Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:2]([CH2:10][OH:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][N+:18]([O-:21])=[CH:17][CH:16]=1.[NH4+].[OH-]>O1CCOCC1.CN(C=O)C.O1CCOCC1.C(Cl)Cl.CO>[N:1]1[C:2]([CH2:10][O:11][C:15]2[CH:20]=[CH:19][N+:18]([O-:21])=[CH:17][CH:16]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: [O-][n+]1ccc(Cl)cc1
Reactant: OCc1cn2ccccc2n1
Agent: [H-]
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: [O-][n+]1ccc(OCc2cn3ccccc3n2)cc1
Temperature: 60 °C
Yield: 54.1 %

Procedure:
Imidazo[1,2-a]pyridine-2-ylmethanol (3.01 g, 20.3 mmol) was partially dissolved in 5:1 dioxane/DMF (30 mL) and the resulting slurry was added slowly to a stirring suspension of NaH (60% in mineral oil, 0.812 g, 16.9 mmol) in dioxane (29 mL). The resulting mixture was heated to 60° C. for 15 min. 4-Chloropyridine-N-oxide (1.5 g, 11.5 mmol) was added and the reaction mixture was heated for 1 h at 110° C. Upon cooling, the mixture was diluted with methylene chloride and a 20% NH4OH in MeOH solution. The resulting suspension was filtered through a silica gel plug using CH2Cl2 (200 mL) and 20% 4:1 MeOH/NH4OH in CH2Cl2 (500 mL). The filtrate was collected and concentrated under reduced pressure. Flash chromatography (120 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100 over 60 min) provided the title compound (1.5 g, 30%) as an orange-brown solid: 1H NMR (300 MHz, CD3OD) δ 8.42 (m, 1H), 8.24-8.22 (m, 2H), 7.97 (d, J=0.5 Hz, 1H), 7.54 (dd, J=9.1, 0.7 Hz, 1H) 7.37-7.32 (m, 1H), 7.27-7.25 (m, 2H), 6.94 (m, 1H), 5.37 (s, 2H).
Reaction SMILES: [CH2:1]1[CH:14]2[CH:5]([C:6](=[O:16])[CH:7]3[C:12]([C:13]2=[O:15])=[CH:11][CH2:10][CH2:9][CH2:8]3)[CH2:4][CH2:3][CH2:2]1.[H][H]>[Rh]>[CH:8]1[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1.[CH2:4]1[CH:5]2[CH:14]([C:13](=[O:15])[CH:12]3[C:7]([C:6]2=[O:16])=[CH:8][CH2:9][CH2:10][CH2:11]3)[CH2:1][CH2:2][CH2:3]1
Reactant: [H][H]
Agent: [Rh]
Agent: O=C1C2=CCCCC2C(=O)C2CCCCC12
Product: O=C1c2ccccc2C(=O)c2ccccc21
Yield: 62 %

Procedure:
The octahydro-anthraquinone (OHAQ) reaction is initially a highly exothermic and is immediately followed by the rapid elimination of hydrogen which has a pronounced cooling effect on the reaction system. Reaction times of less than 1 minute past the exotherm with a rhodium on carbon catalyst provided yields of 62 percent anthraquinone, along with isomerized OHAQ and isomerized THAQ. If the same reaction is conducted with palladium on a carbon support, a 75 percent yield of anthraquinone is obtained along with the isomerized OHAQ and isomerized THAQ. The reaction can be visualized to be the following: ##STR6##
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([CH:7]=[CH:8][C:9]3[O:10][C:11](=[O:18])[C:12]([CH3:17])([CH3:16])[C:13]=32)=[CH:5][CH:4]=1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1>C(#N)C>[CH3:16][C:12]1([CH3:17])[C:11](=[O:18])[O:10][C:9]2[CH:8]=[CH:7][C:6]3[C:14]([C:13]1=2)=[CH:15][C:3]([CH2:2][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)=[CH:4][CH:5]=3
Reactant: c1nc[nH]n1
Reactant: CC1(C)C(=O)Oc2ccc3ccc(CBr)cc3c21
Solvent: CC#N
Product: CC1(C)C(=O)Oc2ccc3ccc(Cn4cncn4)cc3c21

