Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15](=[O:18])[CH2:16][CH3:17])[CH2:9]1)C1C=CC=CC=1>[Pd].CO>[C:19]1([N:14]([CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[C:15](=[O:18])[CH2:16][CH3:17])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCC(=O)N(c1ccccc1)C1CCCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CCC(=O)N(c1ccccc1)C1CCCNC1
Reaction time: 24 h
Yield: 97.2 %

Procedure:
A mixture of N-(1-benzyl-piperidin-3-yl)-N-phenyl-propionamide (165) (150 mg) and Pd—C (10%, 50 mg) and MeOH (50 ml) was stirred under H2 (1 atm) for 24 hr. The catalyst was removed by filtration through Celite to give 166 as a colorless oil (105 mg, 97%). 1H-NMR (300 MHz, CDCl3) δ 7.41 (m, 3H), 7.10 (m, 2H), 3.20 (m 1H), 2.90 (m, 1H), 2.40-2.20 (m, 2H), 1.90 (m, 2H), 1.60 (m, 4H), 1.20 (m, 1H), 1.00 (t, 3H) ppm; LRMS (calculated for C14H21N2O) (M+1)+233, found 233.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:6](=[O:23])[C:7](=[O:22])[C:8]=1[Sn](CCCC)(CCCC)CCCC)([CH3:3])[CH3:2].[F:24][C:25]([F:34])([F:33])[C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1>>[CH:1]([O:4][C:5]1[C:6](=[O:23])[C:7](=[O:22])[C:8]=1[C:29]1[CH:30]=[CH:31][C:26]([C:25]([F:34])([F:33])[F:24])=[CH:27][CH:28]=1)([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(OC(C)C)c(=O)c1=O
Product: CC(C)Oc1c(-c2ccc(C(F)(F)F)cc2)c(=O)c1=O
Yield: 49.3 %

Procedure:
In a manner similar to Example 9, Step 1, 3-isopropoxy-4-(tri-n-butylstannyl)-3-cyclobutene-1,2-dione (3.00 g, 6.99 mmol), 4-trifluoromethyl-iodobenzene (2.09 g, 7.69 mmol), benzylchlorobis(triphenylphos-phine)palladium (II) (0.318 g, 0.419 mmol) and cuprous iodide (0.12 g, 0.629 mmol) were reacted together to give 0.98 g (45%) of 3-isopropoxy-4-(4-trifluoromethyl-phenyl)-cyclobut-3-ene-1,2-dione which was of sufficient purity to use in the next step.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[Cl:17])[NH:13][CH:12]=[C:11]2[CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22].[H-].[Na+].[C:26](Cl)(=[O:28])[CH3:27]>C(O)(=O)C>[C:26]([N:13]1[C:14]2[C:10](=[CH:9][C:8]([O:7][CH3:6])=[C:16]([Cl:17])[CH:15]=2)[C:11]([CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])=[CH:12]1)(=[O:28])[CH3:27]
Reactant: COc1cc2c(CCNC(C)=O)c[nH]c2cc1Cl
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cc2c(CCNC(C)=O)cn(C(C)=O)c2cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
To 30 ml. of N,N-dimethylformamide were added 210.7 mg. (0.79 mmole) of N-[2-(5-methoxy-6-chloroindol-3-yl)ethyl]acetamide (prepared as in Example 1) followed by 20.8 mg. of sodium hydride. The resulting mixture was stirred at room temperature for about one hour, and 68.2 mg. (0.06 ml.) of acetyl chloride were added. The mixture was stirred for an additional hour and then was poured into ice water containing a small amount of acetic acid. The resulting mixture was extracted with chloroform, and the extract was washed twice with saturation aqueous sodium chloride solution. The chloroform extract was dried over sodium sulfate and was concentrated in a rotary evaporator. The residue was recrystallized from benzene-ether and was vacuum-dried to obtain 108 mg. (40.8%) of the title compound, m.p. 178°-181° C.
