Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[Te:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1.[F:13][C:14]([F:23])([F:22])[S:15]([O:18][CH2:19][CH:20]=[CH2:21])(=[O:17])=[O:16]>ClCCl>[F:13][C:14]([F:23])([F:22])[S:15]([O-:18])(=[O:17])=[O:16].[CH3:1][C:2]1[Te:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N+:6]=1[CH2:21][CH:20]=[CH2:19]
Reactant: Cc1nc2cc(C)c(C)cc2[te]1
Reactant: C=CCOS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: C=CC[n+]1c(C)[te]c2cc(C)c(C)cc21
Product: O=S(=O)([O-])C(F)(F)F
Reaction time: 18 h

Procedure:
To a solution of 2,5,6-trimethylbenzotellurazole (Example 22) (9.90 g, 0.0033 mole) in dichloromethane (30 ml) was added the solution of 2-propen-1-yl trifluoromethanesulfonate (0.004 mole) rapidly at room temperature under a nitrogen atmosphere, with good stirring. Solid began separating 10 minutes after the addition was complete. Stirring under a nitrogen atmosphere was continued for about 18 hours. The solid was isolated by filtration, washed with diethyl ether, and dried under vacuum at room temperature. Yield 1.0 g, m.p. 162°-164° C. The mass spectra agreed with the assigned structural formula.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)=[O:5])[CH3:2].S(Cl)(Cl)=O.[CH2:19]([O:21][C:22]([C:24]1[C:29](=[O:30])[N:28]2[CH:31]=[CH:32][CH:33]=[C:34]([SH:35])[C:27]2=[N:26][CH:25]=1)=[O:23])[CH3:20]>CN(C=O)C.C1C=CC=CC=1>[CH2:19]([O:21][C:22]([C:24]1[C:29](=[O:30])[N:28]2[CH:31]=[CH:32][CH:33]=[C:34]([S:35][C:10](=[O:12])[C:9]3[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:14][CH:13]=3)[C:27]2=[N:26][CH:25]=1)=[O:23])[CH3:20]
Reactant: CCOC(=O)c1ccc(C(=O)O)cc1
Reactant: CCOC(=O)c1cnc2c(S)cccn2c1=O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(C(=O)Sc2cccn3c(=O)c(C(=O)OCC)cnc23)cc1
Yield: 105.5 %

Procedure:
To a mixture of 1.47 g (2.4 mmol) of 4-ethoxycarbonylbenzoic acid, 3 drops of DMF and 10 ml of benzene is added 0.52 g (4.4 mmol) of thionyl chloride, and the resultant mixture is refluxed for 3 hours under stirring and concentrated in vacuo to dryness. The residue is dissolved in acetone and mixed with 1.4 g of solid potassium carbonate and then 0.5 g (2 mmol) of 3ethoxycarbonyl-9-mercapto-4H-pyrido[1,2-a]pyrimidin-4-one II-1, and the resultant mixture is vigorously stirred at room temperature for 20 minutes. The reaction mixture is concentrated in vacuo to dryness, and the residue is distributed in chloroformwater. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on a column of silica gel, which is eluted with ethyl acetate to give 0.9 g of the titled compound Ie-56.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([N:6]=[N:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)=[N:4][N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O)C>O>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[N:10]3[C:5]([N:6]=[N:7][C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=43)=[N:4][N:3]=2)[CH2:18][CH2:17]1
Reactant: Brc1nnc2nnc3ccccc3n12
Reactant: CN1CCNCC1
Solvent: O
Solvent: CCO
Product: CN1CCN(c2nnc3nnc4ccccc4n23)CC1
Yield: 70 %

