Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][NH:18][O:19][CH3:20].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[O:15])[N:18]([O:19][CH3:20])[CH3:17])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.3 %

Procedure:
Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (3.00 g, 13.93 mmol), N,O-dimethylhydroxylamine hydrochloride (1.63 g, 16.72 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.94 g, 15.32 mmol) and 1-hydroxybenzotriazole (2.07 g, 15.32 mmol) were placed in a 100 mL round bottomed flask and dissolved in DMF (30 mL). Diisopropylethylamine (6.1 mL, 34.82 mmol) was slowly added, and the reaction mixture was stirred at room temperature for 24 hours. The reaction was quenched by addition of water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and evaporated under reduced pressure to give 2.60 g (72% yield) of 3-(methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a pale yellow oil which was used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH:10]2[CH:5]([CH:6]=[CH:7][CH2:8][CH:9]2[C:11]([O:13]CC)=[O:12])[CH2:4][NH:3]1.S(=O)(=O)(O)O>O>[O:1]=[C:2]1[CH:10]2[CH:5]([CH:6]=[CH:7][CH2:8][CH:9]2[C:11]([OH:13])=[O:12])[CH2:4][NH:3]1
Reactant: CCOC(=O)C1CC=CC2CNC(=O)C21
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)C1CC=CC2CNC(=O)C21

Procedure:
8.36 g (40 nmol) of ethyl (1RS,2RS,6RS)-9-oxo-8-azabicyclo[4.3.0]non-4-ene-2-carboxylate (product A from Example K.2.) are stirred at 60° C. for 40 h with 30 ml of water and 5 g of conc. sulphuric acid. On cooling, the product precipitates. The precipitate is washed with a little cold water and dried in a vacuum drying oven at 50° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[C@@H:19]([NH:20][C:21]([C:23]3[S:24][C:25]4[CH2:26][N:27]([CH3:32])[CH2:28][CH2:29][C:30]=4[N:31]=3)=[O:22])[CH2:18][CH2:17][C@@H:16]([C:33]([O:35]C)=[O:34])[CH2:15]1)=[O:12])=[CH:5]2.[OH-].[Li+:38].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[C@@H:19]([NH:20][C:21]([C:23]3[S:24][C:25]4[CH2:26][N:27]([CH3:32])[CH2:28][CH2:29][C:30]=4[N:31]=3)=[O:22])[CH2:18][CH2:17][C@@H:16]([C:33]([O-:35])=[O:34])[CH2:15]1)=[O:12])=[CH:5]2.[Li+:38]
Reactant: COC(=O)[C@@H]1CC[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCc2nc(C(=O)N[C@H]3CC[C@@H](C(=O)[O-])C[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 94.8 %

Procedure:
The compound (1.20 g) obtained in Example 51 was dissolved in tetrahydrofuran (32 mL), and lithium hydroxide (60.8 mg) and water (4 mL) were successively added under ice cooling, followed by stirring at room temperature for 14 hours. The solvent was distilled away under reduced pressure to give the title compound (1.12 g).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:14][C:15]1[CH:45]=[CH:44][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]4[N:34]=[C:33]([CH:35]5[CH2:37][CH:36]5[C:38]([NH2:40])=O)[N:32]([CH3:41])[C:31]=4[CH:42]=3)[C:23](=[O:43])[CH:22]=2)=[CH:17][CH:16]=1.N1C=CC=CC=1>C1COCC1>[Cl:14][C:15]1[CH:45]=[CH:44][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]4[N:34]=[C:33]([CH:35]5[CH2:37][CH:36]5[C:38]#[N:40])[N:32]([CH3:41])[C:31]=4[CH:42]=3)[C:23](=[O:43])[CH:22]=2)=[CH:17][CH:16]=1
Reactant: Cn1c(C2CC2C(N)=O)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cn1c(C2CC2C#N)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 18.7 %

