Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:42])[CH2:6][C@H:5]([O:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17](CC3C=CC(OC)=CC=3OC)[C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)(=[O:16])=[O:15])=[C:10]([F:35])[CH:9]=2)[C@@H:4]([C:36]2[N:40]([CH3:41])[N:39]=[CH:38][CH:37]=2)[CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:42][C:2]1([F:1])[CH2:6][C@H:5]([O:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)(=[O:15])=[O:16])=[C:10]([F:35])[CH:9]=2)[C@@H:4]([C:36]2[N:40]([CH3:41])[N:39]=[CH:38][CH:37]=2)[CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CC(F)(F)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CC(F)(F)C[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 96.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (105 mg, 0.174 mmol) prepared in Example 136a, triethylsilane (0.30 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (3.0 mL), to yield the title compound (76 mg, 96%) as a colorless solid.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][C:9]#[N:10])(=[O:5])[C:2]([CH3:4])=[CH2:3].C(OCCC#N)(=[O:14])C=C>>[C:9]([NH2:10])(=[O:14])[CH:8]=[CH2:7].[C:1]([O:6][CH2:7][CH2:8][C:9]#[N:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=CC(=O)OCCC#N
Agent: C=C(C)C(=O)OCCC#N
Product: C=CC(N)=O

Procedure:
The procedure of Example I was followed with 3.48 g of β-cyanoethyl methacrylate (commercially available from Union Carbide Corp., New York, New York) instead of β-cyanoethyl acrylate.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11](O)=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C1COCC1.O>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1ccc(C(=O)O)c(Br)c1
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(CO)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
Under a nitrogen stream, to a solution of 2-bromo-terephthalic acid (5.0 g, 20.4 mmol) in THF (50 ml), a THF solution of BH3 (1.09 M, 74.9 ml) was added dropwise at 0° C. and the mixture was stirred at room temperature for 4 hours. After addition of THF-water (1:1) to this solution, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:2)) to give the titled compound (4.1 g, 92%).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=[O:4].[CH3:14][Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[Br:1][CH2:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:14])=[O:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)CBr)cc1

Procedure:
4-(Bromoacetyl)benzoic acid (10 g, 41.3 mmol) was dissolved in 75 mL of MeOH and 75 mL of methylene chloride. Trimethylsilyl diazomethane (2.0 M in ether) was slowly added at 0° C. until a yellow color persisted. The volatiles were evaporated to give the title compound. 1H NMR (500 MHz, (CD3OD): 8.18 (d, 2H), 8.16 (d, 2H), 4.68 (s, 2H), 3.96 (s, 3H). LCMS: m/z 258 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:12][CH2:13][CH2:14][Cl:15]
Reactant: ClCCCBr
Reactant: N#Cc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCCCl)c(Cl)c1
Temperature: 100 °C
Yield: 95 %

Procedure:
A mixture of 2-chloro-4-cyanophenol (2.15 g), 3-bromo-1-chloropropane (2.3 g), dimethylformamide (3 ml) and potassium carbonate (1.5 g) was heated at 100° C. for one hour. After the inorganic salt was filtered off, the solvent was distilled off and the residue was dissolved in chloroform. The solution was chromatographed on a column of silica gel (80 g) and eluted with a solution of petroleum ether-ethyl acetate (10:1) to give 3.06 g of 3-(2-chloro-4-cyanophenoxy)propyl chloride as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[CH2:15][CH2:16]O)([CH3:4])[CH3:3].S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[CH2:15][CH2:16][Cl:20])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ccc(CCO)c(C(C)(C)C)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(CCCl)c(C(C)(C)C)c1

Procedure:
A solution of the title product of Example 10 (2.0 grams, 8.5 mmoles) and thionyl chloride (2.03 g, 17.1 mmoles) in toluene (50 ml) is heated at reflux for one hour. After cooling, the mixture is evaporated. Chromatography of the residue over silica gel using mixtures of ethyl acetate and hexane as eluents gives the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9](=[C:12]([C:18]([O:20]CC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:10][CH3:11])=[CH:6][CH:5]=[N:4]1)[CH3:2].N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:10][CH3:11])=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([OH:20])=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)=C(CC)Nc1ccnn1CC
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1O

