Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[CH3:12][N:13]([CH3:22])[CH2:14][CH2:15][O:16][CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1>C1C=CC=CC=1>[CH3:12][N:13]([CH3:22])[CH2:14][CH2:15][O:16][CH:17]1[CH2:21][CH2:20][N:19]([C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[O:11])[CH2:18]1
Reactant: CN(C)CCOC1CCNC1
Reactant: COc1ccc(N=C=O)cc1
Solvent: c1ccccc1
Product: COc1ccc(NC(=O)N2CCC(OCCN(C)C)C2)cc1
Reaction time: 2 h

Procedure:
A solution of 3.0 g. (0.02 mole) of p-methoxyphenyl isocyanate in 10 ml. of dry benzene was added dropwise to a stirring solution of 3.2 g. (0.02 mole) of 3-(2-dimethylaminoethoxy)pyrrolidine in 100 ml. of dry benzene under anhydrous conditions. When the addition was complete, the reaction mixture was allowed to stir for 2 hours. The mixture was concentrated under reduced pressure to give 4.9 g. (80%) of product which crystallized upon standing. Recrystallization from benzeneisooctane gave 4.8 g. of solid melting at 92°-94° C.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH:10]1[CH2:11][CH:12]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:13]2)(C(C)(C)C)(C)C.Cl>CO.O>[OH:8][CH:9]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH:10]1[CH2:11][CH:12]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:13]2
Reactant: COC(=O)CC1CC2CC(O[Si](C)(C)C(C)(C)C)C(C1)N2C(=O)OCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)CC1CC2CC(O)C(C1)N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
crude 109e was dissolved in MeOH (400 mL), 12 N HCl (40 mL, 3.0 eq) was added and then stirred at room temperature for 30 min. The mixture was diluted with water (800 mL), and extracted two times with EA (500 mL). The organic layers were combined, dried over Na2SO4 and concentrated, the residue was purified by silica gel (EA/PE=1:3) to give benzyl 6-hydroxy-3-(2-methoxy-2-oxo-ethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate 109f as a colorless oil, 30 g, yield for two steps, 70%. 1H NMR (400 MHz, DMSO-d6) δ: 7.43-7.26 (m, 5H), 5.09 (s, 2H), 4.90 (dd, J=3.6, 6.8 Hz, 1H), 4.23 (d, J=6.4 Hz, 1H), 4.16-4.09 (m, 1H), 4.12-3.92 (m, 1H), 3.59 (s, 3H), 2.38 (d, J=7.2 Hz, 2H), 2.14-1.93 (m, 5H), 1.72 (br, 1H); MS: calc'd (MH+) 334, measured (MH+) 334.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH3:23]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH3:23])=[CH:4][CH:3]=1
Reactant: CCCOCCCl
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOCCSc1ccc(Br)cc1
Temperature: 90 °C
Reaction time: 14 h

Procedure:
In DMF (96 ml) was dissolved 4-bromobenzenethiol (12 g). To the mixture were added dropwise at room temperature potassium carbonate (12.3 g) and sodium iodide (10.5 g) and then was added dropwise 2-chloroethylpropylether (9.6 ml), and the mixture was stirred at 90° C. for 14 hours and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=10/1) to give 1-bromo-4-(2-propoxyethylthio)benzene (16.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][OH:14])=[CH:4][CH:3]=1.[C:17]([NH:21][NH2:22])([CH3:20])([CH3:19])[CH3:18].Cl.C(N(CC)CC)C>CO>[C:17]([N:21]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:9][C:10]([CH2:11][CH2:12][CH2:13][OH:14])=[N:22]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)NN
Reactant: O=C(CCCO)CC(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)n1nc(CCCO)cc1-c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 14 h