Reaction SMILES: C1(=O)NC(=[O:6])C2=CC=CC=C12.[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[S:21][CH2:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[NH2:30]>>[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[S:21]([CH2:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[NH2:30])=[O:6]
Reactant: Nc1ccc(F)cc1CSc1nc2ccccc2[nH]1
Reactant: O=C1NC(=O)c2ccccc21
Product: Nc1ccc(F)cc1CS(=O)c1nc2ccccc2[nH]1

Procedure:
A solution of 9.0 g (58 mmole) of 3-fluoro-6-nitrotoluene in 200 ml of ethyl acetate was hydrogenated at room temperature with 60 psi of hydrogen gas using 0.9 g of 5% palladium on charcoal as catalyst. The solution was filtered and concentrated to give 6.7 g of 4-fluoro-2-methylaniline as an oil. A mixture of 1.33 g of the oil and 1.57 of phthalic anhydride was heated at 160° C. for 30 minutes and cooled. The resultant solid was washed with methanol and air dried to give 1.96 of the phthalimide derivative of 4-fluoro-2-methylaniline, m.p. 189.5-190.5° C. [Analysis. Calc'd. for C15H10NFO2: C,70.58; H, 3.95; N, 5.49; S, 7.44. Found: C, 70.68; H,3.95; N, 5.42; F, 7.39.] Bromination of the methyl group was effected by heating at reflux under an incandescent light source a mixture of 567 mg (2.22 mmole) of the phthalimide derivative, 435 mg of N-bromosuccinimide, and 59 mg of benzoyl peroxide in 25 ml of carbon tetrachloride. After one hour the mixture was cooled to room temperature, filtered, and concentrated in vacuo to give 720 mg of the crude bromomethyl phthalimide derivative. Using the general method of Example 1 with 284 mg of this bromomethyl phthalimide derivative instead of 2-(chloromethyl)-N,N-dimethylaniline in isopropyl alcohol produced the phthalimide derivative of 2-[(1H-benzimidazol-2-ylthio)methyl]-4-fluorobenzenamine. The residue from the dichloromethane extraction (as in Example 1) was washed with diethyl ether and purified by column chromatography, giving 190 mg of the phthalimide derivative as a white solid. Using the method of Example 3 with 104 mg (0.248 mmole) of this phthalimide derivative of 2-[(1H-benzimidazol-2-ylthio)methyl]-4-fluorobenzenamine instead of the title product of Example 2 produced the corresponding sulfoxide. The reaction mixture was diluted with dichloromethane, washed with aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated in vacuo to give 119 mg of the sulfoxide as an oil. The sulfoxide was stirred in a solution of 0.14 ml of hydrazine hydrate in 5 ml of ethanol for two hours to remove the phthalimide group. The mixture was concentrated in vacuo to a solid, which was washed sequentially with 3% aqueous ammonium hydroxide and water, and air-dried to give 50 mg of the title compound: m.p. 184-185° C. Analysis. Calc'd. for C14H12N3FOS: C, 58.12; H, 4.18; N, 14.52; F, 6.57. Found: C, 58.11; H, 4.21; N, 14.54; F,6.34.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]I)=[CH:14][CH:13]=3)[CH:10]([CH2:26][CH2:27][CH:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[OH:29])[C:9]2=[O:37])=[CH:4][CH:3]=1.[CH3:38][NH:39][CH2:40][CH:41]([OH:50])[CH:42]([OH:49])[CH:43]([OH:48])[CH:44]([OH:47])[CH2:45][OH:46]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:39]([CH3:38])[CH2:40][CH:41]([OH:50])[CH:42]([OH:49])[CH:43]([OH:48])[CH:44]([OH:47])[CH2:45][OH:46])=[CH:14][CH:13]=3)[CH:10]([CH2:26][CH2:27][CH:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[OH:29])[C:9]2=[O:37])=[CH:4][CH:3]=1
Reactant: CNCC(O)C(O)C(O)C(O)CO
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCCCCCI)cc2)N1c1ccc(F)cc1