Procedure:
Diethyl {1-[(1-ethyl-1H-pyrazol-5-yl)amino]propylidene}propanedioate (1.00 g, 3.23 mmol, e.g. which can be as prepared in Intermediate 2B) was dissolved in toluene (8 ml). To the resulting dark orange solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (“DBU”, 0.97 ml, 0.98 g, 6.46 mmol, 2.0 equivalents) was added, and the reaction mixture was heated at reflux for 17 hours. Further toluene (8 ml) was added to the reaction mixture, after a reduction in volume after heating had been noted. The reaction mixture was allowed to cool, and washed with water (8 ml). The two layers were separated, and the organic layer was discarded after HPLC analysis suggested that the majority of the product was in the aqueous layer. The aqueous layer, whose pH was 12, was acidified to pH 1 using concentrated aqueous hydrochloric acid (0.6 ml), whereupon gas was seen to evolve and solid precipitated spontaneously from solution. This solid was filtered and washed with water. The resulting beige solid (0.55 g) was dried in a vacuum oven at 60° C. overnight. The title compound was obtained as a beige solid (0.46 g, about 54% theory yield). HPLC (5 min generic solvent gradient): TRET about 2.33. Mass Spectrum: Found: MH+ 264.1, (M-H)− 262.1.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:6]1[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH2:11][CH:10]([CH2:18][OH:19])[CH2:9][N:8]3[CH:7]=1)=O.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:31]=[C:30]2[C:26]([C:27]([CH2:32][C:33]([NH2:35])=[O:34])=[CH:28][NH:29]2)=[CH:25][CH:24]=1>>[OH:19][CH2:18][CH:10]1[CH2:11][C:12]2[C:17]3=[C:16]([C:6]([CH:4]4[CH:32]([C:27]5[C:26]6[C:30](=[CH:31][C:23]([C:22]([F:36])([F:21])[F:37])=[CH:24][CH:25]=6)[NH:29][CH:28]=5)[C:33](=[O:34])[NH:35][C:3]4=[O:2])=[CH:7][N:8]3[CH2:9]1)[CH:15]=[CH:14][CH:13]=2
Reactant: NC(=O)Cc1c[nH]c2cc(C(F)(F)F)ccc12
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CC(CO)C2
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CC(CO)C3)C1c1c[nH]c2cc(C(F)(F)F)ccc12

Procedure:
Beginning with (5-(hydroxymethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl]oxo-acetic acid methyl ester and (6-(trifluoromethyl)-1H-indol-3-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O)[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:29](=[O:30])[CH2:28][C:27](=[O:31])[NH:26][C:25]3[C:32]4[C:37]([CH:38]=[CH:39][C:24]2=3)=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:19][CH:18]=1>>[CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:29](=[O:30])[CH2:28][C:27](=[O:31])[NH:26][C:25]3[C:32]4[C:37]([CH:38]=[CH:39][C:24]2=3)=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:19][CH:18]=1)=[O:7])[CH3:2]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: CCc1ccccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: CCc1ccccc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 57.8 %