Procedure:
A solution of 8-bromomethyl-1,1-dimethyl-2(1H)-naphtho[2,1-b]furanone in acetonitrile (5 ml), was treated with 1,2,4-triazole (1.4 g) and the mixture was heated under reflux for 18 h. The solution was evaporated to dryness under reduced pressure and the residue was partitioned between 1N aqueous sodium hydrogen carbonate and ethyl acetate. The ethyl acetate extract was separated, dried and evaporated to dryness, and the residue was purified by flash chromatography. Elution with methanol:chloroform, 1:49 v/v, gave 1,1-dimethyl-8-(1H-1,2,4-triazol-1-ylmethyl)-2-(1H)-naphtho[2,1-b]furanone, m.p. 136°-137° after recrystallisation from a mixture of ethyl acetate and cyclohexane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][N+:5]#[C-:6].Cl[CH2:9][C:10]1[C:15]([CH2:16]Cl)=[CH:14][CH:13]=[CH:12][N:11]=1.CC(C)([O-])C.[K+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1([N+:5]#[C-:6])[CH2:9][C:10]2[N:11]=[CH:12][CH:13]=[CH:14][C:15]=2[CH2:16]1)=[O:7]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: ClCc1cccnc1CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: [C-]#[N+]C1(C(=O)OC)Cc2cccnc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isocyano-acetic acid methyl ester (112 mg, 1.13 mmol) and 2,3-bis-chloromethyl-pyridine (200 mg, 1.14 mmol) were dissolved in DMF. Potassium tert-butoxide (0.255 g, 2.27 mmol) was added and the reaction mixture was stirred for 1 h at room temperature. The mixture was partitioned between EA and a saturated aqueous sodium hydrogencarbonate solution, the aqueous phase extracted with EA, and the organic extracts were dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) to give 6-isocyano-6,7-dihydro-5H-[1]pyrindine-6-carboxylic acid methyl ester. This compound was added to a solution of thionyl chloride (147 mg, 1.23 mmol) in ethanol (1 ml) and refluxed overnight. The mixture was evaporated to dryness, and the residue was stirred with HEP, filtered and dried in vacuo. The obtained product was reacted with 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid in analogy to step 1 of example 15 and the title compound purified by preparative RP HPLC (water/ACN gradient).
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[C:4](=[O:7])O[C:2]2=[O:8].[NH2:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17]C)=[O:15])=[CH:12][CH:11]=1.CC1(C)CC(=O)OC(=O)C1>>[O:7]=[C:4]1[N:9]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:19][CH:20]=2)[C:2](=[O:8])[CH:1]2[CH:5]1[CH2:6]2
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C1OC(=O)C2CC12
Agent: CC1(C)CC(=O)OC(=O)C1
Product: COC(=O)c1ccc(N2C(=O)C3CC3C2=O)cc1

Procedure:
The desired product was prepared by substituting methyl 4-aminobenzoate and 3-oxabicyclo(3.1.0)hexane-2,4-dione for ethyl 4-aminobenzoate and 3,3-dimethylglutaric anhydride, respectively, in Example 119A. MS (DCI) m/e 263 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[N:12]=[C:11]([NH:13][CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:10]=[C:9]([C:20]([OH:23])([CH3:22])[CH3:21])[CH:8]=2)=[CH:4][CH:3]=1.Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=1.C(N(CC)CC)C>S1(CCCC1)(=O)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:12]=[C:11]([NH:13][CH:14]3[CH2:19][CH2:18][N:17]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=4)[CH2:16][CH2:15]3)[N:10]=[C:9]([C:20]([OH:23])([CH3:22])[CH3:21])[CH:8]=2)=[CH:24][CH:25]=1
Reactant: Cc1cc(Cl)ccn1
Reactant: CC(C)(O)c1cc(Cc2ccc(Cl)cc2)nc(NC2CCNCC2)n1
Solvent: O=S1(=O)CCCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCC(Nc3nc(Cc4ccc(Cl)cc4)cc(C(C)(C)O)n3)CC2)ccn1
Temperature: 150 °C
Reaction time: 1 h
Yield: 39.6 %

