 (s, 1H) 8.58 (d, J=2.74 Hz, 1H) 8.72-8.82 (m, 1H) 8.99-9.00 (m, OH) 10.16 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH:18]([C:20]4[O:24][N:23]=[C:22]([CH3:25])[N:21]=4)[CH2:19][CH:12]2[C:13](=[CH:27]O)[C:14](=O)[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(O)(=O)C.O.[NH2:34][NH2:35]>CCO.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:16]3[CH2:15][C:14]4[NH:34][N:35]=[CH:27][C:13]=4[CH:12]2[CH2:19][CH:18]([C:20]2[O:24][N:23]=[C:22]([CH3:25])[N:21]=2)[CH2:17]3)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: NN
Reactant: Cc1noc(C2CC3CC(=O)C(=CO)C(C2)N3S(=O)(=O)c2ccc(Cl)cc2)n1
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1noc(C2CC3Cc4[nH]ncc4C(C2)N3S(=O)(=O)c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 9-[(4-chlorophenyl)sulfonyl]-2-(hydroxymethylidene)-7-(3-methyl-1,2,4-oxadiazol-5-yl)-9-azabicyclo[3.3.1]nonan-3-one (53) (0.38 g, 0.902 mmol) in EtOH (5 mL) was added glacial acetic acid (0.1 mL) followed by hydrazine monohydrate (0.44 mL, 9.02 mmol). The reaction mixture was stirred at room temperature for 2 h and then at 50° C. for a further 2 h. The resulting solution was diluted with EtOAc and washed with H2O. The organic phase was dried (Na2SO4), filtered, concentrated and purified by silica gel column chromatography (eluant hexane/EtOAc, 9/1 to 2/8) and preparative HPLC to give 10-[(4-chlorophenyl)sulfonyl]-6-(3-methyl-1,2,4-oxadiazol-5-yl)-4,5,6,7,8,9-hexahydro-1H-4,8-epiminocycloocta[c]pyrazole (54). MS (ESI) 420.1 (M+H). 1H NMR (300 MHz, CDCl3) δ 7.67 (d, J=8.8 Hz, 2H), 7.52 (s, 1H), 7.39 (d, J=8.8 Hz, 2H), 5.43 (bs, 1H), 4.66 (bs, 1H), 3.06 (m, 1H), 2.72 (d, J=17.6 Hz, 1H), 2.34 (s, 3H), 2.32-2.09 (m, 4H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[CH:6]=[C:5]([O:14]C)[C:4]=1[C:16]1[N:21]=[N:20][C:19]([N:22]([CH3:33])[CH:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)=[CH:18][CH:17]=1.C1(S)C=CC=CC=1>>[CH3:33][N:22]([CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]1)[C:19]1[N:20]=[N:21][C:16]([C:4]2[C:5]([OH:14])=[CH:6][C:7]([C:9]3[CH:13]=[N:12][NH:11][CH:10]=3)=[CH:8][C:3]=2[OH:2])=[CH:17][CH:18]=1
Reactant: COc1cc(-c2cn[nH]c2)cc(OC)c1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Agent: Sc1ccccc1
Product: CN(c1ccc(-c2c(O)cc(-c3cn[nH]c3)cc2O)nn1)C1CC(C)(C)NC(C)(C)C1