Procedure:
2-Ethylbenzoic acid (23 mg, 0.15 mmol) was treated with thionyl chloride in the same manner as that of Example 13, and then by using the resultant together with 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.1 mmol) obtained in Example 1, (3), the title compound (26 mg, yield 58%) was obtained as slightly brown crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[CH3:12].[B:13](OC)([O:16]C)[O:14]C.S(=O)(=O)(O)O>BrC1C=C(C)C=CC=1C.C1COCC1>[CH3:12][C:6]1[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=1[B:13]([OH:16])[OH:14]
Reactant: COB(OC)OC
Reactant: Cc1ccc(C)c(Br)c1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(C)c(B(O)O)c1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
Magnesium turnings (13.3 g; 0.55 mol) are introduced into a baked-out, argon-blanketed apparatus, covered with about 30 ml of THF and a few crystals of iodine are added. Without stirring, a few drops of bromo-p-xylene (cf. Example A1 a)) were subsequently added to the solution. The Grignard reaction began very quickly and the remaining bromo-p-xylene (total amount: 92.5 g; about 70 ml; 0.5 mol) was subsequently added dropwise while stirring. The mixture was refluxed for 4 hours and then cooled. The Grignard solution was then transferred in a countercurrent of protective gas into a 500 ml dropping funnel and added dropwise to a solution of trimethyl borate (62.4 g; 67 ml; 0.6 mol) in 350 ml of THF while stirring at −70° C. (time: about 1 hour). A precipitate was formed during this addition. The reaction mixture was allowed to warm to RT overnight and was then introduced while stirring into a mixture of 700 g of ice and 20 ml of concentrated sulfuric acid. The organic phase was separated off, the aqueous phase was extracted three times with chloroform and the combined organic phases were evaporated. The crude product was recrystallized from chloroform/hexane. This gave a colorless microcrystalline powder 47.71 g (64%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][N:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17](=[O:24])[N:16]([C:25]2[CH:26]=[CH:27][C:28]3[S:32][N:31]=[C:30]([C:33]4[CH:38]=[C:37]([O:39][CH2:40][C:41]([OH:43])=O)[CH:36]=[CH:35][C:34]=4[CH3:44])[C:29]=3[CH:45]=2)[C:15]1=[O:46].[CH3:47][C:48]1[CH:49]=[CH:50][C:51]([S:54]([NH2:57])(=[O:56])=[O:55])=[CH:52][CH:53]=1.N12CCCN=C1CCCCC2.Cl>O1CCCC1>[CH3:13][N:14]1[C:19]([C:20]([F:21])([F:22])[F:23])=[CH:18][C:17](=[O:24])[N:16]([C:25]2[CH:26]=[CH:27][C:28]3[S:32][N:31]=[C:30]([C:33]4[CH:38]=[C:37]([O:39][CH2:40][C:41]([NH:57][S:54]([C:51]5[CH:52]=[CH:53][C:48]([CH3:47])=[CH:49][CH:50]=5)(=[O:55])=[O:56])=[O:43])[CH:36]=[CH:35][C:34]=4[CH3:44])[C:29]=3[CH:45]=2)[C:15]1=[O:46]
Reactant: Cc1ccc(OCC(=O)O)cc1-c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(S(=O)(=O)NC(=O)COc2ccc(C)c(-c3nsc4ccc(-n5c(=O)cc(C(F)(F)F)n(C)c5=O)cc34)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
A mixture of 1,1'-carbonyldiimidazole (0.198 g, 1.22 mmol) and {{2-{5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazol-3-yl}-p-tolyl}oxy}acetic acid (0.300 g, 0.610 mmol) in tetrahydrofuran is stirred overnight at room temperature, refluxed for 30 minutes, cooled to room temperature, treated sequentially with a solution of p-toluenesulfonamide (0.209 g, 1.22 mmol) in tetrahydrofuran and a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (0.204 g, 1.34 mmol) in tetrahydrofuran, stirred at room temperature for three hours, and poured into 10% hydrochloric acid. The resulting aqueous mixture is filtered to obtain a solid. The solid is recrystallized from an acetonitrile/water solution to give the title product as an off-white solid (0.200 g, mp 140-144° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:9]/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:13][C:12](=[O:14])/[CH:11]=[CH:10]/[CH:9]=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=C(O)/C=C/C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(/C=C/C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 104.4 %

Procedure:
As in Example 115, (E)-5,5-bis(4-chlorophenyl)-2,4-pentadienoic acid (4.79 g) and 4-nitrophenol (2.5 g) in dichloromethane (50 mL) was treated with 1,3-dicyclohexylcarbodiimide (3.1 g). The mixture was stirred at 0°-5° C. for 1 hour, then at room temperature for 1 hour. The usual work up furnished 6.9 g of (E)-5,5-bis(4-chlorophenyl)-2,4-pentadienoic acid 4-nitrophenyl ester as a pale yellow oil homogeneous by tlc. This material was used without further purification in subsequent reactions.
Reaction SMILES: Cl.[NH2:2]O.[C:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5]>C(O)C>[C:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:23][N:2]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=2)=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: NO
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(C(C)(C)C)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(C(C)(C)C)cc2)on1
Temperature: 25 °C