Procedure:
Trifluoroacetic anhydride (0.181 ml) was added to a solution of (1RS,2SR)-2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxamide (195 mg) and pyridine (0.105 ml) in THF (5 ml) at 0° C. The mixture was stirred at 0° C. for 2 h. The mixture was quenched with saturated NaHCO3 solution at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/EtOAc). The residue was recrystallized from EtOH/hexane to give the title compound (35 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=C)=[CH:4][CH:3]=1.[C-]#N.[K+].CC[OH:35]>O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:21])([CH3:22])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=[O:35])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: C=C(OCC)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: CCOC(=O)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Temperature: 80 °C
Yield: 78 %

Procedure:
A steel clabe was charged with a mixture of compound 5 (400 mg, 1.39 mmol), KCN (362 mg, 5.57 mmol) in EtOH (4 mL) and H2O (4 mL). The mixture was heated at 80° C. for 24 h. The reaction mixture was cooled to room temperature and poured into ice (10 g) and filtered. The filter cake was washed with water (10 mL×2) and CH2Cl2 (10 mL×2), dried under reduced pressure to give compound 6 (440 mg, 78%) as a white solid. LC-MS tR=1.219 min in 2 min chromatography, MS (ESI) m/z 333, 335 [M+H]+; 1H NMR (DMSO 400 MHz): δ 10.82 (m, 1H), 8.52 (d, J=27.2 Hz, 1H), 7.53 (m, 1H), 7.34 (m, 2H), 5.78 (d, J=6.4 Hz, 2H), 2.61 (m, 4H), 2.23 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([F:15])([C:11]([F:14])([F:13])[F:12])[C:4]([F:10])([F:9])[C:5](I)([F:7])[F:6].[CH:18]1[C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=[C:20](I)[CH:19]=1.CS(C)=O>[Cu].O>[F:1][C:2]([F:17])([F:16])[C:3]([F:15])([C:11]([F:14])([F:13])[F:12])[C:4]([F:10])([F:9])[C:5]([F:7])([F:6])[C:20]1[CH:19]=[CH:18][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: FC(F)(F)C(F)(C(F)(F)F)C(F)(F)C(F)(F)I
Agent: [Cu]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1ccc(C(F)(F)C(F)(F)C(F)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 130 °C
Reaction time: 14.5 h
Yield: 29.7 %

Procedure:
A mixture of 3-trifluoromethylperfluorobutyl iodide (19.5 g, 50 mmol), p-iodobenzoic acid (12.4 g, 50 mmol), activated copper (15.9 g, 250 mmol) and dried dimethyl sulfoxide (100 ml) is stirred at 130° C. in an autoclave for 14.5 hours. After cooling, the reaction mixture is poured into water (400 ml), and the precipitated solid material is collected by filtration and dried. Then, the solid material is extracted with ethanol (200 ml), and the ethanol extract is concentrated to yield crude p-(3-trifluoromethylperfluorobutyl)benzoic acid (5.8 g). The crude product is recrystallized from ethanol-water. The melting point of the purified product is 189°-190° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].N#N>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH2:6][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[CH:8]=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: CCOP(OCC)OCC
Agent: N#N
Product: CCOP(=O)(Cc1cccc(C(F)(F)F)c1)OCC
Temperature: 160 °C

Procedure:
3-Trifiuoromethylbenzylchloride (50 g, 257 mmol) and triethyl phosphite (53.4 g, 321 mmol) were combined,under N2, and heated to 160° C. for 18 hours. The reaction mixture was distillated at 105°-110° C. to give 69.5 g (91.3%) of analytically pure product as a colorless oil. 300 MHz 1H NMR (CDCl3): δ, 3.20 (d,2H, J=21.78 Hz, PCH2). MS: 297 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2].[Cl:15][CH2:16][Si:17](Cl)([CH3:19])[CH3:18]>>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4](=[O:12])[C:5]1[C:10]([Si:17]([CH2:16][Cl:15])([CH3:19])[CH3:18])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:14]
Reactant: CCN(CC)C(=O)c1ccccc1Cl
Reactant: C[Si](C)(Cl)CCl
Product: CCN(CC)C(=O)c1c(Cl)cccc1[Si](C)(C)CCl