Procedure:
A mixture of 12.0 g (0.048 mole) of 1-bromo-s-triazolo[3,4-c]benzo-as-triazine, 40 ml of N-methyl-piperazine and 80 ml of ethanol is refluxed for 2 hours. The solution is poured into water and the product is extracted mit methylene chloride. The solvent is evaporated from the extract and the residue is recrystallized from benzene. 9.7 g (70%) of 1-(N-methyl-piperazino)-s-triazolo[3,4-c]benzo-as-triazine are obtained; m.p.: 162°-163° C. This product is added to a suspension of 12 g (0.068 moles) of sodium dithionite in 100 ml of water, and reduced into the respective dihydro compound under argon atmosphere. The separated precipitate is filtered off, dried, admixed with 50 ml of propionic anhydride, and the mixture is heated at 120° to 125° C. for 2 hours. The reaction mixture is cooled and the separated product is filtered off. 12.3 g (67.0%) of the title compound are obtained; m.p.: 173°-175° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([NH:11][C:12](OC(C)(C)C)=O)([CH3:10])[CH2:8][F:9])([CH3:4])([CH3:3])[CH3:2].CI.[H-].[Na+].[OH2:24]>CN(C=O)C>[C:1]([O:5][C:6](=[O:19])[C:7]([NH:11][CH2:12][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:24])([CH3:10])[CH2:8][F:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(CF)C(=O)OC(C)(C)C
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNC(C)(CF)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 3 (200 mg, 0.72 mmol) in dry DMF under an argon atmosphere was added 8 eq of CH3I (0.36 mL) followed by 2 eq of 95% NaH (37 mg). The reaction mixture was stirred overnight at room temperature. The reaction mix was added to 15 mL of H2O and extracted with 3×15 mL of Et2O. The combined organic layers were washed with 3×20 mL H2O followed by the usual work up. Purification of the crude product via silica gel column chromatography (7.5% EtOAc in hexane) afforded the methylated species 4 (181 mg, 86%) as a colorless oil: 1H NMR (CDCl3) δ 1.44 (9H, s), 1.46 (9H, s), 1.51 (3H, s), 2.94 (3H, s), 4.51-5.04 (2H, m). Anal. (C14H26FNO4) C, H, N.
Reaction SMILES: [OH:1][C:2]([CH3:27])([CH2:11][CH2:12][CH2:13][CH:14]([CH3:26])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:3][CH2:4][C:5](=O)[CH2:6][C:7](=O)[CH3:8].[CH3:28][O:29][C:30]([CH2:32][C:33]([CH2:35][C:36]([O:38][CH3:39])=[O:37])=[O:34])=[O:31].C[O-].[Na+]>CO>[OH:34][C:33]1[C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:7]([CH3:8])[CH:6]=[C:5]([CH2:4][CH2:3][C:2]([OH:1])([CH3:27])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:26])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:23])[CH3:24])[C:32]=1[C:30]([O:29][CH3:28])=[O:31]
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: CC(=O)CC(=O)CCC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(C)cc(CCC(C)(O)CCCC(C)CCCC(C)CCCC(C)C)c(C(=O)OC)c1O
Temperature: 25 °C
Reaction time: 44 h
Yield: 103.5 %

Procedure:
To a solution of 7-hydroxy-7,11,15,19-tetramethyleicosane-2,4-dione (72.5 g) and dimethyl acetonedicarboxylate (29.6 g) in methanol (190 ml) at 0° was added a solution of sodium methoxide in methanol (from 2.44 g of sodium and 90 ml of methanol). The solution was stirred at room temperature for 44 hr and was concentrated on a rotary evaporator to remove approx. 100 ml of methanol. The residual solution was poured onto ice (500 g) and 20% (v/v) aqueous hydrochloric acid (45 ml). The mixture was extracted with ether (3×300 ml) and the combined extracts were washed with brine and dried over anhydrous sodium sulfate and were concentrated on a rotary evaporator to give 91.65 g of crude dimethyl 2-hydroxy-4-methyl-6-(3-hydroxy-3,7,11,15-tetramethyl-hexadecanyl)-benzene-1,3-dicarboxylate as an orange oil. A 90.2 g portion of the oil was dissolved in ether (400 ml) and was washed with 20% by weight aqueous potassium carbonate (to remove the unreacted dimethyl acetonedicarboxylate), brine and was dried over anhydrous sodium sulfate. The solution was concentrated on a rotary evaporator to give 83.13 g of partially purified diester dimethyl 2-hydroxy-4-methyl-6-(3-hydroxy-3,7,11,15-tetramethyl-hexadecanyl)-benzene-1,3-dicarboxylate. The total material was chromatographed on 2.45 kg of silica gel eluting with 20-30% by volume ether in hexane to give 30.83 g of dimethyl 2-hydroxy-4-methyl-6-(3-hydroxy-3,7,11,15-tetramethyl-hexadecanyl)-benzene-1,3-dicarboxylate as a colorless oil.
Reaction SMILES: C(O)(=O)C.[C:5]1([CH3:20])[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[C:13]1[C:14]([CH3:19])=[N:15][NH:16][C:17]=1[NH2:18].[C:21]([CH:24]([C:30](OCC)=[O:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26])(=O)[CH3:22]>C1(C)C(C)=CC=CC=1>[C:5]1([CH3:20])[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[C:13]1[C:14]([CH3:19])=[N:15][N:16]2[C:30](=[O:31])[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH3:22])[NH:18][C:17]=12
Reactant: Cc1cc(C)c(-c2c(C)n[nH]c2N)c(C)c1
Reactant: CCOC(=O)C(C(C)=O)C(=O)OCC
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1c(C)[nH]c2c(-c3c(C)cc(C)cc3C)c(C)nn2c1=O
Yield: 36.6 %

