Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:14]S(C3C=CC(C)=CC=3)(=O)=O)[N:11]=2)=[CH:3][CH:2]=1.C([O:34][C:35](=[O:57])[C:36]([CH3:56])([O:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:48][CH:47]=1)[CH2:37][C:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1)C>C(O)C>[C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:2]=[CH:3][C:4]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:14][C:41]3[CH:40]=[CH:39][C:38]([CH2:37][C:36]([CH3:56])([O:45][C:46]4[CH:51]=[CH:50][C:49]([C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:48][CH:47]=4)[C:35]([OH:57])=[O:34])=[CH:43][CH:42]=3)[N:11]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C(C)(C)C)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(CC(C)(Oc2ccc(C(C)(C)C)cc2)C(=O)O)cc1
Temperature: 55 °C
Yield: 22 %

Procedure:
Toluene-4-sulfonic acid 2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethyl ester (0.132 mmol) (see Ex. 1, Part I)was added to a one dram, screw-cap vial and diluted with ethanol (0.5 mL). To this solution are added 3-(4-hydroxyphenyl)-2-methyl-2-(4-tert-butylphenoxy)-propionic acid ethyl ester (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100–125 mg, 2.6 mmol/g) and the vial was tightly closed. The reaction vessel was heated in a block heater for 24–48 h at 55° C., or until TLC or MS analysis indicates the disappearance of starting materials. The suspension was filtered while warm and the residue washed with ethanol (1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl) and the vial resealed tightly. The solution was heated in a block heater at 55° C. for 3–16 h, or until MS analysis indicates the completion of the hydrolysis. The solvents are removed with a stream of nitrogen or under reduced pressure and the residue redissolved in 1 mL water. The solution was acidified with aqueous HCl (5N solution, 150 μl), often causing precipitation of product. The suspension was diluted with dichloromethane (3 mL) and the resultant biphasic solution was filtered through a Chrom-Elut column to remove water. The filtrate was concentrated in vacuo and the resultant residue was purified by preparative thin-layer silica chromatography eluting with 93:7 CH2Cl2:methanol to produce a white solid (22%). MS [EI+] 590 (M+H)+, [EI−] 588 (M−H)+
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:10][N:11]1[C@@H:28]2[CH2:29][C:16]3[CH:17]=[CH:18][C:19]([O:31][CH3:32])=[C:20]4[O:21][C@H:22]5[C:23]([CH2:25][CH2:26][C@:27]2([OH:30])[C@:14]5([C:15]=34)[CH2:13][CH2:12]1)=[O:24].CN(C)C=O.CN1CCOCC1.[N:45]1(C(OC(C)(C)C)=O)[CH2:66][CH2:65][CH2:64][C@H:46]1[C:47]([N:49]1[CH2:63][CH2:62][CH2:61][C@H:50]1[C:51](ON1C(=O)CCC1=O)=[O:52])=[O:48]>>[NH:45]1[CH2:66][CH2:65][CH2:64][C@H:46]1[C:47]([N:49]1[CH2:63][CH2:62][CH2:61][C@H:50]1[C:51]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:52])=[O:48].[CH3:10][N:11]1[C@@H:28]2[CH2:29][C:16]3[CH:17]=[CH:18][C:19]([O:31][CH3:32])=[C:20]4[O:21][C@H:22]5[C:23]([CH2:25][CH2:26][C@:27]2([OH:30])[C@:14]5([C:15]=34)[CH2:13][CH2:12]1)=[O:24]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)ON1C(=O)CCC1=O
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1)C(=O)O
Reaction time: 18 h

Procedure:
To a solution of Leu-Oxycodone (1.0 eq) in dimethylformamide (10 ml/0.1 mmol) was added 4-methylmorpholine (10 eq) and Boc-Pro-Pro-OSu (2 eq). The reaction was stirred at ambient temperatures for 18 hours, quenched with water, and solvents removed. Crude protected product was purified using reverse phase HPLC. Deprotection occurred using 4N HCl in dioxane (20 ml/mmol) to obtain Pro-Pro-Leu-Oxycodone.
Reaction SMILES: [C:1]([C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=O)(=[O:3])[CH3:2].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[C:1]([C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ncccc1C(=O)Cl
Reactant: C1COCCN1
Product: CC(=O)c1ncccc1CN1CCOCC1