Solvent: CN(C)C=O
Product: CN(CCCCCCOc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)CC(O)C(O)C(O)C(O)CO
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
136 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(6-iodohexyloxy)phenyl]azetidin-2-one are dissolved in 10 ml of absolute dimethylformamide. 172 mg of 6-methylaminohexane-1,2,3,4,5-pentaol are then added, and the reaction solution is stirred at 50° C. for 2.5 h. After concentration using a rotary evaporator and oil pump vacuum at 40° C., the residue is purified by preparative HPLC. The product is obtained as an oil. C37H48F2N2O8 (686) MS (ESI): M+
Reaction SMILES: [Br:1]C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.[CH2:23]([C:25]1[C:26]([NH:33][C@@H:34]2[C:39]3[CH:40]=[CH:41][S:42][C:38]=3[CH2:37][CH2:36][C@H:35]2[CH2:43][CH2:44][CH3:45])=[N:27][C:28]([CH2:31][CH3:32])=[CH:29][N:30]=1)[CH3:24]>>[Br:1][C:29]1[N:30]=[C:25]([CH2:23][CH3:24])[C:26]([NH:33][C@@H:34]2[C:39]3[CH:40]=[CH:41][S:42][C:38]=3[CH2:37][CH2:36][C@H:35]2[CH2:43][CH2:44][CH3:45])=[N:27][C:28]=1[CH2:31][CH3:32]
Reactant: CCC[C@@H]1CCc2sccc2[C@H]1Nc1nc(CC)cnc1CC
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCC[C@@H]1CCc2sccc2[C@H]1Nc1nc(CC)c(Br)nc1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-[Trans-5-propyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ 7.07, 6.82, 5.12, 4.41, 2.82, 2.56, 2.15–1.71, 1.68–1.40, 1.28, 0.92; HRMS (FAB) calcd for C19H26BrN3S+H 408.1109, found 408.1123.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:5]1=[O:29])[CH:2]=C.I([O-])(=O)(=O)=[O:32].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:6]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:5](=[O:29])[C@:4]([CH2:1][CH:2]=[O:32])([CH3:30])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(CC)CC)C1=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)N1C(=O)[C@@](C)(CC=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of 240 mg (0.54 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one (Example 71, Step E) in THF (8 mL) and water (2.8 mL) added a catalytic amount of osmium tetroxide. After 1.25 h, 323 mg (1.51 mmol) of sodium periodate were added. The resulting light brown slurry was stirred at room temperature for 18.5 h, and then filtered through a fritted funnel. The filtrate was partially concentrated under reduced pressure, then was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were washed with saturated aqueous sodium thiosulfate and then saturated aqueous sodium chloride. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. The crude title compound was used directly in the next step.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35]C(=O)OC(C)(C)C)[CH2:30]1>>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:29]5[CH2:34][CH2:33][CH2:32][C@@H:31]([NH2:35])[CH2:30]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Product: Cn1cc(-c2cc3c(-c4cccc(N5CCC[C@@H](N)C5)n4)n[nH]c3cn2)cn1
Yield: 59.5 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and (R)-tert-butyl piperidin-3-ylcarbamate were reacted and the product was deprotected to give 177 as a white solid (59.5% over two steps). 1H NMR (400 MHz, DMSO) δ 9.03 (d, J=1.1 Hz, 1H), 8.60 (s, 1H), 8.34 (s, 1H), 7.95 (s, 1H), 7.69-7.56 (m, 1H), 7.42 (d, J=7.3 Hz, 1H), 6.83 (d, J=8.6 Hz, 1H), 4.47 (d, J=9.0 Hz, 1H), 4.22 (d, J=12.8 Hz, 1H), 3.89 (s, 3H), 3.04-2.90 (m, 1H), 2.81-2.66 (m, 2H), 2.01-1.92 (m, 2H), 1.88-1.74 (m, 2H), 1.56-1.52 (m, 2H), 1.37-1.27 (m, 1H). LC/MS: m/z 375.1 [M+1].