Procedure:
Acetic acid (5 mL) was added to a solution of 4-mesityl-3-methyl-1H-5-pyrazoleamine (5 g, 23.22 mmol) and diethyl 2-acetylmalonate (4.7 g, 23.22 mmol) in xylene (40 mL), followed by heating under reflux for seven hours. The reaction mixture was evaporated as it was, and water was added thereto. After extracting with ethyl acetate, the organic layer was washed with an aqueous saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane), to give the title compound (3 g).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[F:18][C:19]([F:36])([F:35])[C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]2[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=2)=[N:24][CH:25]=1.[BH4-].[Na+]>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([NH:1][CH2:31][C:30]3[CH:29]=[CH:28][C:27]([O:26][C:23]4[CH:22]=[CH:21][C:20]([C:19]([F:36])([F:18])[F:35])=[CH:25][N:24]=4)=[CH:34][CH:33]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCNCC1
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1NCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Yield: 42.6 %

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide (300 mg) was suspended in EtOH (5 mL) and 4-[{5-(Trifluoromethyl)pyridin-2-yl}oxy]benzaldehyde (318 mg, 1 eq.) and piperidine (3 drops) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr (360 mg, 60% yield). Resulting imine (360 mg) was suspended in 10 mL MeOH and sodium borohydride (10 eq., 272 mg) was added. HPLC confirmed reaction was complete (absence of imine). After completion (1 hr), precipitate was filtered to obtain D33 as a light yellow powder. Product was washed with deionized water to remove excess sodium borohydride. Product was allowed to dry under vacuum for 18 hrs. 255 mg (70% yield) of final product was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][N:12]1[CH3:17])[CH3:10].[C:18](Cl)(=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH:9]([CH3:10])[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[CH3:17])=[O:27])=[CH:20][CH:21]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(Cc1ccccc1N)C1CCCCN1C
Product: COc1ccc(C(=O)Nc2ccccc2CC(C)C2CCCCN2C)cc1

Procedure:
Reaction of 2-[2-(2-aminophenyl)-1-methylethyl]-1-methylpiperidine with anisoyl chloride, according to the procedure of Example 25, provides 4-methoxy-2'-[2-methyl-2-(1-methyl-2-piperidyl)ethyl]benzanilide as a 72:28 mixture of diastereoisomers (according to nmr), m.p. 125.5°-136.5° C. (corr.).
Reaction SMILES: [CH2:1]([S:8][S:9][CH2:10][CH2:11][C@H:12]([NH2:16])[C:13]([OH:15])=[O:14])[CH2:2][C@H:3]([NH2:7])[C:4]([OH:6])=[O:5].[OH-].[Na+].[CH2:19]([O:26][C:27](Cl)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>O1CCOCC1.O.O1CCOCC1>[CH2:19]([O:26][C:27]([CH:1]([S:8][S:9][CH2:10][CH2:11][C@H:12]([NH2:16])[C:13]([OH:15])=[O:14])[CH2:2][C@H:3]([NH2:7])[C:4]([OH:6])=[O:5])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](CCSSCC[C@H](N)C(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: N[C@@H](CCSSC(C[C@H](N)C(=O)O)C(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C