Procedure:
Hydroxylamine hydrochloride (6.14 g, 88.0 mmol) was added to a suspension of ethyl 4-(4-tert-butylphenyl)-2,4-dioxobutanoate (20.4 g, 73.7 mmol) in absolute ethanol (300 mL) and the reaction was heated to reflux for 3 hours. After cooling to room temperature, the organics were removed in vacuo and the resulting residue was purified by silica gel chromatography, eluting with heptane to 10% methanol in dichloromethane, to obtain afford the title compound white solid was filtered, washed with water and cold ethanol and dried in vacuo to obtain ethyl 5-(4-tert-butylphenyl)isoxazole-3-carboxylate (15.9 g, 58.0 mmol).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[CH3:6][CH:7]([O:14][N:15]1[C:20]([CH3:22])([CH3:21])[CH2:19][C:18](=O)[CH2:17][C:16]1([CH3:25])[CH3:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(#N)C.O1CCCC1>CCOCC.C1(C)C=CC=CC=1>[CH2:1]([NH:5][CH:18]1[CH2:19][C:20]([CH3:22])([CH3:21])[N:15]([O:14][CH:7]([CH3:6])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:16]([CH3:24])([CH3:25])[CH2:17]1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(ON1C(C)(C)CC(=O)CC1(C)C)c1ccccc1
Reactant: CCCCN
Solvent: CCOCC
Solvent: CC#N
Solvent: C1CCOC1
Product: CCCCNC1CC(C)(C)N(OC(C)c2ccccc2)C(C)(C)C1
Yield: 74 %

Procedure:
The title compound is prepared in 74% yield as a colorless syrup from n-butylamine and 1-alpha-methylbenzyloxy-2, 2,6,6-tetramethylpiperidin-4-one (made in Example 11A) according to the procedure of Example 11B. Acetonitrile is substituted for tetrahydrofuran as the reaction solvent and toluene is substituted for ether in the isolation steps.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[CH2:9][CH2:10][C:11]2[S:12][C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]=2[CH3:16])=[CH:4][C:3]=1[CH3:22].C(=O)([O-])[O-].[K+].[K+].Br[C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32].[Cl-].[NH4+]>CC(=O)CC>[CH3:36][C:30]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[CH2:9][CH2:10][C:11]2[S:12][C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]=2[CH3:16])=[CH:4][C:3]=1[CH3:22])([CH3:37])[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1cc(C(=O)CCc2sc3ccccc3c2C)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C(=O)CCc2sc3ccccc3c2C)cc1C
Temperature: 0 °C
Yield: 72.3 %

Procedure:
To an ice-cold suspension of 1-(4-hydroxy-3-methylphenyl)-3-(3-methylbenzothiophen-2-yl)propan-1-one [Example 1 (1)] (200 mg, 0.645 mmol) and potassium carbonate (445 mg, 3.22 mmol) in 2-butanone (6.4 mL) was added slowly ethyl 2-bromo-2-methylpropionate (0.48 mL, 3.2 mmol). The mixture was heated under reflux for 20 hours, to which was added saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/1), to give the titled compound as a pale yellow oil (198 mg, yield 72%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.[CH3:32][N:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)N>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:33]([CH3:32])[C:35]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(F)cc3)CC2)c1
Reactant: CN(N)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(F)cc4)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 512.2 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH:15]=[CH:16][C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:12]([Cl:26])[CH:11]=[C:10]([Cl:27])[CH:9]=2)=[O:5])C.[OH-].[Li+]>C(O)C>[C:19]1([NH:18][C:17](/[CH:16]=[CH:15]/[C:14]2[C:13]3[C:8](=[CH:9][C:10]([Cl:27])=[CH:11][C:12]=3[Cl:26])[NH:7][C:6]=2[C:4]([OH:5])=[O:3])=[O:25])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1C=CC(=O)Nc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(/C=C/c1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12)Nc1ccccc1
Reaction time: 6 h
Yield: 98.9 %

