Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].[C:13]([C:17]1[N:21]([CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:20]2[CH:29]=[CH:30][C:31]([S:33](Cl)(=[O:35])=[O:34])=[CH:32][C:19]=2[N:18]=1)([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[C:13]([C:17]1[N:21]([CH2:22][CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[C:20]2[CH:29]=[CH:30][C:31]([S:33]([N:8]3[CH:9]=[CH:10][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:7]3)(=[O:34])=[O:35])=[CH:32][C:19]=2[N:18]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CCNC(=O)c1cc[nH]c1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNC(=O)c1ccn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)c1
Yield: 52.9 %

Procedure:
Following the same procedure in Example 29, using N-ethyl-1H-pyrrole-3-carboxamide (2.7 g, 20 mmol) (see following step B for preparation), sodium hydride (4.0 g, 60%, 100 mmol) and 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (6.1 g, 16 mmol) in THF (250 mL). The crude product was purified by MPLC using Hex/EtOAc (1:4) on silica gel to give 4.0 g (53%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.13 (t, J=7.23 Hz, 3 H), 1.41-1.58 (m, 4 H), 1.61 (s, 9 H), 2.24-2.38 (m, 1 H), 3.24-3.35 (m, 4 H), 3.85-3.94 (m, 2 H), 4.44 (d, J=7.42 Hz, 2 H), 6.65 (dd, J=3.32, 1.56 Hz, 1 H), 7.29 (dd, J=3.32, 2.34 Hz, 1 H), 7.77-7.82 (m, 1 H), 7.95-7.98 (m, 2 H), 8.24-8.30 (m, 1 H); MS (ESI) (M+H)+=472.8; Anal. Calcd for C24H32N4O4S+1.20 TFA+0.10 EtOAc+0.30H2O (624.86): C, 51.71; H, 5.58; N, 8.97. Found: C, 51.73; H, 5.66; N, 8.91.
Reaction SMILES: [F-].[Cs+].[C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][C:10]=1[F:11])#[N:4].Cl[C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][N:25]=1)[C:19]([O:21][CH3:22])=[O:20]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][N:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH:8]=[CH:9][C:10]=1[F:11])#[N:4]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: N#Cc1cc(B(O)O)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: COC(=O)c1ccnc(-c2ccc(F)c(C#N)c2)c1

Procedure:
Cesium fluoride and tetrakis(triphenylphosphine)palladium were added to a 1,2-dimethoxyethane solution of (3-cyano-4-fluorophenyl)boronic acid and methyl 2-chloroisonicotinate, and the mixture was heated under reflux under an argon atmosphere to obtain methyl 2-(3-cyano-4-fluorophenyl)isonicotinate. F: 257.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Sn](Cl)Cl>Cl>[F:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=[N+]([O-])c1ccc(F)c2cccnc12
Agent: Cl
Agent: Cl[Sn]Cl
Product: Nc1ccc(F)c2cccnc12
Yield: 106.7 %

Procedure:
In a similar fashion using route 1 general procedure 4, 5-fluoro-8-nitroquinoline (Intermediate 38) (500 mg, 2.60 mmol), tin (II) chloride (1.48 mg, 7.80 mmol) and 6N HCl (4 drops) gave the title compound (450 mg, >100% crude) which was used in the next step without purification. The structure was confirmed by 1H NMR.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:5][OH:6])=[O:4].[C:7](Cl)(=[O:11])[CH2:8][CH2:9][CH3:10]>N1C=CC=CC=1>[C:7]([O:1][CH2:2][CH:3]([OH:4])[CH2:5][O:6][C:7](=[O:11])[CH2:8][CH2:9][CH3:10])(=[O:11])[CH2:8][CH2:9][CH3:10]
Reactant: CCCC(=O)Cl
Reactant: O=C(CO)CO
Solvent: c1ccncc1
Product: CCCC(=O)OCC(O)COC(=O)CCC