Procedure:
L-homocystine (5 g) was dissolved in a mixture (80 ml) of dioxane/H2O. At 0° C. and under stirring, 1.52 g (2.1 eq) of NaOH and a solution of 7.8 g (2.4 eq) of benzylchloroformate in 40 ml dioxane were added. The pH was maintained at 9 by addition of a solution of NaOH 1M. After stirring for 2.30 h at room temperature, 100 ml H2O were added and the white precipitate was extracted by Et20 (2×50 ml). The aqueous phase was acidified to pH 1 and the precipitate was extracted by EtOAc (4×80 ml). The organic phase was washed, dried over Na2SO4, filtered and evaporated in vacuo. White solid 10.2 g (100%).
Reaction SMILES: [C:1]1(=[O:7])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:10]([O:12][C:13](=[O:16])[CH2:14]Br)[CH3:11].O>CN(C)C=O.C(Cl)Cl>[O:7]=[C:1]1[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:14][C:13]([O:12][CH2:10][CH3:11])=[O:16]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCCCC1=O
Reaction time: 0.5 h

Procedure:
9.9 parts of δ-valerolactam (purchased from Aldrich Chemical Co., Milwaukee, Wisc. 53233) were dissolved in 100 part of dimethylformamide. To this solution was added 4.8 parts of a 50% dispersion of sodium hydride in mineral oil (purchased from Callgary Chemical Company, Callgary, Pa.). The reaction mixture was stirred for a period of 30 minutes. To the above reaction mixture 16.7 parts of ethylbromoacetate was added dropwise keeping the temperature less than 25° C during the addition. After the addition was completed, the reaction was stirred at room temperature for an additional 30 minutes. The reaction mass was poured into 200 parts of water. The product was isolated by extraction from the aqueous solution with three successive 200-part portions of methylene chloride. The combined organic extracts of the product were dried with anhydrous sodium sulfate. The solution of the product was filtered and the solvent was removed by evaporation at a reduced pressure of 50-300 mm on a rotary evaporator. The crude product obtained was further purified by vacuum distillation at 115° -120° C at 1.5 mm; 8.2 parts of product were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11]3[C:20](=[O:21])[O:19][C:18]4[CH:17]=[C:16]([N:22]5[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)[N:15]=[CH:14][C:13]=4[CH:12]=3)[N:10]=[C:4]2[CH:3]=1.[ClH:35]>C(Cl)Cl.O1CCOCC1>[ClH:35].[CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11]3[C:20](=[O:21])[O:19][C:18]4[CH:17]=[C:16]([N:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[N:15]=[CH:14][C:13]=4[CH:12]=3)[N:10]=[C:4]2[CH:3]=1
Reactant: Cc1ccn2cc(-c3cc4cnc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4oc3=O)nc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccn2cc(-c3cc4cnc(N5CCNCC5)cc4oc3=O)nc2c1
Reaction time: 2 h