Procedure:
From compound 6-(2,6-dimethoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (43 mg, 0.095 mmol), following GENERAL METHOD 3-1 for methoxy deprotection using thiophenol (22.1 mg, 0.2 mmol), compound 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)benzene-1,3-diol was afforded as a pale yellow solid (20 mg, 45% yield) after HPLC purification. LCMS Rt=0.41 min [Method Q], MS (M+1)=423.3. 1H NMR (METHANOL-d4) δ 8.60 (d, J=10.1 Hz, 1H), 7.91 (s, 2H), 7.20 (d, J=10.1 Hz, 1H), 6.66 (s, 2H), 5.01 (t, J=12.4 Hz, 1H), 2.90-3.01 (m, 3H), 1.64-1.73 (m, 2H), 1.52-1.61 (m, 2H), 1.38 (s, 6H), 1.23 (s, 6H).
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[Cl:10][C:11]1[N:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.[Cl-].[NH4+]>O1CCCC1>[Cl:10][C:11]1[C:12]([C:13](=[O:15])[C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[CH:4]=2)=[CH:16][CH:17]=[C:18]([CH3:20])[N:19]=1
Reactant: Cc1cccc(Br)c1
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)c2ccc(C)nc2Cl)c1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
Magnesium (4.82 g, 200 mmol) was added to a tetrahydrofuran (300 ml) solution of 3-bromotoluene (35.1 g, 200 mmol), and the mixture was stirred at room temperature. Since spontaneous exothermic reaction occurred, the stirring was continued until the exothermicity was ceased. The reaction solution was cooled to -40° C., mixed with 2-chloro-6-methylnicotinic acid (11.6 g, 68 mmol) and then stirred for 16 hours at room temperature. The reaction solution was mixed with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration and then the filtrate was concentrated under a reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2-chloro-6-methyl-3-(3-methylbenzoyl)pyridine (8.70 g, 52%) as a pale yellow oily material.
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1.[BH4-].[Na+]>CO>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:7]([OH:8])[CH2:6][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:10][CH:11]=1
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(Cn1cncn1)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
A suspension of α-1,2,4-triazol-1-yl-p-chloroacetophenone (4 g) in methanol (12 ml) was treated with sodium borohydride (0.5 g) with cooling and stirring. The mixture was then left at room temperature for 0.5 hour and refluxed for 1 hour. The methanol was removed under reduced pressure and water (25 ml) was added followed by dilute hydrochloric acid (10 ml). The white solid was filtered, washed with water and dried. Crystallisation from ethyl acetate-petroleum ether (60°-80°) gave the title compound as a white crystalline solid. Analysis:
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([O:9][CH2:10][C:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[CH3:15])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([C@H:14]([NH:13][C:11](=[O:12])[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:26][CH:25]=2)[CH3:15])=[CH:17][CH:18]=1
Reactant: C[C@@H](NC(=O)COc1ccc(C(C)(C)C)cc1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H](NC(=O)COc1ccc(C(C)(C)C)cc1)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 128.7 %

Procedure:
A mixture of 2-(4-tert-butylphenoxy)-N-[(1R)-1-(4-nitrophenyl)ethyl]acetamide (360 mg, 1.0 mmol) and 10% Pd—C (50 mg) in methanol (10 ml) was stirred under H2 balloon pressure for 1 hour at ambient temperature. Then, filtration to remove 10% Pd—C, evaporation gave 420 mg of the title compound as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][O:8][CH2:9][CH:10]=[CH:11][CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[OH-:25].[Na+].[BH4-].[Na+].[Cl-].[Na+]>O1CCCC1.FC(F)(F)C([O-])=O.[Hg+2].FC(F)(F)C([O-])=O>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][O:13][CH2:12][CH:11]([OH:25])[CH2:10][CH2:9][O:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:24][CH:23]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(COCC=CCOCc2ccc(OC)cc2)cc1
Reactant: [OH-]
Agent: O=C([O-])C(F)(F)F
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1ccc(COCCC(O)COCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To a solution of mercury (II) trifluoroacetate (17.1 g, 40 ml) in aqueous tetrahydrofuran (1:1, 80 ml) was added a solution of 1,4-bis(4-methoxybenzyloxy)but-2-ene (12.8 g, 39 mmol) in tetrahydrofuran (10 ml) over 5 minutes. The resulting 2-phase mixture was stirred vigorously at room temperature for 15 minutes. To the mixture was added aqueous sodium hydroxide (40 ml, 3M) followed by sodium borohydride (0.5M solution in 3M sodium hydroxide; 40 ml) with water-bath cooling. The solution was saturated with sodium chloride and allowed to stand. The organic layer was collected, dried (magnesium sulphate) and filtered through celite. The solvent was removed to afford 1,4-bis(4-methoxybenzyloxy)butan-2-ol (12.27 g, 91%), IR: υmax (KBr) 3440, 2940, 2860, 1610, 1510 and 1250 cm-1 ; 1H NMR: δH (CDCl3) 1.76 (2H, q, J=6.0 Hz, 3-H), 2.90 (1H, br, D2O exchangeable, OH), 3.41 (2H, AB of ABX JAX =6.9 Hz, JBX =4.2 Hz and JAB =9.5 Hz, 1-H), 3.62 (2H, m, 4-H), 3.80 (6H, s, 2×CH3), 4.00 (1H, m, 2-H), 4.43 (2H, s, ArCH2), 4.48 (2H, s, ArCH2), 6.86 (4H, m, ArH) and 7.24 (4H, m, ArH).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([OH:16])[C:8]=1[CH2:17][CH2:18][CH3:19])[CH3:2].[S:21]([O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33]OS(=O)(=O)C)(=[O:24])(=[O:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][S:21]([CH3:22])(=[O:23])=[O:24])[C:8]=1[CH2:17][CH2:18][CH3:19])[CH3:2]
Reactant: CS(=O)(=O)OCCOCCOCCOS(C)(=O)=O
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOCCOS(C)(=O)=O
Yield: 52 %