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][O:7][C:8]1[CH:9]=[C:10](/[CH:20]=[CH:21]/[C:22]([NH:24][CH2:25][C:26]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=O)=O)[CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1>C(O)(=O)C>[CH3:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]2[N:5]=[C:22](/[CH:21]=[CH:20]/[C:10]3[CH:11]=[CH:12][C:13]([N:14]4[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]4)=[C:8]([O:7][CH3:6])[CH:9]=3)[NH:24][CH:25]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc(C(=O)CNC(=O)/C=C/c2ccc(-n3cnc(C)c3)c(OC)c2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1ccc(-c2c[nH]c(/C=C/c3ccc(-n4cnc(C)c4)c(OC)c3)n2)cc1
Temperature: 120 °C
Reaction time: 12 h
Yield: 15.7 %

Procedure:
Ammonium acetate (379 mg) was added to a solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-[2-(4-methoxyphenyl)-2-oxoethyl]acrylamide (100 mg) in acetic acid (3 mL), and the reaction solution was stirred at 120° C. for 12 hours. The reaction solution was concentrated. Ethyl acetate and saturated sodium bicarbonate water were added to the resulting residue, and the organic layer was separated. The resulting organic layer washed with brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate:2-propanol=20:1) to obtain 15 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:8][C:9]=1[NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:4].O1CCCC1.CO.[OH-].[Li+]>O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([NH:10][C:9]2[CH:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])=[O:19])=[CH:13][CH:14]=1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(=O)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1cc(-c2ccccc2)sc1C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3-(4-Chloro-benzoylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester (30 mg, 0.081 mmol) in 1 ml of a 3:2:1 solution made with tetrahydrofuran, methanol and water respectively was added lithium hydroxide monohydrated (20 mg, 0.484 mmol). The mixture was stirred 30 minutes at 60 C, cooled to room temperature, diluted with water and washed with ether (2×). The collected aqueous layer was then acidified with KHSO4 20% to pH 3 and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried (Na2SO4) and concentrated. The resulting crude was taken in ethyl acetate and reexctracted with NaOH 0.5 N (2×). The combined aqueous layers were then back-washed with ethyl acetate and acidified to pH3 with KHSO4 20% and back-extracted with ethyl acetate (2×). The combined organic layers were washed with brine and dried (Na2SO4). 1H NMR (DMSO-d6, 400 MHz) 8.35 (s, 1H), 8.02-7.99 (m, 2H), 7.71-7.68 (m, 2H), 7.56-7.53 (m, 2H), 7.43-7.39 (m, 2H), 7.35-7.31 (m, 1H).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[C:7]12([CH3:17])[C:13]([CH3:15])([CH3:14])[CH:10]([CH2:11][CH2:12]1)[CH2:9][CH:8]2[NH2:16]>C(OC(C)C)(C)C>[C:7]12([CH3:17])[C:13]([CH3:14])([CH3:15])[CH:10]([CH2:11][CH2:12]1)[CH2:9][CH:8]2[NH:16][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1]
Reactant: C=C1CC(=O)O1
Reactant: CC1(C)C2CCC1(C)C(N)C2
Solvent: CC(C)OC(C)C
Product: CC(=O)CC(=O)NC1CC2CCC1(C)C2(C)C
Temperature: 20 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
16.8 g of diketene were added with stirring to a mixture of 30 g of 2-bornylamine and 200 ml of isopropyl ether and after stirring for 4 hours at 20° C., the mixture was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and elution with a 9-1 methylene chloride-acetone mixture gave 39 g of N-(2-bornyl)-acetylacetamide. 30 g of the latter product and 1 g of p-toluene sulfonic acid were added to a mixture of 20 g of methyl orthoformate and 30 ml of methanol and the mixture stood at 20° C. for 16 hours. 2 ml of quinoline were added thereto and the mixture was evaporated to dryness under reduced pressure. The residue was added to toluene and the mixture was heated at 145° C. for 3 hours while distilling a toluene-methanol azeotrope. The mixture was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. The product was eluted with an 8-2 methylene chloride-acetone mixture and was crystallized from isopropyl ether to obtain 19 g of N-(2'-bornyl)-3-methoxy-crotonamide melting at 149° C. The RMN spectra showed it was the E somer.
Reaction SMILES: Cl[CH2:2][C:3](=[O:25])[C@:4]1([OH:24])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[C:26]([O-:29])(=[O:28])[CH3:27].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:26]([O:29][CH2:2][C:3](=[O:25])[C@:4]1([OH:24])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1)(=[O:28])[CH3:27]
Reactant: CC(=O)[O-]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CCl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
1.0 g of 21-chloro-17-hydroxy-4-pregnene-3,20-dione in 20 ml of dimethylformamide is agitated at 80° C. with 1.0 g of potassium acetate. After 30 minutes, the reaction mixture is introduced into ice water, the precipitated product is suctioned off, dissolved in ethyl acetate, and dried over sodium sulfate, thus obtaining 940 mg of 21-acetoxy-17-hydroxy-4-pregnene-3,20-dione; mp 236.5° C.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:7][C:8]1[C:16]([CH2:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11]>>[OH:7][C:8]1[C:16]([CH2:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:11]