Procedure:
To a suspension of t-butyl 4-(3-(7-methylimidazo[1,2-a]pyridin-2-yl)-2-oxo-2H-pyrano[3,2-c]pyridin-7-yl)piperazine-1-carboxylate (115 mg, 0.25 mmol) in CH2Cl2 (2 mL) was added 4N HCl in dioxane (1 mL). The mixture was stirred for 2 hours, and then filtered. The solid was washed with ether and dried under nitrogen to give 3-(7-methylimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-2H-pyrano[3,2-c]pyridin-2-one hydrochloride quantitatively which was used in the next step without further purification. MS m/z 362.2 [M+H]+.
Reaction SMILES: CC(C[C@H](NC([C@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](N[C:84]([C@@H:86]([NH2:92])[CH2:87][CH2:88][C:89]([OH:91])=[O:90])=[O:85])CC1NC=NC=1)=O)CC1C2C(=CC=CC=2)NC=1)=O)CO)=O)CC1NC=NC=1)=O)CC1C=CC(O)=CC=1)=O)C(N[C@H](C(N1[C@H](C(NCC(O)=O)=O)CCC1)=O)CCCN=C(N)N)=O)C.C[OH:94].ClCl.CC1C=C(C2C=CC(N)=C(C)C=2)C=CC=1N.II>CC(O)=O>[NH2:92][C@H:86]([C:84]([OH:85])=[O:94])[CH2:87][CH2:88][C:89](=[O:90])[OH:91]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](Cc1ccc(O)cc1)NC(=O)[C@H](Cc1cnc[nH]1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1cnc[nH]1)NC(=O)[C@@H](N)CCC(=O)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1CCC[C@H]1C(=O)NCC(=O)O
Reactant: CO
Agent: Cc1cc(-c2ccc(N)c(C)c2)ccc1N
Agent: ClCl
Agent: II
Solvent: CC(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
A stirred mixture of pGlu--His--Trp--Ser--Tyr--Gly--OH (XXXVIII) (16.6 gm) and 1-hydroxybenzotriazole (3 gm) in dry DMF (250 ml) was treated with DCI (4.5 gm) at 0°C and after 3 hours, the dihydrofluoride salt of Leu--Arg--Pro--Gly--NH2 (LXVI) (10.5 gm) and Et3N (3.1 ml) in dry DMF were added and stirring was continued at room temperature for a further 36 hous. The reaction mixture was evaporated in vacuo and the residue was treated with H2O (200 ml). The insoluble DCI-urea was removed and the filtrate was evaporated in vacuo to afford 38 g of crude LHRH. A portion of this (6.47 gm) in 1% AcOH (250 ml) was passed over Bio-Rad AG1-8 (OAc) (1×15 cm) and the filtrate was evaporated in vacuo. The residue, in H2O (15 ml), was chromatographed over CMC (4.5 × 27 cm) and eluted in a stepwise manner with NH4OAc buffers of pH 6.9: (0.005, 0.01, 0.025, 0.075 and 0.1 M). The pooled LHRH fractions, located in the 0.075 M eluate by the Pauly reaction, were lyophilized. The LHRH (3 gm) was further purified by gel filtration over Bio-Gel P-2 (400 gm) (110 cm × 2.5 cm) with 1.3% AcOH. Individual fractions (5 ml) were collected at a flow rate of about 5 ml.min and the pure LHRH was located in fractions 21-31 by the Pauly reaction and by tlc. Fractions showing one spot on tlc were pooled and lyophilized to constant weight affording 2.85 gm. (59%) of pure pGlu--His--Trp--Ser--Tyr--Gly--Leu--Arg--Pro--Gly--NH2 (XXII) (LHRH): [α]D22 -33.9 (c, 0.66, MeOH); [α]D22 -46.6 (c, 0.73, 1% AcOH); Rf1 0.64 and Rf3 0.37, single spot with Pauly, chlorine-tolidine and I2 reagents. Amino acid analysis gave Glu 1.08; His 0.99; Trp 0.87; Ser 0.85; Tyr 0.98; Gly 2.07; Leu 1.04; Arg 1.02; Pro 0.97; NH3 1.08.
Reaction SMILES: [F:1][CH2:2][S:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[CH3:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=1[CH3:19].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[H+].[B-:36]([F:40])([F:39])([F:38])[F:37]>C(OCC)C>[F:37][B-:36]([F:40])([F:39])[F:38].[CH3:12][C:13]1[CH:14]=[C:15]([S+:3]([CH2:2][F:1])[C:5]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]
Reactant: Cc1ccc(S(=O)CF)cc1
Reactant: Cc1ccccc1C
Agent: F[B-](F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [H+]
Solvent: CCOCC
Product: Cc1ccc([S+](CF)c2ccc(C)c(C)c2)cc1