Procedure:
By following the procedure of Example 1(a) and 1(b) using 13.05 g. of 1,3-dihydroxyacetone, 23.7 g. of pyridine and 31.1 g. of butyryl chloride, 17.9 g. of 1,3-dibutanoyloxy-2-propanol is obtained. The reaction of 12.2 g. of this material and 9.4 g. of valproyl chloride and 4.98 g. of pyridine as described in Example 1(c) yields an oil which is purified by chromatography as described in Example 3. The pure 1,3-dibutanoyl-2-valproyl-glyceride is eluted from the column with petroleum ether/ether (95:5); it is obtained in a yield of 9.1 g.; Rf 0.61 (petroleum ether/ether 3:1); mass spectrum m/e 316 (M+ -42).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([O:9][CH:10]2[CH2:14][CH2:13][N:12]([C:15](=[O:18])[CH2:16][CH3:17])[CH2:11]2)[N:3]=1.[CH:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])[CH3:20]>N1C=CC=CC=1.ClCCl.[OH-].[Na+]>[CH:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:8][C:7]2[C:2]([CH3:1])=[N:3][C:4]([O:9][CH:10]3[CH2:14][CH2:13][N:12]([C:15](=[O:18])[CH2:16][CH3:17])[CH2:11]3)=[CH:5][CH:6]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])[CH3:20]
Reactant: CCC(=O)N1CCC(Oc2ccc(N)c(C)n2)C1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)N1CCC(Oc2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)c(C)n2)C1

Procedure:
2-Methyl-6-[(1-propionylpyrrolidin-3-yl)oxy]pyridin-3-amine (340 mg) was dissolved in pyridine (3.3 mL) and 4-isopropylbenzenesulfonyl chloride (358 mg) was slowly added under stirring. After 19 h stirring at room temperature, the reaction mixture was diluted with dichloromethane and 2 M aqueous NaOH was added. After stirring for 1 h at room temperature the phases were separated. The organic phase was dried (sodium sulfate), concentrated and the crude product purified by flash chromatography (silica, dichloromethane, 0.5 to 5% methanol gradient). Yield: 460 mg (78%, pale yellow oil).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21]([OH:23])=O)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]([F:18])([F:17])[F:16])[CH:7]=1.[CH:24]([NH:27][NH:28][C:29]([C:31]1[CH:35]=[CH:34][O:33][CH:32]=1)=[O:30])([CH3:26])[CH3:25].C(NC(C)C)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21]([N:27]([CH:24]([CH3:26])[CH3:25])[NH:28][C:29]([C:31]2[CH:35]=[CH:34][O:33][CH:32]=2)=[O:30])=[O:23])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]([F:16])([F:18])[F:17])[CH:7]=1
Reactant: CC(C)NNC(=O)c1ccoc1
Reactant: O=C(O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC(C)N(NC(=O)c1ccoc1)C(=O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Yield: 55.9 %

Procedure:
A solution of (5-fluoro-2′-trifluoromethoxy-biphenyl-2-yloxy)-acetic acid (180 mg, 0.54 mmol) and furan-3-carboxylic acid N′-isopropyl-hydrazide (110 mg, 0.65 mmol) in DMF (5 ml) was treated with diisopropyl amine (0.237 ml, 1.36 mmol) and PyBroP (381 mg, 0.82 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with aqueous saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate in hexanes gradient to afford the product as a solid (145 mg, 56%). MS m/e 481.35 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)#[CH:10]>>[Cl:1][C:2]1[N:7]=[C:6]([C:10]#[C:9][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C#Cc1ccc(F)cc1
Product: Fc1ccc(C#Cc2ccnc(Cl)n2)cc1

Procedure:
The title compound was prepared from 2,4-dichloropyrmidine and 1-ethynyl-4-fluorobenzene using methods analogous to those described in Example 2 (65%). TLC (25% EtOAc/hexanes): Rf=0.21. mp 125-126° C. IR: 3049 (w), 2210 (w), 1559 (s). 1H NMR (CDCl3): 8.61 (d, J=5.0 Hz, 1H), 7.70-7.60 (m, 2H), 7.38 (d, J=5.0 Hz, 1H), 7.13-7.06 (m, 2H). 13C NMR (CDCl3): 163.99 (d, JC-F=252 Hz), 161.86, 159.66, 153.39, 134.96 (d, JC-F=8.6 Hz), 121.77, 116.96 (d, JC-F=3.4 Hz), 116.40 (d, JC-F=22 Hz), 95.27, 85.89. Anal. Calcd for C12H6ClFN2: C, 61.95; H, 2.60; N, 12.04; Found: C, 62.15; H, 2.83; N, 12.00.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][CH2:6][CH:7]1[O:11][C:10](=[O:12])[N:9]([CH:13]([CH:18]([CH3:20])[CH3:19])[C:14](OC)=[O:15])[CH2:8]1.[BH4-].[Li+].O1CCCC1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][CH2:6][CH:7]1[O:11][C:10](=[O:12])[N:9]([CH:13]([CH:18]([CH3:19])[CH3:20])[CH2:14][OH:15])[CH2:8]1
Reactant: COC(=O)C(C(C)C)N1CC(COc2cccc(Cl)c2)OC1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C(CO)N1CC(COc2cccc(Cl)c2)OC1=O
Yield: 55 %