Procedure:
A mixture of 3.3 g (0.012 mole) of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid ethyl ester, 18.0 g (0.059) of triethyleneglycol dimesylate and 3.3 g (0.024 mole) of anhydrous potassium carbonate in 100 ml of anhydrous acetone and 45 ml of anhydrous dimethylformamide was stirred at reflux for 26 hours. The reaction mixture was concentrated in vacuo to yield an oil which was dissolved in 60% ethyl acetate-toluene and passed through a column of 60 g of silica gel. The eluent was concentrated in vacuo and purified by HPLC using 35% ethyl acetate-toluene to give 3.06 g (53% yield) of [4-acetyl-3-[2-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[N:5][N:4]([CH3:9])[N:3]=1.[H-].[Na+].Cl[C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22]>O1CCCC1>[CH3:9][N:4]1[N:3]=[C:2]([NH:1][C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[CH:15][C:14]=2[N+:21]([O-:23])=[O:22])[C:6]([C:7]#[N:8])=[N:5]1
Reactant: Cn1nc(N)c(C#N)n1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1nc(C#N)c(Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])n1
Reaction time: 0.25 h

Procedure:
To a solution of 4-amino-2-methyl-1,2,3-triazole-5-carbonitrile (1.7 g) in tetrahydrofuran (40 ml) under nitrogen was added sodium hydride (1.0 g, 50% oil dispersion) at room temperature. After 15 minutes, 2,4,5-trichloronitro-benzene (3.13 g) was added to the mixture, which was stirred for six hours under nitrogen. The deep-red solution was then quenched in ice/water/HCl and filtered to leave a yellow-orange solid. The solid was chromatographed on a magnesium silicate column using dichloromethane. The purified product was recrystallised from ethanol to give an orange crystalline solid, melting point 148°-150° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl.Cl[CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][CH:3]=1
Reactant: CCN(CC)CCCl
Reactant: Oc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCOc1ccc(Br)cc1

Procedure:
4-Bromophenol (0.870 g, 5.00 mmol), 2-chloro-N,N-diethylethanamine hydrochloride (0.90 mg, 5.24 mmol) and Cs2CO3 (8 g, 25 mmol) were combined in DMF (20 mL) and the mixture was heated at reflux over night. H2O (20 mL) was added and the mixture was extracted with EtOAc, then washed with 2N NaOH and brine. The organic layers were combined, dried over Na2SO and concentrated to a brown oil which was then purified by flash chromatography (eluent: 20% EtOAc in hexanes).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C.CS(C)=O>O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:16]1[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ccnc2ccc(Br)cc12
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccnc3ccc(Br)cc23)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
A mixture of 243 mg 6-bromo-4-chloroquinoline, 373 mg t-butyl 1-piperazine carboxylate, 0.28 mL triethylamine and 10 mL dimethyl sulfoxide was stirred at 80° C. overnight. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated, washed twice with water and then with brine and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 282 mg of the title compound as a pale yellow oil.