Procedure:
1-(4-chlorophenyl)-6-hydroxyhexane-1,3-dione (2.0 g, 8.310 mmol) was dissolved in 15 mL of methanol. t-BuNHNH2.HCl (2.1 g, 16.620 mmol) was dissolved in 15 mL of methanol and then added with triethylamine (TEA; 2.3 mL, 16.620 mmol). After they were all dissolved, the mixture was added into a solution of 1-(4-chlorophenyl)-6-hydroxyhexane-1,3-dione, and then stirred for 14 hours at 40° C. The reaction progress and completion were confirmed by TLC. Upon completion of the reaction, while the temperature was kept at room temperature, the solvent was removed under reduced pressure. The reaction residue was diluted with EtOAc, and added with water. The aqueous layer was extracted with EtOAc and the organic layer was dried with anhydrous MgSO4 and filtered and concentrated under reduced pressure. The concentrate was separated by column chromatography (EtOAc:Hexane=2:3, v/v) to obtain 1.57 g (64%) of target compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[F:21][C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42]>>[C:41]([O:40][C:39]([NH:38][CH2:37][C:23]1[CH:24]=[CH:25][C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:27][C:22]=1[F:21])=[O:45])([CH3:44])([CH3:42])[CH3:43]
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC(C)(C)OC(=O)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(CNC(=O)OC(C)(C)C)c(F)c3)ccn2c1=O
Yield: 31.7 %

Procedure:
The general Suzuki coupling method described above was used to couple methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate with tert-butyl N-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]carbamate. Purification by flash silica column chromatography yielded methyl 8-[4-[(tert-butoxycarbonylamino)methyl]-3-fluoro-phenyl]-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylate (24 mg, 31.7%).
Reaction SMILES: [OH:1][CH:2]([C:7]([O:20][CH2:21][C:22](=[O:32])[N:23]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5]C)=[O:4].[OH-].[Na+].O>O1CCOCC1>[OH:1][CH:2]([C:7]([O:20][CH2:21][C:22](=[O:32])[N:23]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: CCCCN(CCCC)C(=O)COC(c1ccccc1)(c1ccccc1)C(O)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCCN(CCCC)C(=O)COC(c1ccccc1)(c1ccccc1)C(O)C(=O)O
Yield: 80 %

Procedure:
1.42 g of methyl 2-hydroxy-3-(N,N-dibutylcarbamoylmethoxy)-3,3-diphenylpropionate were dissolved in 10 ml of dioxane and 4.8 ml of 1N sodium hydroxide solution and stirred at room temperature for 3 hours. Water was then added to the mixture, and the aqueous phase was extracted with ether. The aqueous phase was acidified with hydrochloric acid and extracted with ethyl acetate, and the organic phase was dried over magnesium sulfate. After removal of the solvent by distillation, 1.1 g of oil were isolated and were immediately employed further.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=S)=[CH:4][CH:3]=1.CI.[N:17]#[C:18][NH2:19].O.NN>CC#N>[I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10]/[C:9]/2=[N:19]\[C:18]#[N:17])=[CH:4][CH:3]=1
Reactant: N#CN
Reactant: S=c1ccccn1-c1ccc(I)cc1
Agent: NN
Solvent: O
Solvent: CI
Solvent: CC#N
Product: N#C/N=c1\ccccn1-c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
To a solution of 1-(4-iodophenyl)pyridine-2(1H)-thione (180 mg, 0.575 mmol) in CH3CN (15 mL), CH3I (0.50 mL, 8.0 mmol) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo to give a solid. The solid was dissolved in CH3CN (5 mL). To the solution, cyanamide (200 mg, 4.76 mmol) and hydrazine monohydrate (0.100 mL, 2.06 mmol) were added. After being stirred at room temperature for 2 h, the mixture was purified by HPLC to give (E)-(1-(4-iodophenyl)pyridin-2(1H)-ylidene)cyanamide (25 mg).
Reaction SMILES: OCCCCCCC[CH2:9][NH:10][C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12].CN[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][OH:53]>>[OH:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][N:10]([CH3:9])[C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:20])=[O:21])[CH:16]=[CH:17][CH:18]=1)=[O:12]
Reactant: CNCCCCCCO
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCO)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)CCCCCCO)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 70, using Intermediate 21 in place of 8-aminooctanol. ES/MS calcd. for C32H37N4O6S+ 605.2. Found m/z=605 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:9](C)=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].OC1C(C(C)(C)C)=CC=CC=1C=O.OC1C(C(C)(C)C)=CC(C)=CC=1C=O.OC1C(C(C)(C)C)=CC(C(C)(C)C)=CC=1C=O.OC1C(C(C)C)=CC=C(C)C=1C=O.OC1C(C2CCCCC2)=CC=CC=1C=O.OC1C=C(C(C)(C)C)C=CC=1C=O.OC1C=C(Cl)C=CC=1C=O.OC1C=CC=C(Cl)C=1C=O.OC1C(C2C=CC=CC=2)=CC=CC=1C=O.OC1C=CC(OC)=CC=1C=O.OC1C(CCCCCCCCC)=CC=CC=1C=O.OC1C=CC(O)=CC=1C=O.OC1C=C(NC(=O)C)C=CC=1C=O>>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Cc1cccc(C=O)c1O
Agent: CC(=O)Nc1ccc(C=O)c(O)c1
Agent: CC(C)(C)c1cc(C=O)c(O)c(C(C)(C)C)c1
Agent: CC(C)(C)c1ccc(C=O)c(O)c1
Product: O=Cc1ccccc1O