Procedure:
A procedure similar to that described in Preparation 5 was repeated, except that 0.93 g of methyl 2-[5-(3-chlorophenoxymethyl)-2-oxooxazolidin-3-yl]-3-methylbutanoate (polar isomer), obtained as described in Preparation 99, 118 mg of lithium borohydride, 10 ml of anhydrous tetrahydrofuran and 87 mg of anhydrous methanol were used, to give 0.47 g of the title compound having an Rf value of 0.48 (on silica gel thin layer chromatography, using a 2:1 by volume mixture of ethyl acetate and hexane as the developing solvent) from the polar diastereomer.
Reaction SMILES: [C-:1]#[N:2].[Na+].[NH:4]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16]Cl)[N:12]=1)[C:5]([NH2:7])=[NH:6].C(Cl)(Cl)Cl>CS(C)=O>[NH:4]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][C:1]#[N:2])[N:12]=1)[C:5]([NH2:7])=[NH:6]
Reactant: N=C(N)Nc1nc(CCCCCl)cs1
Reactant: [C-]#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: N#CCCCCc1csc(NC(=N)N)n1
Temperature: 70 °C
Yield: 80.2 %

Procedure:
In 24 ml of dimethylsulfoxide was added 4.9 g of sodium cyanide, and the obtained mixture was heated at 70° C. Under stirring, 19.5 g of 2-guanidino-4-(4-chlorobutyl)thiazole was added to the solution at 70° to 75° C., and the solution was stirred at the same temperature for 3 hours. The reaction solution was cooled, and 100 ml of chloroform was added to the solution. After filtering off the undissolved material, the residue was purified by a silica gel column chromatography using a mixture of chloroform and methanol as the developing solvent to provide 15 g of 2-guanidino-4-(4-cyanobutyl)thiazole. The product shows a melting point of 104°-105° C. after recrystallization from a mixture of ethyl acetate and n-hexane. ##STR53## 10 g of 2-guanidino-4-(4-cyanobutyl)thiazole was suspended in a mixture of 60 ml of methanol and 110 ml of chloroform, and hydrogen chloride gas was passed through the solution under stirring at -5° to 5° C. for 2 hours. The resulting solution was allowed to stand at 5° C. for 2 days and the solvent was distilled off. The residue was suspended in a mixture of chloroform and methanol, and the suspension was poured into ice water containing 60 g of potasium carbonate. The chloroform layer was separated, and the aqueous layer was extracted further three times each time with 150 ml of chloroform. The extracts were combined, and dried over anhydrous potassium carbonate. The solvent was distilled off to provide 11 g of methyl 5-(2-guanidinothiazol-4-yl)pentanoimidate having a melting point of 143°-145° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:39][CH3:40])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[NH:23][C:22]3=[O:30])[CH2:17][CH2:16]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.O>CN(C)C=O>[CH2:39]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]([CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:22]3=[O:30])[CH2:17][CH2:16]2)=[CH:10][CH:11]=1)=[O:5])[CH3:40]
Reactant: CCN(CC)C(=O)c1ccc(C(CCN2CCC(n3c(=O)[nH]c4ccccc43)CC2)c2cccc(OC)c2)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)C(=O)c1ccc(C(CCN2CCC(n3c(=O)n(Cc4ccccc4)c4ccccc43)CC2)c2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57 %