Procedure:
The title compound was prepared according to General Method A from the compound of Example e and 1.5 eq (chloromethyl)dimethylsilyl chloride. Purification by HPLC using 1:9 ethyl acetate/hexanes gave 5.4 g of the desired compound as a yellow oil, an 85% yield.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10](=[O:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:13][C:14]1[CH:23]=[CH:22][C:17]([CH:18]=[CH:19][CH2:20]Br)=[CH:16][CH:15]=1.Cl.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>C(COC)OC.O>[C:3]1([CH:9]([CH2:20][CH:19]=[CH:18][C:17]2[CH:22]=[CH:23][C:14]([CH3:13])=[CH:15][CH:16]=2)[C:10](=[O:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)Cc1ccccc1
Reactant: Cc1ccc(C=CCBr)cc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: O
Solvent: COCCOC
Product: CC(=O)C(CC=Cc1ccc(C)cc1)c1ccccc1

Procedure:
Sodium hydride (6 g., 0.14 mole, oil dispersion) is suspended in glyme (200 ml.) and phenyl acetone (19.2 g., 0.14 mole) in glyme (50 ml.) is added dropwise with stirring. After complete addition the mixture is heated to reflux for 0.5 hour. The mixture is cooled in a cold water bath and a solution of p-methylcinnamyl bromide (32.2 g., 0.14 mole) in glyme (50 ml.) is added dropwise. When addition is complete, the mixture is refluxed for 18 hours then allowed to cool. Cold water (1000 ml.) is added and the mixture acidified with dilute hydrochloric acid. The mixture is saturated with ammonium sulfate and the organic material is extracted into ether. The extracts are washed with water, saturated brine, and dried (MgSO4). Filtration and removal of solvent in vacuo produces the crude product as a dark oil.
Reaction SMILES: [C@H:1]12[CH2:9][O:8][C:7](=[O:10])[C@H:6]1[CH2:5][CH2:4][CH2:3][CH2:2]2.[NH3:11].ClCCl.CO>C(O)C>[OH:8][CH2:9][C@@H:1]1[CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]1[C:7]([NH2:11])=[O:10]
Reactant: O=C1OC[C@@H]2CCCC[C@H]12
Reactant: N
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: NC(=O)[C@H]1CCCC[C@H]1CO
Yield: 62.4 %