Procedure:
Following the procedures of Example 14, 2-acetylnicotinic acid chloride (1.0 g, 5.5 mmol) and morpholine (0.6 g, 6.7 mmol) are reacted together to give 4-(2-acetylnicotinyl)morpholine, which compound (1.0 g, 4.2 mmol) is then reacted with 4-(3-fluorophenyl)semicarbazide (0.7 g, 4.2 mmol) to give 4-(2-acetylnicotinyl)morpholine 4-(3-fluorophenyl)semicarbazone, m.p. 193°-195° compound 150).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH2:21][CH2:20][NH:19][CH2:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:23]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH2:21][CH2:20][N:19]([C:23]4[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(Nc2ncnc3c2CCNC3)cc1
Reactant: CS(=O)(=O)c1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1ccc(Nc2ncnc3c2CCN(c2ncccc2S(C)(=O)=O)C3)cc1
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of N-(4-tert-butylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine prepared as described in Example 3.A. (0.066 g, 0.23 mmol), 2-chloro-3-(methylsulfonyl)pyridine (Ponticello et al, J. Org. Chem., 44(17), 1979), (0.088 g, 0.47 mmol) and N,N-diisopropylethlamine (0.041 mL, 0.23 mmol) was heated in a sealed tube via microwave (Emrys Optimizer model, Personal Chemistry) for 30 min at 150° C. The reaction mixture was cooled to r.t. and poured into water (20 mL). The mixture was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated to leave an oil which was purified by silica gel chromatography (ethyl acetate/hexane gradient) to give the title compound as a white solid (0.049 g, 48%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[C:29](Cl)=[O:30]>C1COCC1.C(Cl)Cl>[C:19]([NH:18][C:14]1[CH:13]=[C:12]([CH:9]2[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:26]([O:25][CH3:24])[CH:27]=3)[CH2:11][CH2:10]2)[CH:17]=[CH:16][CH:15]=1)(=[O:23])[CH:20]([CH3:21])[CH3:22]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN)CC2)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(C(=O)NCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1OC

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-{3-[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3,4-dimethoxybenzoyl chloride: ESMS m/e: 482.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:15](=[O:16])[N:14]([CH2:17][C:18]([O:20]CC)=[O:19])[C:13]3[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=3[S:11][CH2:10]2)=[CH:5][CH:4]=1>O.C(O)(=O)C.S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:15](=[O:16])[N:14]([CH2:17][C:18]([OH:20])=[O:19])[C:13]3[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=3[S:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)CN1C(=O)C(c2ccc(OC)cc2)CSc2ccccc21
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C2CSc3ccccc3N(CC(=O)O)C2=O)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 84.3 %

Procedure:
6.8 g of the product of Step A were dissolved in 136 ml of a mixture of equal parts of water, of acetic acid and sulfuric acid and the mixture was stirred for 19 hours at ambient temperature. 400 ml of water were added slowly with stirring for 10 minutes, and separation was effected to obtain 5.3 g of the expected product melting at 180° C. which was used as is for following step. An analytical sample was prepared by two successive crystallizations from 20 volumes of ether at reflux starting with 2.7 g of the acid to obtain 1.15 g of the product melting at 190° C. (approx.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH2:24]([O:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([O:36][CH2:37][CH3:38])[CH:35]=1)[C:30](O)=[O:31])[CH3:25]>>[CH2:37]([O:36][C:34]1[CH:33]=[C:29]([CH:28]=[C:27]([O:26][CH2:24][CH3:25])[CH:35]=1)[C:30]([NH:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1)=[O:31])[CH3:38]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: CCOc1cc(OCC)cc(C(=O)O)c1
Product: CCOc1cc(OCC)cc(C(=O)Nc2c[nH]nc2-c2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)N4CC)c1