Procedure:
The 1-[3-(4-diethylcarbamoylphenyl)-3-(3-methoxyphenyl)propyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine (50 mg) obtained in Example 1 was dissolved in N,N-dimethylformamide (1 ml), added with sodium hydride (60% in oil, 7.4 mg) and stirred at room temperature for 1.5 hours. The reaction mixture was added with benzyl bromide (22 μl) and further stirred at 60° C. for 2 hours. The reaction mixture was added with water (5 ml) and extracted twice with ethyl acetate (5 ml). The organic layer was washed with water (10 ml) and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: ethyl acetate:methanol=10:1) to obtain 33 mg of the title compound. Yield: 57%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([N:21]([CH2:29][C:30]3[N:35]=[N:34][C:33]4[O:36][CH2:37][CH2:38][O:39][C:32]=4[CH:31]=3)C(=O)OC(C)(C)C)[CH2:17][CH2:16]1)[C:7](=[O:40])[CH:6]=[N:5]2.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>C(Cl)Cl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[N:34]1[C:33]2[O:36][CH2:37][CH2:38][O:39][C:32]=2[CH:31]=[C:30]([CH2:29][NH:21][CH:18]2[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][N:8]3[C:9]4[C:4](=[CH:3][C:2]([F:1])=[C:11]([F:12])[CH:10]=4)[N:5]=[CH:6][C:7]3=[O:40])[CH2:20][CH2:19]2)[N:35]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(nn1)OCCO2)C1CCN(CCn2c(=O)cnc3cc(F)c(F)cc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1cnc2cc(F)c(F)cc2n1CCN1CCC(NCc2cc3c(nn2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
A solution of 1,1-dimethylethyl {1-[2-(6,7-difluoro-2-oxo-1(2H)-quinoxalinyl)ethyl]-4-piperidinyl}(6,7-dihydro[1,4]dioxino[2,3-c]pyridazin-3-ylmethyl)carbamate (0.17 g, 0.305 mmol) in DCM (0.65 ml) was treated with trifluoroacetic acid (0.43 ml, 5.78 mmol) stirred at rt for 1 h and evaporated. The residue was triturated with ether and dried at 50° C. under vacuum to give the title compound (0.149 g).
Reaction SMILES: [N+:1]([CH2:4][C:5]([CH3:9])=[CH:6][CH2:7][OH:8])([O-:3])=[O:2].CC(C)=[O:12].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[N+:1]([CH2:4][C:5]([CH3:9])=[CH:6][C:7]([OH:12])=[O:8])([O-:3])=[O:2]
Reactant: CC(C)=O
Reactant: CC(=CCO)C[N+](=O)[O-]
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC(=CC(=O)O)C[N+](=O)[O-]
Reaction time: 2 h

Procedure:
A stirred solution of 0.1 Mol of 4-Nitro-3-methyl-2-butenol in acetone at 10°-15° was titrated with approximately 0.26 Mol of Jones reagent until the reaction mixture stayed dark orange colored. After 2 hours stirring at 10°-15° C. the mixture was decanted from the green chromium salts and the acetone removed. The residue was dissolved in ether and washed several times with saturated NaCl solution. After evaporation, the residue was crystallized from hot benzene and off-white crystals, mp 85°, were obtained. Two more recrystallizations from benzene yielded the pure nitroacid, mp 100°-102°.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])=[C:6]([C:20]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH:21]=2)[CH:5]=1)(=[O:3])[CH3:2].C[Mg+].[Br-].CO.[CH:33](Cl)(Cl)Cl>C1COCC1>[CH3:26][C:23]1([CH3:27])[CH2:24][CH2:25][C:20]([C:6]2[CH:5]=[C:4]([C:1]([OH:3])([CH3:33])[CH3:2])[CH:9]=[CH:8][C:7]=2[NH:10][C:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])=[CH:21][CH2:22]1
Reactant: CC(=O)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCC(C)(C)CC2)c1
Reactant: ClC(Cl)Cl
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CC=C(c2cc(C(C)(C)O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 0 °C
Yield: 100 %

Procedure:
To a slurry of 4-cyano-1H-imidazole-2-carboxylic acid [4-acetyl-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (6.00 g, 0.0160 mol) in 100 mL of THF at −78° C. was added a solution of MeMgBr (3.0 M in THF, 22 mL, 0.066 mol) via syringe over a 20-min period. The reaction was allowed to warm to ca. 0° C. over a 30-min period at which point there was no starting material evident by thin layer chromatography (10% MeOH—CHCl3). The reaction was cooled to −78° C., quenched by the addition of saturated aqueous NH4Cl (100 mL) and allowed to warm to 0° C. The mixture was extracted with ether (2×150 mL) and dried (Na2SO4). The solvent was concentrated to afford the title compound as a white solid (6.40 g, 100%). The NMR and mass spectral data were identical to those for the compound produced in Example 14, step (d).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].C([N+]1(C)[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1)C1C=CC=CC=1.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]([F:34])=[C:28]([CH:33]=1)[C:29]([O:31][CH3:32])=[O:30].C(O)C>O>[F:34][C:27]1[CH:26]=[CH:25][C:24]([N:23]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)=[CH:33][C:28]=1[C:29]([O:31][CH3:32])=[O:30]
Reactant: C[N+]1(Cc2ccccc2)CCC(=O)CC1
Reactant: COC(=O)c1cc(N)ccc1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(N2CCC(=O)CC2)ccc1F
Yield: 67.3 %

