Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][CH:13]=[CH2:14])[CH:6]=1)C.[OH-].[Na+].Cl>O>[CH2:12]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[OH:11])[C:4]([OH:15])=[O:3])[CH:13]=[CH2:14]
Reactant: C=CCc1cc(C(=O)OCC)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCc1cc(C(=O)O)ccc1O
Reaction time: 18 h
Yield: 91 %

Procedure:
Ethyl-3-allyl-4-hydroxybenzoate (1.03 g) was added to a cold solution of sodium hydroxide pellets (0.8 g) in water (10 ml) and the mixture was stirred for 18 hours. 2N aqueous hydrochloric acid was added to acidify the reaction mixture and to give a solid which was extracted into dichloromethane. The organic phase was separated, washed with water, saturated brine and dried (MgSO4). Evaporation gave 3-allyl-4-hydroxybenzoic acid (0.81 g) as a solid, m.p. 119°-123° C.; microanalysis, found C, 66.1; H, 5.9%; C10H10O3 0.2H2O requires: C, 66.1; H, 5.77%; NMR(DMSO-d6): 3.31(2H,d), 4.95-5.17(2H,m), 5.85-6.05(1H,m), 6.85(1H,d), 7.55-7.75(2H,m), 10.15(1H,s), 12.30(1H,s); m/z 179(M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][S:8][C:4]=2[CH:3]=1.[F-:15].[K+].C1OCCOCCOCCOCCOCCOC1.C(Cl)Cl>C(#N)C.C(OCC)(=O)C>[F:15][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: Cc1nsc2cc(Cl)c([N+](=O)[O-])cc12
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: ClCCl
Product: Cc1nsc2cc(F)c([N+](=O)[O-])cc12

Procedure:
A mixture of 6-chloro-3-methyl-5-nitro-1,2-benzisothiazole (2.25 g, 9.80 mmol), potassium fluoride (2.85 g, 49.0 mmol), and 18-crown-6 (1.50 g, 5.70 mmol) in acetonitrile is heated in a sealed tube for 29 days, filtered to remove solids, and partially concentrated in vacuo to obtain a liquid. The liquid is diluted with ethyl acetate, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a dark, brown solid. Flash column chromatography of the solid using silica gel and a 10% to 50% ethyl acetate in hexanes gradient gives a yellow solid containing two components. Flash column chromatography of the yellow solid using silica gel and a 50% to 70% methylene chloride in hexanes gradient gives the title product as a pale, yellow solid (0.870 g, mp 118-119° C.) which is identified by NMR spectral analyses.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+].Cl>O.CO>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc(O)c(C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(O)c(CNc2ccccc2)c1
Reaction time: 20 h

Procedure:
A mixture of 15.2 g 2-hydroxy-5-methoxy benzaldehyde, 93 g of aniline and 100 ml of methanol was stirred at 25° for 20 hours. The mixture was then cooled with an ice-bath and stirred, and 3.9 g of sodium borohydride was added slowly. The mixture was stirred for 1 hour at 25°, 150 ml of water was added and the pH was adjusted to 7.0 with 2.5N hydrochloric acid. The resultant solid was collected, washed with water and purified by chromatography on silica gel using 3:17 ethyl acetate:n-hexane as an eluant. A 17.7 g yield of N-(2-hydroxy-5-methoxybenzyl)aniline was obtained. M.p. 82°-84°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:29][CH2:30][C:31](Cl)=[O:32].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([C:31](=[O:32])[CH2:30][Cl:29])[C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1CC[C@H](NCCNC(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@H](N(CCNC(=O)OC(C)(C)C)C(=O)CCl)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl trans-4-({2-[(t-butoxycarbonyl)amino]ethyl}amino)-cyclohexanecarboxylate (785 mg) obtained in Reference Example 71 (1) is dissolved in chloroform (8 ml), and thereto are added triethylamine (1.82 ml) and chloroacetyl chloride (249 μl) under ice-cooling. The mixture is then stirred at room temperature for 2 hours. The reaction solution is cooled with ice again, and chloroacetyl chloride (62 μl) is supplied thereto. The mixture is stirred at room temperature for 1 hour. To the reaction solution, saturated aqueous sodium hydrogen carbonate solution is poured and the mixture is extracted with chloroform. The organic layer is washed with water and saturated brine successively, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1, followed by 1/1) to give methyl trans-4-[{2-[(t-butoxycarbonyl)amino]ethyl}-(chloroacetyl)amino]cyclohexanecarboxylate (568 mg).
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[Br:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br.[CH3:21][C:22]([NH:25][C:26]1[O:27][C:28]([C:35]([OH:37])=[O:36])=[C:29]([C:31]([F:34])([F:33])[F:32])[N:30]=1)([CH3:24])[CH3:23]>O>[CH3:24][C:22]([NH:25][C:26]1[O:27][C:28]([C:35]([O:37][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[Br:12])=[O:36])=[C:29]([C:31]([F:32])([F:34])[F:33])[N:30]=1)([CH3:21])[CH3:23]
Reactant: BrCc1ccccc1Br
Reactant: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)OCc2ccccc2Br)o1
Temperature: 25 °C
Yield: 145.4 %

Procedure:
A reaction vessel was charged with 100 ml of dimethylformamide, 6.11 g (50 mmol) of potassium carbonate, and 18 g (72 mmol) of o-bromobenzyl bromide. With this mixture stirred at ambient temperature under a nitrogen atmosphere, there was added 10 g (40 mmol) of 2-[(1,1-dimethylethyl)amino]-4-trifluoromethyl-5-oxazolecarboxylic acid (prepared by Example 26). The reaction mixture was stirred at ambient temperature for 18 hours. Then, the mixture was added to water and extracted three times with ethyl ether. The ether extracts were washed with large amounts of water, then dried over magnesium sulfate, and concentrated under reduced pressure to yield 24.5 g of a gold oil. This oil was subjected to Kugelrohr distillation (65°-70° C. @ 0.4 mm Hg) to yield 9.7 g of a gold oil. The remaining still residue upon standing at ambient temperature for 30 minutes formed a solid material. Trituration of this solid material in hexane at ambient temperature resulted in 11.48 g of a white solid product (m.p.=74°-77° C.) identified in Table I.
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]2[O:7][C:8]3[C:13]([C:14](=[O:18])[C:15]=2[O:16][CH3:17])=[C:12]([OH:19])[CH:11]=[C:10]([O:20][CH3:21])[CH:9]=3)=[CH:4][C:3]=1[O:24][CH3:25].C([O:29][C@@H:30]1[C@@H:35]([O:36]C(=O)C)[C@H:34]([O:40]C(=O)C)[C@@H:33]([CH2:44][O:45]C(=O)C)[O:32][C@@H:31]1Br)(=O)C.[OH-].[Na+]>CC(C)=O>[C@@H:31]1([O:1][C:2]2[CH:23]=[CH:22][C:5]([C:6]3[O:7][C:8]4[C:13]([C:14](=[O:18])[C:15]=3[O:16][CH3:17])=[C:12]([OH:19])[CH:11]=[C:10]([O:20][CH3:21])[CH:9]=4)=[CH:4][C:3]=2[O:24][CH3:25])[O:32][C@H:33]([CH2:44][OH:45])[C@@H:34]([OH:40])[C@H:35]([OH:36])[C@H:30]1[OH:29]
Reactant: COc1cc(O)c2c(=O)c(OC)c(-c3ccc(O)c(OC)c3)oc2c1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1cc(O)c2c(=O)c(OC)c(-c3ccc(O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c(OC)c3)oc2c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 106.1 %

Procedure:
To an ice-cooled solution containing 250 mg of 4',5-dihydroxy-3,3',7-trimethoxyflavone in 10 ml of acetone were alternately added a solution of 400 mg of 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide in 10 ml of acetone, and 5 ml of 0.8% aqueous sodium hydroxide over 30 minutes, while stirring. After allowing the reaction mixture to stand at room temperature for 3 hours, 20 ml of 0.2% aqueous sodium hydroxide were added thereto. Stirring was continued at room temperature for 3 hours, during which time crystallization took place. The crystals were collected by filtration and recrystallized from ethanol to give 390 mg (80% yield) of 4'-(β-D-glucopyranosyloxy)-5-hydroxy-3,3',7-trimethoxyflavone as pale yellow needles: m.p. 203°-204° C.
Reaction SMILES: [CH2:1]([S:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([O:17]CC)=[O:16])=[CH:10][C:9]=1[F:21])(=[O:5])=[O:4])[CH3:2].[OH-].[Na+]>O1CCCC1.O>[CH2:1]([S:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([OH:17])=[O:16])=[CH:10][C:9]=1[F:21])(=[O:5])=[O:4])[CH3:2]
Reactant: CCOC(=O)C(C)c1ccc(CNS(=O)(=O)CC)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCS(=O)(=O)NCc1ccc(C(C)C(=O)O)cc1F
Reaction time: 8 h
Yield: 100.6 %

Procedure:
To a solution of ethyl 2-(4-(ethylsulfonamidomethyl)-3-fluorophenyl)propanoate (60 mg, 0.189 mmol) in tetrahydrofuran and water co-solvent, sodium hydroxide (19 mg) was added at room temperature. The mixture was stirred for overnight and extracted with ethyl acetate, dried over magnesium sulfate, the solvent was evaporated in vacuo. It was purified by column chromatography to give 2-(4-(ethylsulfonamidomethyl)-3-fluorophenyl)propanoic acid (55 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:25]=[CH:26]/[C:27](O)=[O:28])[CH:5]=[C:6]([CH3:24])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:11][N:10]=1.[CH3:30][N:31]([CH3:54])[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([CH2:47][N:48]3[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]3)=[CH:43][CH:42]=2)=[CH:34][CH:33]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:25]=[CH:26]/[C:27]([N:51]2[CH2:50][CH2:49][N:48]([CH2:47][C:44]3[CH:45]=[CH:46][C:41]([CH2:40][CH2:39][O:38][C:35]4[CH:34]=[CH:33][C:32]([N:31]([CH3:30])[CH3:54])=[CH:37][CH:36]=4)=[CH:42][CH:43]=3)[CH2:53][CH2:52]2)=[O:28])[CH:5]=[C:6]([CH3:24])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:11][N:10]=1
Reactant: CN(C)c1ccc(OCCc2ccc(CN3CCNCC3)cc2)cc1
Reactant: Cc1ccc(COc2ccc(Oc3c(C)cc(/C=C/C(=O)O)cc3Cl)nc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(COc2ccc(Oc3c(C)cc(/C=C/C(=O)N4CCN(Cc5ccc(CCOc6ccc(N(C)C)cc6)cc5)CC4)cc3Cl)nc2)cc1
Yield: 51.6 %

Procedure:
To a CH2Cl2 (5 mL) solution of (E)-3-[3-chloro-5-methyl-4-({5-[(4-methyl-benzyl)oxy]pyridin-2-yl}oxy)phenyl]prop-2-enoic acid (200 mg) was added N,N-dimethyl-4-{2-[4-(piperazin-1-ylmethyl)phenyl]ethoxy}aniline (191 mg), DCC (151 mg), and DMAP (5.96 mg) at room temperature, then the resultant mixture was stirred over night. The mixture was evaporated. The residue was added AcOEt, then filtered off, and the filtrate was evaporated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=1/1 to 1/0 and then AcOEt/MeOH=4/1) to afford (E)-3-[3-chloro-5-methyl-4-({5-[(4-methylbenzyl)oxy]-pyridin-2-yl}oxy)phenyl]-1-[4-(4-{2-[4-(dimethylamino)phenoxy]ethyl}benzyl)piperazin-1-yl]prop-2-en-1-one as a pale brown amorphous powder (184 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[CH:9]=[O:10].[BH4-].[Na+]>C(O)C>[CH3:1][C:2]1([CH3:11])[CH2:6][CH2:5][C:4]([CH3:7])([CH3:8])[CH:3]1[CH2:9][OH:10]
Reactant: CC1(C)CCC(C)(C)C1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1(C)CCC(C)(C)C1CO
Reaction time: 24 h

Procedure:
2,2,5,5-Tetramethylcyclopentane-1-carboxaldehyde is dissolved in 95% ethanol and sodium borohydride is added. After 24 hours, the reaction is quenched with 1M HCl and extracted with ether. The extract is washed, dried over MgSO4 and evaporated to yield 2,2,5,5-tetramethyl-1-cyclopentylmethanol.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][CH:12]=[C:13]([C:19]([F:22])([F:21])[F:20])[C:14]=2[C:15]([F:18])([F:17])[F:16])=[CH:6][CH:5]=1>C(Cl)(Cl)Cl>[Br:1][C:12]1[NH:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)=[C:14]([C:15]([F:16])([F:17])[F:18])[C:13]=1[C:19]([F:22])([F:20])[F:21]
Reactant: FC(F)(F)c1c[nH]c(-c2ccc(Cl)cc2)c1C(F)(F)F
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1c(Br)[nH]c(-c2ccc(Cl)cc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under a nitrogen purge, a solution of bromine (0.05 mL, 0.001 mol) and chloroform (5 mL) is added dropwise to a solution of 2-(p-chlorophenyl)-3,4-bis(trifluoromethyl)pyrrole (0.39 g, 0.001 mol) and chloroform (10 mL). The orange reaction mixture is stirred for 16 hours at room temperature then concentrated in vacuo to give an oil. The oil is extracted with methyl cyclohexane and the combined organic extracts are treated with carbon black and the solvent is removed in vacuo. The residue is dissolved in a small amount of hot hexane, decanted from insolubles and cooled in the freezer. Filtration of the cold solution gives the title compound as white crystals containing a half mole of HMPA (0.32 g mp 97°-100° C., 68%). Identified by IR and NMR spectral analyses.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:25](I)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCCCI
Reactant: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Product: CCCCCCCCn1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cccnc21

Procedure:
3-(3,5-Di-tertiary butyl-4-hydroxyphenyl)-1-octyl-1H-pyrazolo[3,4-b]pyridine is prepared by reacting the compound of Example 1 with octyl iodide as yellowish brown oil in a similar manner as Example 9.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:11]([CH:14]1[CH2:16][CH2:15]1)([CH3:13])[CH3:12])C(OCC)=O)[CH3:2].[Cl-].[Li+].O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:11]([CH:14]1[CH2:15][CH2:16]1)([CH3:12])[CH3:13])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)C(C)(C)C1CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CC(C)(C)C1CC1
Temperature: 170 °C

Procedure:
A mixture of 2-(1-cyclopropyl-1-methylethyl)malonic acid diethyl ester (5.10 g, 21.2 mmol), lithium chloride (1.79 g, 42.2 mmol), water (0.5 mL) and DMSO (40 mL) was heated at 170° C. for 24 h, and then poured into ice-water. The product was extracted with ethyl acetate (3×200 mL), and the extracts were washed with brine (200 mL), dried over sodium sulfate and concentrated to give 3-cyclopropyl-3-methylbutyric acid ethyl ester, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3Cl)[C:3]=12.[CH3:25]N1C(N)=CC(C2C=CC=CC=2)=N1.C1(C)C=CC=C(C#C)C=1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([CH3:25])[CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: Cn1nc(-c2ccccc2)cc1N
Reactant: Cn1nc(-c2ccccc2Cl)c2c(Cl)c(-c3ccccc3)nnc21
Agent: C#Cc1cccc(C)c1
Product: Cc1cccc(-c2nnc3c(c(-c4ccccc4)nn3C)c2Cl)c1

Procedure:
Compound 16 was synthesised following similar procedures outlined in Example 1 (Compound 37), starting from Step 2 using 1-methyl-3-phenyl-1H-pyrazol-5-amine instead of 3-(2-chlorophenyl)-1-methyl-1H-pyrazol-5-amine and 3-tolylacetylene instead of phenyl acetylene in Step 4.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8])(=[O:4])=[O:3].[CH3:15][C:16]([CH3:36])=[CH:17][CH2:18][CH2:19]/[C:20](/[CH3:35])=[CH:21]/[CH2:22][CH2:23]/[C:24](/[CH3:34])=[CH:25]/[CH2:26][S:27][CH2:28][C@H:29]([NH2:33])[C:30]([OH:32])=[O:31].C(N(CC)C(C)C)(C)C.O[Li].O>C1COCC1.C(OCC)(=O)C.O>[C:30]([C@@H:29]([NH:33][S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8])(=[O:4])=[O:3])[CH2:28][S:27][CH2:26]/[CH:25]=[C:24](\[CH3:34])/[CH2:23][CH2:22]/[CH:21]=[C:20](\[CH3:35])/[CH2:19][CH2:18][CH:17]=[C:16]([CH3:15])[CH3:36])([OH:32])=[O:31]
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Agent: [Li]O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NS(=O)(=O)c1ccccc1C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a 100 mL round bottom flask, to a solution of methyl 2-(chlorosulfonyl)benzoate (281 mg, 1.2 mmol) and S-trans, trans-farnesyl-L-cysteine (325 mg, 1 mmol) in THF (5 mL) was added N,N-diisopropyl-ethyl-amine (0.52 mL, 3 mmol) dropwise. The solution was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate (60 mL) and washed sequentially with an NH4Cl saturated solution (10 mL×2), H2O (10 mL×1) and brine (10 mL×1). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was dissolved in THF (3 mL) and a solution of LiOH.H2O (210 mg, 5 mmol) in H2O (2 mL) was added slowly at 0° C. The reaction was left at room temperature overnight. The reaction was quenched with 1 N HCl and pH was adjusted to 2.0. The solution was then extracted by ethyl acetate (30 mL×3). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was then further purified by preparative HPLC (290 mg, 57%) to yield Compound N-81. 1H-NMR (500 MHz, CD3OD): δ 1.50 (s, 6H), 1.55 (s, 3H), 1.57 (s, 3H), 1.86-1.89 (m, 2H), 1.94-2.02 (m, 6H), 2.71 (dd, J=6.0, 14.0 Hz, 1H), 2.77 (dd, J=5.5, 14.0 Hz, 1H), 3.01-3.08 (m, 2H), 4.10 (t, J=6.0 Hz, 1H), 5.00-5.06 (m, 3H), 7.56-7.62 (m, 2H), 7.84 (d, J=6.5 Hz, 1H), 7.93 (d, J=7.5 Hz, 1H). 13C-NMR (125 MHz, CD3OD): δ 16.17, 16.28, 17.81, 24.24, 25.96, 27.36, 27.78, 30.52, 34.79, 40.75, 40.89, 57.80, 121.53, 125.14, 125.46, 130.07, 132.13, 132.56, 133.78, 136.28, 140.63, 140.72, 170.16, 173.07; ES-MS: mass calcd for Chemical Formula: C25H35NO6S2 509.68. Found (M+Na) m/z 532.1.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1.I[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:12][CH2:11][CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:13])([F:14])[F:1])[CH:5]=1)[CH3:21]
Reactant: OCCc1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)CI
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CCOC(=O)COCCc1cccc(OC(F)(F)F)c1