Procedure:
2-hydroxy-3-methylbenzaldehyde; 2-hydroxy-3-tert.butylbenzaldehyde; 2-hydroxy-3-tert.butyl-5-methylbenzaldehyde; 2-hydroxy-3,5-ditert.butylbenzaldehyde; 2-hydroxy-3-isopropyl-6-methylbenzaldehyde; 2-hydroxy-3-cyclohexylbenzaldehyde; 2-hydroxy-4-tert.butylbenzaldehyde; 2-hydroxy-4-chlorobenzaldehyde and 2-hydroxy-6-chlorobenzaldehyde; 2-hydroxy-3-phenylbenzaldehyde; 2-hydroxy-5-methoxybenzaldehyde; 2-hydroxy-3-nonylbenzaldehyde; 2,5-dihydroxybenzaldehyde; and 2-hydroxy-4-acetylaminobenzaldehyde;
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C>C(#N)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:2]2[N:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:4][N:3]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: Clc1ncc(-c2ccccc2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc(-c3ccccc3)cn2)CC1

Procedure:
A mixture of 2-chloro-5-phenyl-pyrimidine (1.2 g, 6.29 mmol, 1.0 equiv; commercially available from Acme Bioscience Inc., USA), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.52 g, 12.59 mmol, 2.0 equiv; commercially available) and triethylamine (1.75 mL, 1.27 g, 12.59 mmol, 2.0 equiv) in anhydrous acetonitrile (5 mL) was heated by microwave irradiation to 150° C. for 30 min. The organic phase was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 1.06 g (48%) of the title compound. MS (ISP): 355.5 [M+H]+.
Reaction SMILES: [Zn](CC)[CH2:2]C.FC(F)(F)C(O)=O.ICI.[CH:16]([O:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)=[CH2:17]>ClCCl>[F:26][C:21]1[CH:20]=[C:19]([O:18][CH:16]2[CH2:2][CH2:17]2)[CH:24]=[C:23]([F:25])[CH:22]=1
Reactant: C=COc1cc(F)cc(F)c1
Reactant: CC[Zn]CC
Solvent: ClCCl
Solvent: ICI
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(F)cc(OC2CC2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.3 %

Procedure:
To a nitrogen flushed 250 ml round bottom flask equipped with magnetic stirring bar and septa was added 80 ml dichloromethane and Et2Zn (7.18 g, 58.1 mmol). The resulting solution was cooled with ice bath. Trifluoroacetic acid (4.23 ml, 55 mmol) was added by a syringe slowly (septa was opened slightly to release pressure). The reaction mixture was stirred at 0° C. for 10 minutes after addition. Diiodomethane (4.88 ml, 60.4 mmol) was added by a syringe and the resulting reaction mixture was stirred at 0° C. for 10 minutes. A dichloromethane solution of 3,5-difluorophenyl vinyl ether (3.3 g, 21.1 mmol in 10 ml CH2Cl2) was added. The reaction mixture was allowed to warm up to room temperature over 30 minutes, then quenched by addition of 50 ml water and 50 ml 3N HCl. The layers were separated. The aqueous portion was extracted with 50 ml ether. The organics were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel column eluted with hexane to give 3.6 g desired product as light yellow liquid.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([S:11][CH2:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:14]=2[C:15]([O:17]C)=[O:16])[CH:8]=[CH:9][CH:10]=1>CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([S:11][CH2:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:14]=2[C:15]([OH:17])=[O:16])[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1c(CSc2cccc(OC)c2)cccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(SCc2cccc([N+](=O)[O-])c2C(=O)O)c1
Yield: 92 %