Procedure:
1-((Fluoromethyl)sulfinyl)-4-methylbenzene (576 mg, 3.34 mmol) of example 5 was dissolved in dry diethyl ether (15 mL) under argon atmosphere. O-Xylene (0.445 mL, 1.10 eq) was added to the previous solution. The mixture was cooled to a temperature below −50° C. After stabilizing the temperature below −50° C., trifluoromethanesulfonic anhydride (0.562 mL, 1 eq) was added slowly maintaining the same temperature. The mixture was stirred, until the reaction was complete. HBF4 in diethyl ether solution (54%, 0.921 mL, 2 eq) was added. The resulting suspension was stirred for 30 minutes. The precipitate tetrafluoroborate salt was isolated by filtration and washed with diethyl ether at 0° C. The desired product was obtained as an oily solid (1.42 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[C:10](=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])([CH3:12])C.Cl.[CH2:25](OCC)C>[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:12]([CH3:25])[CH2:10][CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:3]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)C
Reactant: CCOCC
Agent: [Cu]I
Agent: Cl
Product: CCOC(=O)C(CC(C)c1ccc(F)cc1)C(=O)OCC
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
A mixture of 4-fluorophenylmagnesium bromide (82 ml of a 2N solution in ethyl ether, 0.164 mol, Aldrich) and copper(I) iodide (0.310 mg, 1.63 mmol, Aldrich) was stirred for 15 min at -10° C. while blanketed with a nitrogen atmosphere. To this mixture was added a solution of diethyl isopropylidenemalonate (29.6 g, 0.148 mol) in anhydrous diethyl ether (250 ml) in a thin stream with rapid stirring. The resulting solution was stirred at -10° C. for 2 h, at 25° C. for 30 min and then poured with rapid stirring into 0.5 kg of crushed ice containing 30 ml of 12N hydrochloric acid. The layers were separated and the aqueous layer was extracted with ethyl ether (3×400 ml). All ether layers were combined and washed with deionized water (2×25 ml), saturated aqueous sodium bicarbonate (25 ml), and deionized water (25 ml). The etheral layer was concentrated by spin evaporation in vacuo and the residue was distilled to give 25.9 g (59%) of diethyl 2-(2-(4-fluorophenyl)-2-methylethyl)malonate as a clear oil (b.p., 140°-145° C./0.01 mmHg);
Reaction SMILES: [CH:1]1([C:7]2[C:16]3[C:11](=[C:12](Cl)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cu](C#N)[C:19]#[N:20]>CN(P(N(C)C)(N(C)C)=O)C>[CH:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:19]#[N:20])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#C[Cu]C#N
Reactant: Clc1cccc2c(C3CCCCC3)nccc12
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#Cc1cccc2c(C3CCCCC3)nccc12

Procedure:
1-Cyclohexyl-5-chloroisoquinoline, copper cyanide and hexamethylphosphotriamide were reacted in the same way as in step (d) of Example 13 to afford 1-cyclohexyl-5-cyanoisoquinoline having a melting point of 94.7° C.
Reaction SMILES: CCCCCC.[H-].[Na+].[CH2:9]([C:13]1[NH:14][CH:15]=[CH:16][N:17]=1)[CH2:10][CH2:11][CH3:12].[CH3:18][Si:19]([CH3:26])([CH3:25])[CH2:20][CH2:21]OCCl.CN(C)[CH:29]=[O:30]>>[CH2:9]([C:13]1[NH:14][CH:15]=[C:16]([CH2:29][O:30][CH:20]([Si:19]([CH3:18])([CH3:25])[CH3:26])[CH3:21])[N:17]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCCCc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: CCCCc1nc(COC(C)[Si](C)(C)C)c[nH]1
Yield: 96 %

Procedure:
Hexane washed 80% sodium hydride (1.45 g, 0.0483 mol) in dimethylformamide (80 mL) under argon was treated with a solution of 2-n-butylimidazole (5.45 g, 0.0439 mol) in dimethylformamide (14 mL) dropwise at 25° C. and the reaction was stirred an additional hour. Then 2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl) (7.68 g, 0.0461 mol) was added, the mixture was stirred for 18 hours at ambient temperature and then partitioned between ice water and ethyl acetate. The washed, dried, concentrated organic solution was chromatographed over silica gel with 1:1 hexane in ethyl acetate to yield 10.8 g (96%) of 2-n-butyl-1-(trimethylsilyl)ethoxymethylimidazole.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[C:10]1[CH:15]=[C:14](Br)[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:11]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O.[CH2:41]1[CH2:45]OC[CH2:42]1>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>[CH2:1]([O:8][C:9](=[O:33])[C:10]1[CH:15]=[C:14]([C:41]([CH3:45])=[CH2:42])[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:11]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: O=C(OCc1ccccc1)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
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: [Cs+]
Solvent: O
Product: C=C(C)c1cc(C(=O)OCc2ccccc2)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
To a mixture of 2,4-bis-benzyloxy-5-bromo-benzoic acid benzyl ester (42.9 g, 85.7 mmol), potassium isopropenyl trifluoroborate (14.0 g, 95.2 mmol) and caesium carbonate (83.8 g, 257.1 mmol) in THF (800 mL) was added Pd(PPh3)4 (2.0 g) followed by water (150 mL). The mixture was heated at reflux for 72 h then allowed to cool to ambient. The mixture was reduced in vacuo to remove THF and then partitioned between water (500 mL) and EtOAc (300 mL). The organic portion was washed with brine, dried (MgSO4), filtered and reduced in vacuo to give the title compound (40.9 g) as a brown oil.