Procedure:
Potassium carbonate (149 mg) and 1-benzyl-1-methyl-4-oxopiperidinium iodide (2.87 g) were sequentially added to a solution of methyl 5-amino-2-fluorobenzoate (1.22 g) obtained in Preparation Example 6-1 in a mixed solvent of ethanol 10 ml) and water (5 ml). The reaction mixture was refluxed for 2.5 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (1.22 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4](/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[N:3]=1>CC(C)=O.[Cl-].[Cl-].[Ti+2]>[CH3:1][C:2]1[O:6][N:5]=[C:4](/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[N:3]=1
Reactant: Cc1nc(/C=C/c2ccc([N+](=O)[O-])cc2)no1
Agent: [Ti+2]
Agent: [Cl-]
Solvent: CC(C)=O
Product: Cc1nc(/C=C/c2ccc(N)cc2)no1
Reaction time: 0.5 h

Procedure:
trans-5-Methyl-3-p-nitrostyryl-1,2,4-oxadiazole (6.93g) was dissolved in acetone (400 ml) at about 30°. 15% Acidic titanous chloride solution (250 ml) was added with stirring during 30 min. after which the reaction mixture remained purple in colour The acetone was then removed under reduced pressure and the residual mixture cooled to 5°. The crystalline precipitate was filtered off and washed with cold 2N-hydrochloric acid (15 ml). The solid was dissolved in water (400 ml) and the solution neutralized by the addition of sodium carbonate. The mixture was extracted with chloroform (400 ml). The extract was dried (MgSO4) and the chloroform removed under reduced pressure to give title compound as pale yellow needles, 5.61g (93%), m.p. 139°-140°. λmax. (EtOH) 231, 335 nm., (ε 10,700, 22,000) ξmax. (CHBr3) 3490, 3398 (NH2), 967 cm.-1 (trans CH=CH), τ (CDCl3) values include 2.39 and 3.18 (AB quartet, J = 16; trans CH=CH), 7.42 (CH3).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:9][C:8]([C:10]2[C:11]3[Se:23][CH:22]=[CH:21][C:12]=3[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1)=[O:4].C(OCC)(=O)C.O>[OH-].[Na+]>[OH:4][C:3]([C:5]1[O:9][C:8]([C:10]2[C:11]3[Se:23][CH:22]=[CH:21][C:12]=3[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1)=[O:2]
Reactant: COC(=O)c1ccc(-c2nn(-c3ccccc3)c3cc[se]c23)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc(-c2nn(-c3ccccc3)c3cc[se]c23)o1
Yield: 78 %

Procedure:
Compound 34 (1.49 g, 0.004 mole) in 40 ml of 10% NaOH solution was heated under refluxing for 2 h. The progress of the hydrolysis reaction was monitored by TLC with ethyl acetate (EA). When the reaction was completed, the reaction mixture was poured into water to stop the reaction, and then was extracted with toluene. The aqueous layer was recovered, and acidified with 10% HCl solution, which was then extracted with EA. The organic layer was recovered and dried over MgSO4 and filtered. The solvent of the filtrate was evaporated under a reduced pressure, and the residue was then recrystallized from EA to afford compound 48 in brown columnar crystals (0.76 g). Yield: 78%; mp 234-237° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>O.CCO.CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:11][C:5]1[CH:4]=[CH:3][C:2]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([F:12])[CH:18]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C(O)c1cc(Br)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cc(-c2cccc(F)c2)ccc1F
Temperature: 100 °C
Yield: 97 %

Procedure:
To a mixture of 5-bromo-2-fluorobenzoic acid (3 g, 13.2 mmol, 1.0 eq) and 3-fluorophenyl boronic acid (2.1 g, 15.1 mmol, 1.1 eq) in water (15 mL), EtOH (15 mL) and DMF (60 mL) was added Na2CO3 (5.81 g, 54.8 mmol, 4.1 eq) and Pd(PPh3)4 (1.58 g, 1.37 mmol, 0.1 eq). The reaction mixture was heated at 100° C. under nitrogen for 4 h, then cooled to room temperature. The resulting mixture was poured into water and extracted with ethyl acetate. The organic extracts were combined, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a white powder (3 g, 97%).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12]CC)=[O:11])=[C:6]([NH:17][C:18](=[O:36])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:21][CH:20]=2)[CH:5]=1.Cl>>[CH3:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[C:6]([NH:17][C:18](=[O:36])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:21][CH:20]=2)[CH:5]=1
Reactant: CCOC(=O)COc1ccc(C)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(OCC(=O)O)c(NC(=O)c2ccc(OCCCCc3ccccc3)cc2)c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
To 20 ml of a 10% potassium hydroxide-90% methanol solution was added 1.5 g of ethyl 4-methyl-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate obtained in Example 24 followed by stirring at 50 to 60° C. for 1 hour. After adding ml of a saturated saline aqueous solution, the reaction mixture was rendered acidic with diluted hydrochloric acid followed by extraction with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 1.12 g of 4-methyl-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid.