Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2].[H-].[Na+].[C:35]1([CH3:45])[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[S:41]([C:38]2[CH:39]=[CH:40][C:35]([CH3:45])=[CH:36][CH:37]=2)(=[O:43])=[O:42])=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(S(=O)(=O)c2ccc(C)cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96.4 %

Procedure:
The reaction was carried out under argon. (4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (278 mg, 604 μmol) was initially charged in dry THF (6 ml), and sodium hydride (60% in mineral oil; 34 mg, 845 μmol; 1.4 eq.) was added at 0° C. The mixture was warmed to RT and stirred for 20 min. A solution of p-toluenesulfonyl chloride (161 mg, 845 μmol; 1.4 eq.) in THF (˜2 ml) was then slowly added dropwise. After a reaction time of 16 h, the reaction mixture was concentrated and the crude product was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a colorless solid (358 mg, 96% of theory).
Reaction SMILES: [OH-].[Na+].[CH:3]12[CH2:12][CH:9]([CH2:10][CH2:11]1)[CH:8]1[C:4]2([C:13]([OH:15])=[O:14])[CH2:5][CH2:6][CH2:7]1.S(OCC)(O[CH2:20][CH3:21])(=O)=O>>[CH:3]12[CH2:12][CH:9]([CH2:10][CH2:11]1)[CH:8]1[C:4]2([C:13]([O:15][CH2:20][CH3:21])=[O:14])[CH2:5][CH2:6][CH2:7]1
Reactant: O=C(O)C12CCCC1C1CCC2C1
Reactant: CCOS(=O)(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)C12CCCC1C1CCC2C1
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
55.0 g (0.275 mole) of 20% aqueous sodium hydroxide solution was added dropwise to a mixture of 90.0 g (0.5 mole) of tricyclo[5.2.1.02,6 ]decane-2-carboxylic acid (mixture of endo and exo compounds) and 84.8 g (0.55 mole) of diethyl sulfate over one hour under stirring at 50 C.°. After completion of the addition, the stirring was continued at that temperature for 30 minutes. After completion of the stirring, the mixture was allowed to stand at room temperature for a while to form layers. The lower aqueous layer was taken out. The temperature was elevated again to 50 C.°. 55.0 g (0.275 mole) of a 20% aqueous sodium hydroxide solution was added dropwise to the remainder over one hour under stirring at that temperature for 30 minutes. Then, 16.5 g (0.0825 mole) of 20% aqueous sodium hydroxide solution was added thereto and the whole reaction mixture was stirred at 100 C.° for 45 minutes in order to decompose unreacted diethyl sulfate. The mixture was allowed to cool and divided into layers. After the distillation, 93.6 g (yield 90.0%) of pure ethyl tricyclo[5.2.1.02,6 ]decane-2-carboxylate was obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[Li].[Br:7][C:8]1[CH:9]=[N:10][C:11]([Cl:14])=[N:12][CH:13]=1.C(O)(=O)C.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1.CO>[Br:7][C:8]1[C:9]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:10][C:11]([Cl:14])=[N:12][CH:13]=1
Reactant: [Li]c1cccs1
Reactant: Clc1ncc(Br)cn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: Clc1ncc(Br)c(-c2cccs2)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Thienyl lithium (1.0 M in THF, 26 mL, 26 mmol) was diluted with anhydrous THF (65 mL) and the mixture cooled down to −78° C. under a nitrogen atmosphere. 5-Bromo-2-chloropyrimidine, dissolved in 10 mL of tetrahydrofuran, was added to the reaction mixture dropwise. The reaction was allowed to stir for 1 h and then warmed to −20° C. Acetic acid (1.5 mL) and methanol (1.2 mL) were successively added to the reaction mixture. The reaction was stirred for 15 min and a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (5.9 g, 20 mmol) in 10 mL of THF was added. The reaction was stirred for an additional 15 min and then the cooling bath was removed. The mixture was stirred for 1 h and then cooled to 0° C. with an ice bath. 5 N sodium hydroxide (5.2 mL) was added to the reaction mixture and stirred for 5 min. The reaction was then diluted with ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, concentrated and purified by flash chromatography on silica gel using 5% ethyl acetate in hexanes as an eluent to obtain a yellow solid. Yield=3.6 g. MS (M+H)+ 275/277.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[CH:15]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](=[O:13])(=[O:12])[NH:23][CH:15]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCCCCC1
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Product: O=C(O)c1ccc(Cl)c(S(=O)(=O)NC2CCCCCCC2)c1

Procedure:
25.5 g of 4-chloro-3-chlorosulfonylbenzoic acid were reacted as prescribed in Example 75(a) with 45 g of cyclooctyl amine and worked up. The crystallized 4-chloro-3-cyclooctylsulfamoylbenzoic acid so obtained was dried end reacted without further purification in thionyl chloride as prescribed in Example 74(a). Colorless crystals, melting point: 134° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH:7]=1.[C:19]([O-])(=O)[CH3:20].[Na+]>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:18][C:19]([CH3:20])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])[C:8]2=[O:17]
Reactant: Cc1ccccc1CC(=O)c1cc(Br)ccc1O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1ccccc1-c1c(C)oc2ccc(Br)cc2c1=O
Temperature: 25 °C
Yield: 33.4 %

Procedure:
Intermediate 11 (5.5 g, 16.38 mmoles) was taken in a RB flask and to this acetic anhydride (50 ml) and sodium acetate (9.40 g, 114.69 mmoles) were added and the mixture was refluxed for 12 h. After cooling to RT, the reaction mixture was quenched by the addition of ice cold water. The solid formed was filtered and washed with water. The product was dried under vacuum to afford the title compound as white solid (1.8 g, 30% yield). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 8.35(d, J=1.7Hz, 1H), 7.75(d, J=6.7 Hz, 1H), 7.37(d, J=8.8Hz, 1H), 7.35-7.26(m, 3H), 7.09(d, J=6.9Hz, 1H), 2.20(s, 3H).2.15(s, 3H).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([CH3:11])[CH:5]=1.Cl.[CH3:14][NH:15][O:16][CH3:17].C([Mg]Cl)(C)C>O1CCCC1>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([N:15]([O:16][CH3:17])[CH3:14])=[O:12])=[CH:5][C:6]=1[CH3:11]
Reactant: CNOC
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(Br)c(C)c1
Temperature: -30 °C
Yield: 88 %

Procedure:
4-Bromo-3-methyl-benzoic acid methyl ester (6 g, 26.19 mmol) was dissolved into anhydrous tetrahydrofuran (THF) (200 mL) and then cooled to −30° C. while stirring under nitrogen. N,O-dimethylhydroxylamine hydrochloride (3.81 g, 39.29 mmol) was then added to the solution in one portion. Isopropyl magnesium chloride (39 mL, 2M soln. in THF, 78.6 mmol) was slowly added to the cooled suspension over 1 h. After complete consumption of starting material, then 30% solution of ammonium chloride was added with stirring. The reaction was diluted with diethyl ether and extracted. The organic layer was collected and washed with cold water (2×) and brine. The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated. The 4-Bromo-N-methoxy-3,N-dimethyl-benzamide (5.94 g, 23.05 mmol) was obtained in purified form after flash column chromatography.
Reaction SMILES: Cl.Cl.[CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])=[CH:16]3)[CH2:8][CH2:7]1)([CH3:5])[CH3:4].[F:30][C:31]([F:38])([F:37])[CH2:32][S:33](Cl)(=[O:35])=[O:34]>>[CH:3]([N:6]1[CH2:7][CH2:8][CH:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22]([N:24]2[CH2:29][CH2:28][N:27]([S:33]([CH2:32][C:31]([F:38])([F:37])[F:30])(=[O:35])=[O:34])[CH2:26][CH2:25]2)=[O:23])=[CH:16]3)[CH2:10][CH2:11]1)([CH3:5])[CH3:4]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCNCC4)cc3c2)CC1
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)CC(F)(F)F)CC4)cc3c2)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone dihydrochloride and 2,2,2-trifluoro-ethanesulfonyl chloride. Off-white solid. MS (m/z): 517.3 (M+H)+.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>N1C=CC=CC=1.C1C=CC=CC=1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[O:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2OC(=O)c1ccccc1

Procedure:
Treat 13β-ethyl-17β-hydroxy-gon-4-en-3-one (2 g.) in pyridine (20 cc.) with benzoyl chloride (3 cc.) in benzene (10 cc.) at -10°. Keep the mixture at that temperature for 18 hours and then pour into 2N hydrochloric acid (200 cc.). Extract the product with ether and wash, dry and evaporate the extracts. Triturate the residue with a mixture of ether and hexane. Filter the crystalline material obtained and dissolved in benzene and purify by chromatography on neutral alumina. Recrystallize from a mixture of ethyl acetate and hexane to give the title compound, m.p. 141°-9°; ultraviolet light absorption peak at 237 mμ(ε27,300).
Reaction SMILES: [CH3:1][Mg]Cl.N#N.COC(=O)[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC[O:21][CH2:22][CH3:23]>>[CH3:1][C:22]([CH3:23])([OH:21])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)CCCc1ccccc1
Reactant: C[Mg]Cl
Reactant: CCOCC
Agent: N#N
Product: CC(C)(O)CCCc1ccccc1
Yield: 94 %

Procedure:
8 L of 3.0 M methylmagnesium chloride in ether was transferred to a 22 L 3-necked, round-bottomed flask using N2 pressure. This flask was equipped with argon flow inlet. The solution had been chilled to 0° in an ice-acetone bath and 1283 g (7.2 moles) quantity of methyl-4-phenylbutyrate was added under argon over 4 h maintaining the temperature between 0° C. and 11° C. The reaction mixture was stirred for 1H and an aliquot was withdrawn, quenched in water and extracted with ether. The ether extract was concentrated and the residual oil was assayed by NMR spectrum. This confirmed that no starting material remained. The reaction mixture was rechilled to 0° and 4 L of water was added over 3 to 4H. This caused vigorous gas evolution and slurrying during the initial stages of the addition and caused precipitation of a white solid. The reaction mixture was stirred for 1H following the water addition and the mixture was then filtered using Buchner funnel and the filtrate was separated. The aqueous phase was extracted with 2 L of ether-hexane mixture and the organic phases combined and concentrated to give 1200 g of yellow oil 94% yield.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[C:7]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(O)(=O)C.C1C=CC=CC=1>C([O-])(=O)C.[NH4+].O>[C:7]1(=[C:3]([C:1]#[N:2])[C:4]([OH:6])=[O:5])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: N#CCC(=O)O
Reactant: O=C1CCCCC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: N#CC(C(=O)O)=C1CCCCC1
Yield: 90 %

Procedure:
170 grams (2 moles) of cyanoacetic acid, 196 grams (2 moles) of cyclohexanone, 10 grams (0.13 moles) of ammonium acetate, 24 grams (0.4 moles) of acetic acid, and 380 milliliters of benzene were combined in a 2-liter round-bottomed flask equipped with a reflux condensor and a water separator, and the mixture heated (with reflux) for 6 hours. Upon cooling, the volatile compounds were removed in vacuo, and the residue washed with water to give 360 grams (1.8 moles, 90% yield) of cyclohexylidene cyanoacetic acid. The cyanoacetic acid was distilled under a vacuum of 50 Torricellis (torr.) thereby producing 196 grams (1.6 moles, 81% yield based on cyclohexanone, or 90% yield based on cyclohexylidene cyanoacetic acid) of cyclohexenyl acetic acid nitrile, which had a boiling point of between 115°-120° C. at 50 torr. (As an alternative to distilling the cyanoacetic acid under vacuum in the lastmentioned step, another portion of the cyclohexylidene cyanoacetic acid when heated to 140°-150° C. under a vacuum of 50-70 torr. for 2.5 hours was found to be readily convertible to an impure cyclohexenyl acetic acid nitrile.)
Reaction SMILES: [F:1][C:2]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)([C:7]([F:10])([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].FC(F)(F)C(C1C=CC(OC)=C(C=1)[CH:31]=[O:32])C(F)(F)F>>[F:1][C:2]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:12]=1)[CH:31]=[O:32])([C:7]([F:8])([F:9])[F:10])[C:3]([F:6])([F:5])[F:4]
Reactant: COc1ccc(C(C(F)(F)F)C(F)(F)F)cc1C=O
Reactant: COc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1
Product: COc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1C=O

Procedure:
This compound was prepared from Compound 16 in the same manner of Compound 9.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.S(Cl)([Cl:16])=O>ClCCl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([Cl:16])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2ccccc2c1
Solvent: ClCCl
Product: O=C(Cl)c1ccc2ccccc2c1
Yield: 93.3 %

Procedure:
To a stirred solution of 2-naphthyl carboxylic acid (76.5 g, 0.45 mol) in dichloromethane (500 ml) was added thionyl chloride (38.7 ml, 0.53 mol) and the mixture was heated at reflux temperature for 48 h. The volatiles were evaporated in vacuo affording 80 g (94%) of 2-naphthoyl chloride.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][N:15](CCCC(N2C3C(=CC=CC=3)CCC2)=O)[CH2:14][CH2:13]1.ClC1C=C2C(=CC=1)NC=C2C1CCNCC1.ClC[CH2:51][CH2:52][C:53]([N:55]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH2:58][CH2:57][CH2:56]1)=[O:54]>>[ClH:2].[Cl:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]2[C:4]=1[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:13][CH2:14][N:15]([CH2:51][CH2:52][C:53]([N:55]2[CH2:56][CH2:57][C:58]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[CH2:64]2)=[O:54])[CH2:16][CH2:17]1
Reactant: O=C(CCCCl)N1CCCc2ccccc21
Reactant: O=C(CCCN1CCC(c2c[nH]c3ccc(Cl)cc23)CC1)N1CCCc2ccccc21
Agent: Cl
Agent: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Product: O=C(CCN1CCC(c2c[nH]c3c(Cl)cccc23)CC1)N1CCc2ccccc2C1

Procedure:
5-Chloro-3-{1-[4-(3,4-dihydro-2H-quinolin-1-yl)-4-oxobutan-1-yl]piperidin-4-yl}-1H-indole, hydrochloride from 5-chloro-3-(piperidin-4-yl)-1H-indole and 4-chloro-1-(3,4-dihydro-2H-quinolin-1-yl)butan-1-one. Mp 158-162° C. 1H NMR (DMSO-d6): 1.85-1.95 (m, 2H); 1.95-2.20 (m, 6H); 2.60-2.75 (m, 4H); 2.95-3.15 (m, 5H); 3.55 (d, 2H); 3.70 (t, 2H); 7.05-7.25 (m, 6H); 7.40 (d, 1H); 7.75 (s, 1H); 10.45 (broad s, 1H); 11.15 (s, 1H). MS m/z: 436 (MH+), 303.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-])=O)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]>C(O)C.C(O)(=O)C.C1COCC1.[Pd]>[NH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(F)ccc1Oc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1cc(F)ccc1Oc1ccccc1N
Reaction time: 20 h
Yield: 94.9 %

Procedure:
To a stirring solution of title compound 18 (3.48 g, 11.9 mmol) in ethanol (30 mL), acetic acid (1.0 mL) and THF (10 mL) was added palladium on charcol 10% (0.37 g, 10% w/w). The reaction mixture was stirred under hydrogen atmosphere for 20 hours. The catalyst was filtered and the filtrate was concentrated in vacuo. The residue was diluted with ether and this organic mixture was washed with a saturated aqueous solution of bicarbonate, water and brine then solvent evaporated to afford title compound 19 (2.95 g, 95%) as a beige solid. LRMS (ESI): (calc) 261.08 (found) 262.3 (MS)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:22])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1)C=O.ClC1C=C(C=CC=1)C(OO)=[O:28].[OH-].[Na+].Cl>ClCCl.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([OH:28])[CH:7]=[C:8]([CH3:22])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1
Reactant: COc1ccc(Oc2c(C)cc(C=O)cc2C)cc1C(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(Oc2c(C)cc(O)cc2C)cc1C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
To a solution of 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)benzaldehyde (0.18 g, 0.60 mmol, Example 28, step a) in dichloromethane (6.0 mL) at 0° C. was added m-chloroperoxybenzoic acid (0.22 g, 0.905-mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate. The organic solution was washed with saturated sodium bicarbonate (2×10 mL) and water. The solvent was removed under reduced pressure and the residue was dissolved in methanol (5 mL). To the solution was added 1 N NaOH (1.81 mL, 1.81 mmol) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate, acidified with 2 N HCl and washed with brine. The solvent was evaporated and the residue was purified by preparatory TLC eluting with acetone-hexanes (1:4) to afford 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)phenol as an oil (0.08 g, 47%): 1H NMR (200 MHz, DMSO-d6): δ 9.17 (s, 1 H), 6.82 (m, 1 H), 6.70 (m, 1 H), 6.51 (s, 2 H), 6.32 (m, 1 H), 3.71 (s, 3 H), 3.18 (m, 1 H), 1.95 (s, 6 H), 1.12 (d, J=6.0 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-acetone (4:1); Rf=0.44.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[C:25]([CH:30]([CH3:32])[CH3:31])[CH:24]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:21])[C:2]=1[S:29][C:26]1[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][C:25]=1[CH:30]([CH3:32])[CH3:31]
Reactant: Cc1ccc(S)c(C(C)C)c1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Solvent: C1CCNCC1
Solvent: ClCCl
Product: Cc1ccc(SC2=C(O)CC(c3ccccc3)(c3ccccc3)OC2=O)c(C(C)C)c1

Procedure:
The title compound was prepared as described in General Method 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 2.1 mmol of 4-methyl-2-isopropylbenzenethiol, and 2.1 mmol of piperidine in 30 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform (m.p. 185-186° C.). 1H NMR (DMSO-d6) δ 1.17 (d, J=10 Hz, 6 H), 2.15 (s, 3 H), 3.17 (m, 1 H), 3.76 (bs, 2 H), 5.56 (d, 1 H), 6.29 (d, 1 H), 6.94 (s, 1 H), 7.32-7.47 (m, 10 H).
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[Br:11][C:12]1[C:17]([F:18])=[CH:16][C:15]([NH2:19])=[C:14]([NH2:20])[CH:13]=1>>[Br:11][C:12]1[CH:13]=[C:14]2[C:15](=[CH:16][C:17]=1[F:18])[NH:19][C:1](=[O:8])[C:2](=[O:4])[NH:20]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cc(F)c(Br)cc1N
Product: O=c1[nH]c2cc(F)c(Br)cc2[nH]c1=O
Temperature: 25 °C

Procedure:
The title compound was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (1.97 mL, 13.5 mmol) and 4-bromo-5-fluoro-1,2-diaminobenzene (277 mg, 1.35 mmol) was heated to reflux under N2 for 12 h. The reaction was allowed to cool to room temperature and the dark-brown solid collected by vacuum filtration and rinsed with ethanol (20 mL) and air dried to give 233 mg (67% ) of a powdery brown solid. A portion of this solid (100 mg) was taken and dissolved in 5 mL 1N NaOH. The solution was treated with activated charcoal and filtered through a pad of Celite. The Celite was rinsed with 10 mL additional NaOH solution. The resulting solution was carefully acidified with 1N HCl (pH=5). Bright yellow needles slowly formed in the solution and were collected by vacuum filtration, rinsed with 15 mL of H2O and dried under vacuum (0.1 torr, 78° C.) to yield 40.0 mg of yellow crystals. 1H NMR (d6 -DMSO) δ6.99 (d, 1H, J=9.3, H-8), 7.29 (d, 1H, J=6.3, H-6), 11.95 (br s, 2H, 2(NH)). EIMS m/z 260 (M+2, 96), 258 (M+(bp)), 232 (51), 230 (52), 123 (83). EIHRMS calc. for C8H4BrFN2O2 256.9941, found 257.9441.
Reaction SMILES: [C:1](O)(=O)C(C)C.C(O)(=O)CC.[CH3:12][CH:13]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:14](=[O:22])[CH2:15][P:16](=[O:21])([O:19][CH3:20])[O:17][CH3:18].C(Cl)C1C=CC=CC=1>>[CH3:12][C:13]([CH3:1])([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:14](=[O:22])[CH2:15][P:16](=[O:21])([O:19][CH3:20])[O:17][CH3:18]
Reactant: CC(C)C(=O)O
Reactant: COP(=O)(CC(=O)C(C)Cc1ccccc1)OC
Solvent: CCC(=O)O
Solvent: ClCc1ccccc1
Product: COP(=O)(CC(=O)C(C)(C)Cc1ccccc1)OC

Procedure:
Further, following the procedure of Preparation 1, but using in place of the isobutyric acid of Preparation 1, part A, propionic acid, there is prepared dimethyl 3-methyl-2-oxo-4-phenylbutylphosphonate. Following the procedure of Preparation 1, but using the substituted benzyl chlorides described above in place of benzyl chloride and propionic acid in place of isobutyric acid there are prepared the various dimethyl 3-methyl-2-oxo-4-(substituted phenyl)-butylphosphonates wherein the phenyl substitution is as described above.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6]([C:8]1[O:12][N:11]=[C:10]([CH2:13][NH2:14])[N:9]=1)=[O:7])[CH3:4].C(N(C(C)C)C(C)C)C.[Cl:24][C:25]1[S:29][C:28]([C:30](O)=[O:31])=[CH:27][CH:26]=1>CN(C=O)C.CCOC(C)=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>[CH2:3]([O:5][C:6]([C:8]1[O:12][N:11]=[C:10]([CH2:13][NH:14][C:30]([C:28]2[S:29][C:25]([Cl:24])=[CH:26][CH:27]=2)=[O:31])[N:9]=1)=[O:7])[CH3:4]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CCOC(=O)c1nc(CN)no1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nc(CNC(=O)c2ccc(Cl)s2)no1
Yield: 81.6 %

Procedure:
To a stirred solution of 3-aminomethyl-[1,2,4]oxadiazole-5-carboxylic acid ethyl ester dihydrochloride (555 mg) at r.t. in DMF (10 ml) under an argon atmosphere were added N-ethyldiisopropylamine (1.82 ml), 5-chloro-2-thiophenecarboxylic acid (565 mg) and BOP (1.54 mg). The mixture was stirred over night, then diluted with EtOAc and washed with H2O. The aqueous phase was back extracted with EtOAc and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane->cyclohexane/EtOAc 1:1) to give 3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-[1,2,4]oxadiazole-5-carboxylic acid ethyl ester (586 mg) as off-white solid. MS 316.0 ([M+H]+)