Procedure:
(1R,6S)-(+)-8-oxabicyclo[4.3.0]nonan-7-one (1 gram) was dissolved in 5 ml of absolute ethanol, followed by the addition of 0.5 gram of gaseous ammonia. The solution was kept in a stoppered flask, and the progress of the reaction was followed by thin layer chromatography (eluent dichloromethane/methanol 20:1). After the reaction was judged complete, the ethanol was evaporated and the resulting residue redissolved in ethyl acetate. Ammonia was removed by extraction with 1% HCl, and the ethyl acetate solution was dried over MgSO4, filtered, and rotary evaporated to leave 0.7 grams of (1S,2R)-2-hydroxymethyl-1-cyclohexanecarboxamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[NH2:30][C@@H:31]([CH:42]([CH3:44])[CH3:43])[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33].CN1CCOCC1>C(Cl)Cl>[CH2:35]([O:34][C:32](=[O:33])[C@@H:31]([NH:30][C:10](=[O:12])[C@@H:9]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:14])[CH3:13])[CH:42]([CH3:44])[CH3:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 23 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (4.06 g, 20.0 mmol, Eq: 1), HOAT (4.08 g, 30.0 mmol, Eq: 1.5) and EDC (5.74 g, 30.0 mmol, Eq: 1.5) in DCM (200 mL), was added a solution of (S)-benzyl 2-amino-3-methylbutanoate hydrochloride (5.35 g, 22.0 mmol, Eq: 1.1) and N-methylmorpholine (4.45 g, 4.83 mL, 43.9 mmol, Eq: 2.2) in 50 mL of DCM. The reaction mixture was stirred at 23° C. for 3 h. The clear yellow solution was concentrated in vacuo. The residue was taken up in EtOAc and washed with saturated aqueous NaHCO3 (1×300 mL), 5% aqueous KHSO4 and brine (1×300 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 80% EtOAc in hexanes) to afford (S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyric acid benzyl ester as a colorless oil (7.02 g), m/z=393 (M+H).
Reaction SMILES: [CH3:1]O.[Bi](Br)(Br)Br.[OH:7][CH:8]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)[CH3:9]>ClC(Cl)(Cl)Cl>[CH3:17][O:16][C:14](=[O:15])[C:13]1[CH:18]=[CH:19][C:10]([CH:8]([O:7][CH3:1])[CH3:9])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(C(C)O)cc1
Reactant: CO
Agent: Br[Bi](Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C(C)OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
To the solution of methanol (53 mg, 1.67 mmol) in perchloromethane (80 mL) was added bismuth (III) bromide (743 mg, 1.67 mmol), the mixture was stirred for 30 minutes at room temperature, the methyl 4-(1-hydroxyethyl)benzoate (300 mg, 1.67 mmol) was added, the mixture was stirred at room temperature for 12 hours. Then the mixture was concentrated and purified by column chromatography (silica gel, Petroleum ether/ethyl acetate=20:1) to give methyl-4-(1-methoxyethyl)benzoate (185 mg, 57%), as oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:6]=1[CH3:13])=O.[NH2:14][C:15]([NH2:17])=[S:16]>CCO>[Cl:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([C:3]2[N:14]=[C:15]([NH2:17])[S:16][CH:2]=2)=[C:6]([CH3:13])[CH:7]=1
Reactant: Cc1cc(Cl)cc(C)c1C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1cc(Cl)cc(C)c1-c1csc(N)n1
Yield: 72 %

Procedure:
A mixture of 2-bromo-1-(4-chloro-2,6-dimethylphenyl)ethanone (6.54 g, 25.0 mmol) and thiourea (1.90 g, 25.0 mmol) in 95% EtOH (35.7 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50 mL) followed by saturated aqueous Na2CO3 (4.0 mL). The resultant precipitate was filtered and recrystallized in toluene (30 mL). The solids were filtered and dried under vacuum to give 4-(4-chloro-2,6-dimethylphenyl)thiazol-2-amine (4.30 g) as white solids in 72% yield: 1H NMR (500 MHz, DMSO-d6) δ 7.16 (s, 2 H), 6.43 (s, 1 H), 2.10 (s, 6 H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:36])[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:28]=[N:29][C:30]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][CH:32]=2)[CH:22]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:28]=[N:29][C:30]([CH:33]5[CH2:35][CH2:34]5)=[CH:31][CH:32]=4)[CH:22]=3)[CH2:18][C:17](=[O:36])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C4CC4)nc3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccc(C4CC4)nc3)c1)=N2