Procedure:
In methanol (10 ml) was dissolved methyl 2-(3-methoxyphenylthiomethyl)-6-nitrobenzoate obtained in Reference Example 16 (0.96 g, 2.88 mmol), and a 4 mol/l aqueous solution of sodium hydroxide (10 ml) was added thereto, followed by heating under reflux for 2 hours. After the reaction, the reaction mixture was concentrated and adjusted to pH 3 with a 1 mol/l aqueous solution of hydrochloric acid to give 2-(3-methoxyphenylthiomethyl)-6-nitrobenzoic acid as a precipitated white solid (0.85 g, 92%).
Reaction SMILES: C(O[C:4](=O)[C:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:9])[CH2:6][O:7][NH2:8])C.[BH4-].[Li+].C1C[O:23]CC1>>[C:10]([C:5]([CH3:9])([CH3:4])[CH:6]([O:7][NH2:8])[OH:23])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CCOC(=O)C(C)(CON)C(=O)OC(C)(C)C
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Li+]
Product: CC(C)(C)OC(=O)C(C)(C)C(O)ON
Temperature: 0 °C
Reaction time: 17 h
Yield: 71 %

Procedure:
2-Boc-aminooxy-2-methyl-propionic acid ethyl ester (2.54 g, 10.27 mmol) was dissolved in freshly distilled THF (100 mL), cooled to 0° C. and charged with 2.0 M lithium borohydride solution (10.3 mL, 20.54 mmol) in THF. The ice bath was removed and reaction was heated to reflux. After 17 hours, the reaction was cooled to 0° C. and quenched with methanol and concentrated in vacuo. The afforded residue was partitioned between ethyl acetate and 1M sodium hydroxide solution. The organic layers were washed twice with 1M sodium hydroxide solution, twice with saturated sodium chloride solution, collected and dried over Na2SO4, filtered and concentrated in vacuo, affording 2-Boc-aminooxy-2-methyl-propan-1-ol (1.50 g, 71%) as a white solid: 1H NMR (400 MHz; CDCl3) δ 6.84 (bs, 1H), 3.37 (s, 2H), 1.45 (s, 9H), 1.18 (s, 6H); MS (APCI−)=204.0.
Reaction SMILES: C[O:2][C:3](=[O:28])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][CH2:25][CH3:26])=[CH:14][C:13]1=[O:27])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:24][CH2:25][CH3:26])=[CH:14][C:13]2=[O:27])[C:3]([OH:28])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCCc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)OC)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Temperature: 23 °C
Reaction time: 2 h
Yield: 106.3 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[2-oxo-4-(2-propyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (440 mg, 0.001 mol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (143 mg, 0.006 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-[2-oxo-4-(2-propyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid (395 mg, 93%) as a yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[S:8][CH2:7]1.[ClH:14].[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:16]1.[Na+].[I-].[Br-]>C(OCC)(=O)C.CO.C(Cl)Cl.C(#N)C>[ClH:14].[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([N:24]2[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[S:8][CH2:7]3)[CH2:28][CH2:29]2)=[N:16]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: CC1(C)SCN(CCCCBr)C1=O
Agent: Cl
Agent: [Br-]
Agent: [I-]
Solvent: CC#N
Solvent: CO
Solvent: ClCCl
Product: CC1(C)SCN(CCCCN2CCN(c3nsc4ccccc34)CC2)C1=O
Temperature: 95 °C
Reaction time: 21 h
Yield: 60 %

Procedure:
A mixture of 3-(4-bromobutyl)-5,5-dimethyl-4-thiazolidinone (3.50 g), 1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride (3.70 g), K2 CO3 (6.34 g), NaI (330 mg) and acetonitrile (175 mL) was heated at 95° C. (bath temperature) under nitrogen. After 21 hours, TLC analysis (silica gel, 5% MeOH/CH2Cl2) showed the absence of starting bromide and the presence of a major product, Rf =0.33. The reaction mixture was cooled to room temperature, ethyl acetate (150 mL) was added, and the mixture filtered. The filtrate was concentrated in vacuo to an oil which was triturated with ethyl acetate. The mixture was filtered again and the filtrate, after concentration, was chromatographed (Waters Prep 500, one silica gel column, 3% MeOH/CH2CL2) to give 3.48 g of a viscous oil. The oil was dissolved in diethyl ether (500 mL), the solution filtered to remove a fluffy solid, and the filtrate acidified to pH=1 (hydrion paper) with an HCl/diethyl ether solution. The resultant salt (3.23 g) was recrystallized from ethanol/ethyl acetate yielding 2.29 g of white needles, mp 222°-227° C.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][S:6][C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)C.C(=O)([O-])[O-].[K+].[K+]>O>[S:6]1[C:7]2=[CH:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]2[CH:4]=[CH:5]1
Reactant: CCOC(CSc1cc2ccccc2[nH]1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: c1ccc2c(c1)cc1sccn12
Temperature: 130 °C
Yield: 56.7 %