Reactant: CCc1cccc(C(=O)Cl)c1O
Reactant: c1ccccc1
Product: CCc1cccc(C(=O)c2ccccc2)c1O
Yield: 58.1 %

Procedure:
This compound (44.67g) was prepared from benzene (172g.,2.2 mole) and 2-hydroxy-3-ethyl benzoic acid chloride (63.15g,0.34 mole), using the same conditions as in Example 30. The b.p. of the compound was 123°-126°C./0.14mm, ηD22 1.6081,νmax.(film) 1630cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH:10]=O)[C:6]=2[CH:12]=1.[S:13]([NH2:17])([NH2:16])(=[O:15])=[O:14].[BH4-].[Na+].O>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][NH:16][S:13]([NH2:17])(=[O:15])=[O:14])[C:6]=2[CH:12]=1
Reactant: NS(N)(=O)=O
Reactant: O=Cc1csc2ccc(Br)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)NCc1csc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5-Bromobenzothiophene (1.60 g, 7.51 mmol) and dichloromethyl methyl ether (1.29 g, 11.3 mmol) were dissolved in anhydrous 1,2-dichloroethane (75 mL). Titanium tetrachloride (2.14 g, 11.3 mmol) was added, turning the solution dark. After one hour at room temperature, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 30 minutes and then was extracted with DCM (2×100 mL). The extracts were concentrated and chromatographed (0 to 5% ethyl acetate in hexane) to yield 5-bromo-benzo[b]thiophene-3-carbaldehyde (1.32 g). The 5-bromobenzothiophene-3-carboxaldehyde (1.20 g, 4.98 mmol) and sulfamide (4.0 g, 42 mmol) were combined in anhydrous ethanol (25 mL) and heated to reflux for three days. The reaction was cooled to room temperature and sodium borohydride (0.207 g, 5.47 mmol) was added. After five hours, water (50 ml) was added and the solution was extracted with chloroform (3×50 mL). The extracts were concentrated, suspended in a minimal amount of DCM, and filtered to provide the title compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[C:5](I)=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(NC(C)C)(C)C.[C:30]1([C:36]#[CH:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[C:5]([C:37]#[C:36][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1nc(I)c2c(-c3ccccc3)noc2c1O
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1nc(C#Cc2ccccc2)c2c(-c3ccccc3)noc2c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
Ethyl 7-hydroxy-4-iodo-3-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (300 mg, 0.73 mmol), copper iodide (56 mg, 0.29 mmol), and PdCl2(PPh3)2 (103 mg, 0.15 mmol) were added to a flask and the flask evacuated. After refilling with nitrogen, THF (5 mL), diisopropylamine (0.6 mL) and phenylacetylene (0.1 mL, 0.95 mmol) were added and the resulting mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was partitioned between 25 mL of 1M hydrochloric acid and 25 mL of EtOAc. The aqueous layer was extracted with additional EtOAc and the combined organic layer was dried over MgSO4 and concentrated. The residue was purified flash chromatography (0-40% EtOAc/hexanes) to afford 195 mg of the title compound. MS: (+) m/z 385.29 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:16](O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:6][C:5]([CH2:4][CH2:3][C@H:2]([NH2:1])[C:8]([OH:10])=[O:9])=[O:7])=[CH:18][CH:19]=1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: OCc1ccccc1
Agent: O=S(=O)(O)O
Product: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 45.7 %

Procedure:
1416 grams (g) of L-glutamic acid, 1560 g of 60% sulfuric acid and 1152 g of benzyl alcohol were placed in a 12 liter round bottom flask equipped with a distillation head. The mixture was heated to 70° C. and stirred for 45 minutes. Upon cooling, the resulting solution was stirred and was subjected to a reduced pressure. When the vacuum had stabilized at about 100 millimeters (mm) the reaction temperature was again raised to 70° C. and water was distilled off for about 4.5 hours. Upon standing overnight, the reaction mixture became viscous and was slowly added to a stirred mixture of 1613 g of sodium bicarbonate, 1.2 kilograms (kg) of ice and 12 liters of water. A precipitate formed which was collected by filtration and then washed with about 8 liters of carbon dioxide-free water and 8 liters of acetone and subsequently air-dried. The precipitate was triturated with 2 liters of ether and dried, yielding 1044 g of the desired γ-benzyl L-glutamate, melting point (m.p.) 156°-157° C. Thin layer chromatography detected the presence of unreacted glutamic acid in the crude product. The crude product was recrystallized from 12.5 liters of hot water and filtered through a plug of glass wool suspended in the neck of a heated glass funnel. After cooling, and overnight refrigeration, the recrystallized product was collected, and washed with 2 liters of cold water, then 2 liters of THF. The product was air dried overnight and then dried in vacuo at room temperature for three hours. 693 g of γ-benzyl L-glutamate was recovered as white, shiny plates, m.p. 156.5°-157° C.