Procedure:
To a solution of Example 1 (250 mg) in ethanol (2.5 ml), lithium hydroxide (104 mg) was added at 23°. The reaction was stirred at 50° for 6 hours then the solvent was evaporated and the residue dissolved in water (5 ml). The aqueous layer was acidified with 1N hydrochloric acid until a white solid precipitated. The latter was collected by filtration and dried to give the title compound as a white solid (230 mg).
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@@:20]1([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:37])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH:34]([CH3:36])[CH3:35])[CH:28]=2)[CH2:21]1)(=O)=O.C(#N)C>>[Cl:45][C:40]1[CH:39]=[C:38]([C@@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][N:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:37])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH:34]([CH3:35])[CH3:36])[CH:28]=3)[CH2:21]2)[CH:43]=[CH:42][C:41]=1[Cl:44]
Reactant: C1CCC(N2CCNCC2)CC1
Reactant: CC(C)Oc1cccc(CC(=O)N2CC[C@@](CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)c1
Solvent: CC#N
Product: CC(C)Oc1cccc(CC(=O)N2CC[C@](CCN3CCN(C4CCCCC4)CC3)(c3ccc(Cl)c(Cl)c3)C2)c1

Procedure:
In 30 ml of acetonitrile (R)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-[(3-isopropoxyphenyl)acetyl)pyrrolidine (3.17 g), prepared as described, suora, is mixed with an equimolar amount of 1-cyclohexylpiperazine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum and the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[C:16]1([NH:22]N)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)C.Cl>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:22][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)Cc1ccc(Cl)cc1
Reactant: NNc1ccccc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1[nH]c2ccccc2c1-c1ccc(Cl)cc1
Temperature: 120 °C
Yield: 11.9 %

Procedure:
A mixture of Example 52A (4.75 g, 21.0 mmol) and phenyl hydrazine (2.07 mL, 21.0 mmol) was treated with concentrated sulfuric acid (5 drops), heated to 120° C. for 15 minutes, cooled to room temperature, treated with ethanol (25 mL), treated with bubbling HCl gas for 2 minutes, and heated to reflux for 1 hour. The mixture was poured into water (30 mL) and extracted with diethyl ether. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was recrystallized from ethanol to provide 750 mg (12%) of the desired product.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:16])([C:6](=[O:15])[CH:7]([CH3:14])[C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:5].[CH3:17]I>O1CCCC1>[CH3:10][C:9]([CH3:12])([C:8](=[O:13])[C:7]([CH3:17])([CH3:14])[C:6](=[O:15])[C:4]([CH3:3])([CH3:16])[CH3:5])[CH3:11]
Reactant: CC(C(=O)C(C)(C)C)C(=O)C(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)C(C)(C)C(=O)C(C)(C)C
Temperature: 25 °C

Procedure:
To a suspension of 1.6 g of NaH at 80% by weight in 42 ml of anhydrous tetrahydrofurane are added dropwise 8 g of 2,2,4,6,6-pentamethyl-3,5-heptanedione (0.04 moles). The content is stirred at ambient temperature until a homogeneous solution is obtained. 7.7 ml of methyl iodide are then added and a white precipitate forms almost immediately. The content is allowed to agitate at ambient temperature for 12 hours and then the solvent is evaporated. Some water is added (10 ml) and the content is extracted with ether and then anhydrated on Na2SO4. The ether is evaporated to the rotavapor, isolating a white needle-shaped solid, which is then purified by way of sublimation.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([O:12]C)=[O:11].[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: COC(=O)CCc1ccccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCc1ccccc1Br
Yield: 96.1 %

Procedure:
To a solution of methyl 3-(2-bromophenyl)propionate (35.77 g) in ethanol (80.7 ml) was added at room temperature dropwise a solution of sodium hydroxide (11.77 g) in water (40 ml). After the reaction mixture was stirred under reflux for 2.5 hrs. and left standing for cooling, methanol was removed by distillation under reduced pressure, the residue was poured into ice-hydrochloric acid and stirred for 20 minutes. Crystalline precipitates were filtered, washed well with water, dried under reduced pressure to give the title compound (32.4 g).