Procedure:
3,5-Diethoxy-N-[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-benzamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 3,5-diethoxybenzoic acid (186 mg, 0.89 mmol). The title compound was obtained as brown powder (99 mg, 24%).
Reaction SMILES: O.S([O-])([O-])=O.[Na+].[Na+].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([C:18]2[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1.Cl[CH2:29][C:30]([O:32][CH3:33])=[O:31]>C(#N)C>[CH3:33][O:32][C:30](=[O:31])[CH2:29][S:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:12]2[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH:19]=1)(=[O:26])=[O:25]
Reactant: O=S(=O)(Cl)c1cccc(S(=O)(=O)c2ccc(Br)cc2)c1
Reactant: COC(=O)CCl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(=O)CS(=O)(=O)c1cccc(S(=O)(=O)c2ccc(Br)cc2)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To 150 ml of water was added 85 g of sodium sulfite and then 54 g of 3-(4-bromophenylsulfonyl)benzenesulfonyl chloride was added thereto. After stirring the mixture for 2 hours at 50° C., the reaction mixture thus obtained was ice-cooled and crystals thus formed were collected by filtration. To the crystals thus obtained were added 40 ml of water, 40 ml of acetonitrile and 15 ml of methyl chloroacetate followed by refluxing for 2 hours. The reaction mixture thus formed was extracted with chloroform and then chloroform was distilled off from the extract to provide 32.7 g of oily 3-(4-bromophenylsulfonyl)phenylsulfonylacetic acid methyl ester. Then, the oily product thus obtained was added to a mixture of 60 ml of water, 60 ml of methanol, and 8.1 g of potassium hydroxide and the resultant mixture was stirred for one hour at room temperature. After adding 20 ml of 35% hydrochloric acid to the reaction mixture, the mixture was ice-cooled and crystals thus deposited were collected by filtration to provide 25.4 g of 3-(4-bromophenylsulfonyl)phenylsulfonylacetic acid. By neutralizing 21 g of the crystals thus obtained with 4.5 g of guanidine carbonate as in Synthesis Example 3 22.3 g of Base Precursor (123) was obtained. The melting point was 85° C. and the decomposition point was 95° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([P:16](=[O:19])([OH:18])[OH:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:24][O:25][C:26](=[O:43])[CH:27](O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:29]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:24][O:25][C:26](=[O:43])[CH:27]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH:29]=1)[O:19][P:16]([CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH:13]([CH3:15])[CH3:14])([OH:18])=[O:17]
Reactant: COC(=O)C(O)c1cccc(NC(=O)OC(C)(C)C)c1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)P(=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)C(OP(=O)(O)C(NC(=O)OCc1ccccc1)C(C)C)c1cccc(NC(=O)OC(C)(C)C)c1
Temperature: -5 °C
Reaction time: 0.42 h
Yield: 90.2 %

Procedure:
Following a procedure reported by Hoffmann, M., Synthesis (1986), 557A, a solution of (R)-1-(benzyloxycarbonyl)amino-2-methylpropylphosphonic acid (691.0 mg, 2.41 mmol) in 8 mL of DMF was cooled to −20° C. using a dry ice/methanol bath. To this solution was added thionyl chloride (0.21 mL, 2.88 mmol) and stirred at −5° C. for 25 minutes. Racemic 2-hydroxy-2-(3-(t-butoxycarbonylamino)phenyl)ethanoic acid methyl ester (683.4 mg, 2.43 mmol) was added as a solution in 2 mL of DMF and the reaction was allowed to warm to ambient temperature. After stirring for 4 days (total reaction time 87 hrs), the reaction had almost gone to completion (95%). To this reaction mixture 5 mL of saturated NaHCO3 was added. The solution was washed with ether (2×), acidified to pH 2 with concentrated HCl, and extracted with ethyl acetate (3×). The combined ethyl acetate extracts were dried over MgSO4, filtered, and concentrated in vacuo to give a mixture of product and starting material. Purification via SiO2 gel flash column chromatography (CH2Cl2, then methanol) provided 1.1966 g (90%) of 2-(3-(t-butoxycarbonylamino)phenyl)-2-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid methyl ester; as a mixture of diastereomers.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1.[CH3:14][O:15][CH2:16]Cl>CN(C=O)C.O>[CH3:14][O:15][CH2:16][O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1
Reactant: COCCl
Reactant: Oc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.1 %

Procedure:
To a suspension of 5.0 g of NaH (208.33 mmol) in 150 mL of DMF under argon flow were added 20.0 g of solid 2-hydroxynaphthalene (138.7 mmol) at a temperature of 0° C., by small portions. The suspension was kept under stirring for 4 h at room temperature, 17.8 g of methoxymethyl chloride (221.2 mmol) were added slowly, and the reaction mixture was stirred for 10 additional hours. The reaction was carefully diluted with 1 L of water and the organic part was extracted with 3 times 50 mL of CH2Cl2. The combined organic extracts were washed twice with 500 mL of water, brine and dried over MgSO4. The solution was evaporated, dried in vacuum at a temperature of 80° C. to give 25.1 g of colorless oily product (133.3 mmol) that was used without further purification.
Reaction SMILES: C([O:8][C:9]([CH2:11][N:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][CH2:15][CH:14]([NH:23][CH:24]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:13]1=[O:38])=[O:10])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:9]([CH2:11][N:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][CH2:15][CH:14]([NH:23][CH:24]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:13]1=[O:38])([OH:10])=[O:8]
Reactant: [H][H]
Reactant: CCOC(=O)C(CCc1ccccc1)NC1CCc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)NC1CCc2ccccc2N(CC(=O)O)C1=O

Procedure:
A solution of 1-benzyloxycarbonylmethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (isomer A of example 3; 1.2 g) in ethanol (125 ml) was hydrogenated at room temperature and atmospheric pressure, using 10% palladium on charcoal (0.5 g) as catalyst. After uptake of hydrogen had ceased, the catalyst was filtered off, and the solvent removed under reduced pressure to give a solid. This material was triturated with ether (8 ml) to give 1-carboxymethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one melting at 126°-129°, and being the lower melting racemic isomer A.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1)=[O:3].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][C:2]1([C:4]2[CH:5]=[C:6]([Br:10])[CH:7]=[CH:8][CH:9]=2)[O:13][CH2:12][CH2:11][O:3]1
Reactant: OCCO
Reactant: CC(=O)c1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(c2cccc(Br)c2)OCCO1
Reaction time: 12 h
Yield: 85 %

Procedure:
5 g (25 mmol) of 3-bromoacetophenone are dissolved in 40 ml of toluene and then 15 ml of ethylene glycol and 500 mg of para-toluenesulphonic acid are added. The reaction medium is then heated under reflux equipped with a Dean-Stark distillation assembly. After 12 h, the medium is cooled and then treated with water and extracted with dichloromethane. After drying and concentrating, the residue is purified on a silica column in order to obtain the desired 3-(2-methyl-[1,3]dioxolan-2-yl)-1-bromobenzene (Y=85%). This product (4 g, 16.4 mmol) is then dissolved in anhydrous THF and the mixture is cooled to −78° C. 7.2 ml (18 mmol) of a 2.5M solution of butyllithium are then added dropwise. After stirring for 1 hour at the same temperature, 1.9 ml (18 mmol) of dimethylformamide are added. The mixture is maintained at −78° C. for 30 minutes and then brought to room temperature. The reaction medium is then treated with a saturated ammonium chloride solution and extracted with dichloromethane. After purification by chromatography on a silica column (ethyl acetate 10-heptane 90), a colourless oil is obtained (m=3.09 g; Y=98%).
Reaction SMILES: [N+:1]([C:4]1[CH:47]=[CH:46][C:7]([O:8][C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([C:17]3[C:22]([F:23])=[C:21]([F:24])[C:20]([O:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([O:34]CC5C=CC=CC=5)=[O:33])=[CH:28][CH:27]=4)=[C:19]([F:42])[C:18]=3[F:43])=[C:11]([F:44])[C:10]=2[F:45])=[CH:6][C:5]=1[O:48]CC1C=CC=CC=1)([O-])=O.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:47]=[CH:46][C:7]([O:8][C:9]2[C:10]([F:45])=[C:11]([F:44])[C:12]([C:17]3[C:22]([F:23])=[C:21]([F:24])[C:20]([O:25][C:26]4[CH:27]=[CH:28][C:29]([C:32]([OH:34])=[O:33])=[CH:30][CH:31]=4)=[C:19]([F:42])[C:18]=3[F:43])=[C:13]([F:16])[C:14]=2[F:15])=[CH:6][C:5]=1[OH:48]
Reactant: O=C(OCc1ccccc1)c1ccc(Oc2c(F)c(F)c(-c3c(F)c(F)c(Oc4ccc([N+](=O)[O-])c(OCc5ccccc5)c4)c(F)c3F)c(F)c2F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2c(F)c(F)c(-c3c(F)c(F)c(Oc4ccc(C(=O)O)cc4)c(F)c3F)c(F)c2F)cc1O
Reaction time: 8 h
Yield: 91 %