Procedure:
The title compound was prepared from (4-chloro-2-{3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example M143) (332 mg, 0.638 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (163 mg, 64%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[CH2:19][C:18]([CH3:20])=[CH:17][C:13]=3[S:14][C:15]=2[CH3:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.[Cu](C#N)C#N.Cl[Si:38]([CH:41]1[C:49]2[C:44](=[C:45]([C:50]3[CH:55]=[CH:54][C:53]([C:56]([CH3:59])([CH3:58])[CH3:57])=[CH:52][CH:51]=3)[CH:46]=[CH:47][CH:48]=2)[CH:43]=[C:42]1[CH:60]([CH3:62])[CH3:61])([CH3:40])[CH3:39].[Cl-].[NH4+]>C(OCC)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]3[CH:19]=[C:18]([CH3:20])[CH:17]([Si:38]([CH:41]4[C:49]5[C:44](=[C:45]([C:50]6[CH:51]=[CH:52][C:53]([C:56]([CH3:58])([CH3:57])[CH3:59])=[CH:54][CH:55]=6)[CH:46]=[CH:47][CH:48]=5)[CH:43]=[C:42]4[CH:60]([CH3:62])[CH3:61])([CH3:39])[CH3:40])[C:13]=3[S:14][C:15]=2[CH3:16])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1=Cc2sc(C)c(-c3ccc(C(C)(C)C)cc3)c2C1
Reactant: CC(C)C1=Cc2c(-c3ccc(C(C)(C)C)cc3)cccc2C1[Si](C)(C)Cl
Agent: N#C[Cu]C#N
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1=Cc2c(sc(C)c2-c2ccc(C(C)(C)C)cc2)C1[Si](C)(C)C1C(C(C)C)=Cc2c(-c3ccc(C(C)(C)C)cc3)cccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution containing 5.64 g (20 mmol) 3-(4-tert-Butyl-phenyl)-2,5-dimethyl-4H-cyclopenta[b]thiophene dissolved in 50 ml of diethyl ether was added a 2.5 M solution of n-butyllithium in hexane (20 mmol, 8 ml). A catalytic amount of copper cyanide was added (0.08 g), then the reaction mixture was stirred for 3 h. The temperature was reduced to −78° C., then a solution containing 7.66 g (20 mmol) chloro-(2-isopropyl-4-(4-tert-butyl-phenyl)-1H-inden-1-yl)-dimethyl-silane dissolved in 20 ml diethyl ether was added drop-wise. After addition was complete, the flask was allowed to warm to room temperature and stirring was continued for 5 h, then poured into a saturated solution of ammonium chloride. The organic fraction was collected with a 30% dichloromethane/70% hexane solution, washed with 2N HCl, saturated bicarbonate, water, then dried over magnesium sulfate. The reaction product was filtered, then solvents removed in vacuo. Yield: 11.92 g (92%) light orange powder.
Reaction SMILES: [CH2:1]([C:7]1[CH:11]=[CH:10][S:9][C:8]=1[CH:12]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH2:15]O>N1C=CC=CC=1.C(O)C>[C:12]([C:8]1[S:9][CH:10]=[CH:11][C:7]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])#[N:15]
Reactant: NO
Reactant: CCCCCCc1ccsc1C=O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCCCCCc1ccsc1C#N
Temperature: 80 °C
Yield: 64.7 %

Procedure:
To a solution of 3-hexylthiophene-2-carboxaldehyde (7.8 g, 40 mmol) in pyridine/ethanol (60 mL, 1/1, v/v) was added hydroxylamine hydrochloride salt (4.2 g, 60 mmol). The solution was stirred with refluxing at 80° C. overnight. After cooling, the solution was rotary evaporated to remove the solvent. The residue was taken up with chloroform (100 mL) and the resulting solution was washed twice with distilled water (50 mL), dried over anhydrous magnesium sulfate, and rotary evaporated to remove the solvent. The viscous liquid residue was then dissolved in acetic anhydride (30 mL) containing 0.2 g of potassium acetate, and the resulting mixture was refluxed at 140° C. for 3 h. After cooling down to room temperature, the solution was poured into 100 mL H2O and extracted three times with hexanes (50 mL). The organic extracts were combined and washed until neutral, dried over anhydrous magnesium sulfate, and rotary evaporated to remove the solvent. The yellow liquid residue was subjected to silica-gel column chromatography (EtOAc/Hex=8/92, v/v, Rf=0.4) to yield a light yellow liquid product (5.0 g, 65% yield). 1H NMR (400 MHz, acetone-d6) δ (ppm): 7.85 (d, 1H, J=5.2 Hz); 7.19 (d, 1H, J=5.2 Hz); 2.80 (t, 2H, J=7.8 Hz); 1.68 (m, 2H); 1.28-1.38 (m, 6 H); 0.88 (m, 3H).
Reaction SMILES: [C:1]([NH:4][C:5](=[O:42])[CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][C@@H:12]1[C@@H:16](/[CH:17]=[CH:18]/[C@@H:19]([O:27]C2CCCCO2)[C:20]([CH3:26])([CH3:25])[CH2:21][C:22]#[C:23][CH3:24])[C@H:15]([O:34]C2CCCCO2)[CH2:14][C:13]1=[O:41])(=[O:3])[CH3:2]>C(O)(=O)C.O.C1COCC1>[C:1]([NH:4][C:5](=[O:42])[CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][C@@H:12]1[C@@H:16](/[CH:17]=[CH:18]/[C@@H:19]([OH:27])[C:20]([CH3:25])([CH3:26])[CH2:21][C:22]#[C:23][CH3:24])[C@H:15]([OH:34])[CH2:14][C:13]1=[O:41])(=[O:3])[CH3:2]
Reactant: CC#CCC(C)(C)[C@@H](/C=C/[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1C/C=C\CCCC(=O)NC(C)=O)OC1CCCCO1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC#CCC(C)(C)[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)NC(C)=O