Procedure:
A well stirred mixture of 2-(2,2-diethoxyethylmercapto)indole (1.5 g, 0.0057 mole) in polyphosphoric acid (30 g) was heated to 130° C. for 20 minutes, then allowed to cool to room temperature and the mixture diluted with water (300 ml). The resulting aqueous solution was basified by addition of solid potassium carbonate and then extracted with ethyl acetate (2×120 ml). The combined extracts were dried (Na2SO4), concentrated in vacuo and the residue chromatographed on silica gel eluting with 10% ether/60-80 petrol to afford the title compound as a white solid (0.56 g, 57%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:16]=[C:15]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:16]=[C:15]([C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)OC)cc(C(=O)N(C)CCC)c1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C(=O)c2ccccc2)c1
Temperature: 60 °C
Yield: 66 %

Procedure:
Dissolve N-methyl-N-propyl-5-tributylstannanyl-isophthalamic acid methyl ester (480 mg, 0.8 mmol), benzoyl chloride (117 mg), tris(dibenzylideneacetone)dipalladium (0) (19.3 mg) and 2-(di-tert-butylphosphino)biphenyl (34.5 mg) in chloroform (8 mL) in a previously degassed sealed vessel. Flush the mixture with nitrogen and heat the sealed mixture overnight at 60° C. Cool the reaction to room temperature and filter though a filtering agent. Concentrate the filtrate and purify (silica gel chromatography, eluting with 0:100 to 30:70 ethyl acetate:hexanes) to give the title compound (66%).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)[CH3:4].S(C1C=CC(C)=CC=1)(O[CH2:14][C@@H:15]1[CH2:29][C@H:28]2[C@@H:18]([CH2:19][C:20]3[C:30]4[C:23](=[CH:24][CH:25]=[CH:26][C:27]2=4)[NH:22][CH:21]=3)[N:17]([CH3:31])[CH2:16]1)(=O)=O>CN(C)C=O>[CH2:3]([C:5]1[N:6]([CH2:14][C@@H:15]2[CH2:29][C@H:28]3[C@@H:18]([CH2:19][C:20]4[C:30]5[C:23](=[CH:24][CH:25]=[CH:26][C:27]3=5)[NH:22][CH:21]=4)[N:17]([CH3:31])[CH2:16]2)[CH:7]=[CH:8][N:9]=1)[CH3:4]
Reactant: CCc1ncc[nH]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nccn1C[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
0.9 g of 50% sodium hydride in an oil was added in small portions to a mixture of 3.0 g of 2-ethylimidazole and 60 ml of dimethylformamide, and the resulting mixture was stirred for 30 minutes. 3.0 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 1.5 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with acetone). The product was recrystallized from methanolisopropyl alcohol to obtain 1.5 g of the titled compound having a melting point of 232°-237° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=O)[C:5]=2[CH2:4][CH2:3]1.C(N=C=NC(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.[NH:34]([CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>ClCCl>[C:39]([O:38][C:36](=[O:37])[CH2:35][N:34]([C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][C:2]2=[O:1])=[O:13])[CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)CNCC(=O)OC(C)(C)C
Reactant: O=C(O)c1cccc2c1CCC2=O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)c1cccc2c1CCC2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of Example 5 (500 mg, 2.84 mmol) in dichloromethane (10 mL) was added 1,3-diisopropylcarbodiimide (0.44 mL, 2.84 mmol), 1-hydroxybenzotriazole hydrate (115 mg, 0.85 mmol), and di-t-butyl iminodiacetate (1.04 g, 4.26 mmol). The mixture was stirred at room temperature for about 24 hours, quenched with water, and extracted with diethyl ether. The combined organic extracts were washed with brine and saturated aqueous sodium bicarbonate, dried (Na2SO4), filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel using hexane/ethyl acetate (1:1) as the mobile phase to provide the desired product. MS (ESI): m/z 402 (M−H)−.