Procedure:
49.9 g of the 4-(4-nitro-3-benzyloxyphenoxy)-4′-(4-benzyloxycarbonylphenoxy)octafluorobiphenyl prepared as described in Example 2 (0.065 mol) are dissolved in 400 ml of a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1:1), and 5 g of Pd/C (palladium/carbon) are then added to the solution. The mixture is then hydrogenated using hydrogen at a pressure of 1 bar at room temperature in an autoclave with vigorous stirring; the reaction is terminated after 3 days. The yellow-beige solution is evaporated to half in a rotary evaporator and left to stand overnight at room temperature, during which the reaction product precipitates out in crystalline form. The reaction product is then separated off and dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 91%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[Cl:10].[C:12]1(=[O:16])[O:15][CH2:14][CH2:13]1.Cl>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[Cl:10])[O:11][CH2:14][CH2:13][C:12]([OH:16])=[O:15]
Reactant: O=C1CCO1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CCOc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride 0.24 g (0.01 mol) was dissolved in 10 ml of dry DMF. After 30 min, a solution of 3,4-dichloro phenol 1.63 g (0.01 mol) dissolved in 5 ml of DMF was added in drops. The reaction mixture was heated to 100 C. After 1 hour, β-propiolactone, 0.72 g (0.628 ml, 0.01 mol) was added slowly for 5 minutes. The reaction mixture was further continued heating for 12 h. The reaction mixture was cooled to room temperature and poured over ice-cold water 10 ml was added. This diluted mixture was acidified by the addition of Con. HCl. The product was extracted twice with diethyl ether (20 ml). The ether layer was then washed with 10% Sodium bicarbonate. The aqueous layer was acidified to pH=2. The precipitated solid was filtered and dried to afford the required product 3-(3,4-dichlorophenoxy)propanoic acid (PC165).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:19])[O:4][N:3]=1.[CH:20]([C:23]1[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=1)([CH3:22])[CH3:21].ClCCl>N1C=CC=CC=1>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:29][C:26]3[CH:25]=[CH:24][C:23]([CH:20]([CH3:22])[CH3:21])=[CH:28][N:27]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:19])[O:4][N:3]=1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)c1ccc(N)nc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)Nc2ccc(C(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.3 %

Procedure:
To a solution of 4-((3,5-dimethylisoxazol-4-yl)methoxy)benzene-1-sulfonyl chloride (241 mg, 0.800 mmol) in pyridine (5 mL), stirred under nitrogen at room temperature, was added 5-isopropylpyridin-2-amine (54.5 mg, 0.4 mmol). The mixture was then stirred at room temperature overnight. Dichloromethane (25 mL) was added to the mixture and the organic phase washed with water (25 mL) and brine (25 mL) then dried using a hydrophobic frit. Solvent was removed in vacuo to give the crude product. This was purified by flash silica (Si) chromatography (0-100% ethyl acetate-cyclohexane gradient), to provide the title compound (39 mg) as an off-white solid. LCMS (2 min, formic) Rt 0.96 min, m/z (ES+) 402 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([OH:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[N:9]2)=[N:6][CH:7]=1.[F-].[K+].Br[CH2:21][N:22]1[C:26](=[O:27])[C:25]2[C:28]([CH:34]([CH3:36])[CH3:35])=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:24]=2[S:23]1(=[O:38])=[O:37]>CN(C=O)C>[CH:34]([C:28]1[C:25]2[C:26](=[O:27])[N:22]([CH2:21][O:13][C:12]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=4)[N:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=3)[S:23](=[O:38])(=[O:37])[C:24]=2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=1)([CH3:36])[CH3:35]
Reactant: Oc1cc(C(F)(F)F)nn1-c1ccc(Cl)cn1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C(F)(F)F)nn1-c1ccc(Cl)cn1)C2=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.2 %

Procedure:
A mixture of 1-(5-chloro-2-pyridyl)-3-trifluoromethyl-5-hydroxypyrazole (527 mg; 2 mmol) and KF (232 mg; 4 mmol) in 4 ml of DMF was stirred under nitrogen at room temperature for 20 minutes and then 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (609 mg, 1.75 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, filtered, and the solid residue was washed with water. The white solid was dissolved in methylene chloride, dried over magnesium sulfate, partially concentrated in vacuo, and the resulting residue was crystallized from ethyl acetate. The combined solid was dried in vacuo to afford 736 mg (79%) of 4-isopropyl-6-methoxy-2-[1-(5-chloro-2-pyridyl)-3-(trifluoromethyl)pyrazol-5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =5-chloro-2-pyridyl; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white solid, m.p. 173°-174° C.