Procedure:
400 mg. of (5Z,13E)-(11R,15R)-16,16-dimethyl-9-oxo-11,15-bis(tetrahydropyran-2-yloxy)-5,13-prostadien-18-ynoic acid acetylamide is agitated for 16 hours at 25° with 12 ml. of a mixture of glacial acetic acid/water/THF (65/35/10), evaporated under vacuum, and the residue purified by column chromatography on silica gel. With methylene chloride/2-5% methanol, 190 mg. of the title compound is obtained as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:14]=1)[C:9](O)=[O:10])=[O:5])[CH3:2].[N:20]1C=CC=CC=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.CCOC(C)=O>O1CCOCC1>[C:9]([C:8]1[CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:14]=[C:6]([CH:7]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:5])(=[O:10])[NH2:20]
Reactant: c1ccncc1
Reactant: CCOC(=O)c1cc(C(=O)O)cc(C(=O)OCC)c1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(C(N)=O)cc(C(=O)OCC)c1
Yield: 92.7 %

Procedure:
NH4HCO3 (0.15 g, 1.89 mmol, 1.26 eq) was added to a stirred solution of 3,5-bis(ethoxycarbonyl)benzoic acid (0.42 g, 1.5 mmol, 1 eq), pyridine (0.24 mL, 0.237 g, 3.0 mmol, 2 eq), and (Boc)2O (0.45 mL, 0.43 g, 1.95 mmol, 1.3 eq) in 2 mL anh. dioxane under Ar. The reaction was stirred over the weekend to form a white solid. EtOAc was added, but the solid did not dissolve. The mixture was washed with 0.1 N HCl (×2) and water (×4). The solid stayed suspended in the organic layer, but did dissolve. The solvent was removed in vacuo yielding 0.369 g (1.39 mmol, 93% yield) of diethyl 5-carbamoylisophthalate as an insoluble white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:18]1([CH2:24][CH2:25][CH2:26][CH:27]([NH2:37])[CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:37][CH:27]([CH2:26][CH2:25][CH2:24][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:28][CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NC(CCCc1ccccc1)CCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.9 %

Procedure:
1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (1 g; 4.36 mmol) is dissolved in methylene chloride (25 mL) at ambient temperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) (1.33 g; 4.38 mmol), triethylamine (1.22 mL; 8.75 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.92 g; 4.8 mmol) are added sequentially. The mixture is stirred for 18 hours at ambient temperature then concentrated in vacuo at 40° C. The residue is diluted with ethyl acetate (150 mL) and washed successively with water (150 mL), 0.1 N HCl (100 mL), saturated aqueous sodium bicarbonate (50 mL), and saturated brine (50 mL). The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography with gradient elution (5%→40% ethyl acetate in hexanes) affording the desired product (0.77 g) as a solid.