Procedure:
In analogy to the procedure described in example 78.1, 2-(3-trifluoromethoxy-phenyl)-ethanol was reacted with ethyl iodoacetate in the presence of silver trifluoromethanesulfonate and 2,6-di-tert-butylpyridin to give [2-(3-trifluoromethoxy-phenyl)-ethoxy]-acetic acid ethyl ester as colorless oil. MS: m/e=293.1 [M+H+].
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:26])[CH3:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:24]([N:21]1[CH2:20][CH2:19][CH:18]([C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:2]3[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[C:6]([Cl:8])[CH:7]=3)=[N:17][CH:16]=2)[CH2:23][CH2:22]1)(=[O:26])[CH3:25]
Reactant: CC(=O)N1CCC(c2ccc(N)nc2)CC1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)N1CCC(c2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
A solution of 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (201 mg, 901 μmol), 1-(4-(6-aminopyridin-3-yl)piperidin-1-yl)ethanone (180 mg, 819 μmol), Xantphos (35.5 mg, 61.4 μmol) and cesium carbonate (801 mg, 2.46 mmol) in dry dioxane (6 ml) was vacuum de-gassed and place under argon atmosphere. To this mixture was added tris(dibenzylideneacetone)dipalladium (0) (8.48 mg, 8.19 μmol) and the vacuum de-gas cycle was repeated. The material was heated at 90° C. (oil bath) with vigorous stirring overnight. The flask was cooled to ambient and the contents were filtered through a plug of celite, rinsing well with dioxane. The combined filtrate and washes were concentrated and the resulting residue was triturated with 1:1 ratio of ether/ethyl acetate. This provided the desired product as a off-white powder (66 mg, 22%). (M+H)+=362, 364 m/e
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Br:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1>CCCCCC.C(Cl)Cl.CO>[Br:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([O:17][CH3:1])=[O:16])=[CH:13][CH:12]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(CCBr)cc1
Solvent: CO
Solvent: ClCCl
Solvent: CCCCCC
Product: COC(=O)c1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A 2 M solution in hexane of trimethylsilyldiazomethane (0.072 mol, 36 mL) was added dropwise to a solution of 4-(bromoethyl)benzoic acid (15 g, 0.065 mol) in DCM (150 mL) and MeOH (36 mL). The resulting solution was stirred at RT for 2 h then was concentrated under reduced pressure to afford the title compound (15.8 g, 98%) as a pale yellow oil. 1H NMR (CDCl3) δ 3.2 (t, 2H), 3.6 (t, 2H), 3.9 (s, 3H), 7.3 (d, 2H), 8.0 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]([CH3:11])[C:8]([OH:10])=[O:9])[CH:6]=1.OS(O)(=O)=O.[CH3:17]O>>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]([CH3:11])[C:8]([O:10][CH3:17])=[O:9])[CH:6]=1
Reactant: CC(C(=O)O)n1cc(Br)cn1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)n1cc(Br)cn1
Temperature: 68 °C
Yield: 82 %

Procedure:
To a solution of 2-(4-bromo-1H-pyrazol-1-yl)propanoic acid (0.20 g, 0.91 mmol) in MeOH (4.0 mL) was added conc H2SO4 (0.20 mL) and the resulting reaction mixture was heated to 68° C. for 2 h. After the completion of reaction (TLC monitoring), the solvent was evaporated and the residue was basified with saturated NaHCO3 solution followed by extraction with EtOAc (3×25.0 mL). The combined organics was dried (Na2SO4), filtered and concentrated to obtain the desired product (0.175 g, 82%).