Procedure:
A solution of 2-[6-(4-chloro-benzyl)-2-(piperidin-4-ylamino)-pyrimidin-4-yl]-propan-2-ol (76 mg, 0.19 mmol), 4-chloro-2-picoline (24 mg, 0.19 mmol) and triethylamine (53 μL, 0.38 mmol) in sulfolane (0.76 mL) was stirred in a preheated oil bath at 150° C. for 30 minutes. After further addition of 4-chloro-2-picoline (24 mg, 0.19 mmol) and triethylamine (53 μL, 0.38 mmol) the solution was stirred for further 60 minutes at 150° C. It was diluted with ethyl acetate (15 mL) and was washed with 1 M aqueous sodium carbonate solution (20 mL), water (15 mL) and brine (15 mL). The combined aqueous layers were extracted with ethyl acetate (15 mL). The organic layer was dried over sodium sulfate. Concentration and purification by chromatography (SiO2, dichloromethane/methanol/triethylamine=95:4.5:0.5) afforded the title compound (34 mg, 40%) as an off-white foam.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:12][C@H:9]([O:10][CH3:11])[CH2:8][CH2:7][C@@H:6]1[OH:13])=[N+]=[N-].[C:14](OC(=O)C)(=[O:16])[CH3:15]>CO.[Pd]>[C:14]([NH:1][CH2:4][C@H:5]1[O:12][C@H:9]([O:10][CH3:11])[CH2:8][CH2:7][C@@H:6]1[OH:13])(=[O:16])[CH3:15]
Reactant: CO[C@@H]1CC[C@H](O)[C@@H](CN=[N+]=[N-])O1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CO
Product: CO[C@@H]1CC[C@H](O)[C@@H](CNC(C)=O)O1
Reaction time: 5 h

Procedure:
Methyl 6-azido-2,3,6-trideoxy-α-D-erythro-hexopyranoside (3.0 g, 16 mmol) in methanol (100 ml) containing acetic anhydride (2 ml) was hydrogenated over 10% palladium-on-charcoal (0.4 g) at room temperature under a pressure of 2.5 atms. for 5 h. The catalyst was filtered off and the filtrate was evaporated to dryness giving a syrupy residue which crystallized upon treatement with ether to yield 3.18 g, 98%. The product was recrystallized from chloroform-ether to give pure methyl 6-acetamido-2,3,6-trideoxy-α-D-erythro-hexopyranoside. M.p.: 117°-118°. [α]546121 -13° (c 1, chloroform).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+]([O-])=O)[C:10]=1C1C=CC=CC=1)[C:5](O)=O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([S:36](=[O:39])(=[O:38])[NH2:37])[C:29]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]([OH:26])=[O:25]>>[CH2:5]([NH:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([S:36](=[O:39])(=[O:38])[NH2:37])[C:29]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]([OH:26])=[O:25])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1-c1ccccc1
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1-c1ccccc1
Product: NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1-c1ccccc1

Procedure:
By replacing in Example 1, step D, 3-amino-5-nitro-4-phenylbenzoic acid with an equimolar amount of 3-amino-4-phenyl-5-sulfamylbenzoic acid, and following the procedure described, 3-benzylamino-4-phenyl-5-sulfamylbenzoic acid is obtained with a melting point of 221°-222° C. The material is identical (IR, analysis) with the material prepared as in Example 1, step G.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH3:16])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCCC1CCC(O)(c2ccc(Br)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC1CC=C(c2ccc(Br)cc2)CC1
Yield: 57.8 %

Procedure:
50.1 g of the compound (15), 0.5 g of p-toluenesulfonic acid and 200 mL of toluene were mixed, and the mixture was refluxed under heating for 3 hours while water distilled out was removed. After cooling the resulting reaction mixture to 30° C., 200 mL of water and 100 mL of toluene were added to and mixed with the reaction mixture, which was separated into an organic layer and an aqueous layer by standing still, so as to attain extraction to the organic layer. The resulting organic layer was fractionated and washed with a 2N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain a residue. The resulting residue was purified by silica gel column chromatography using heptane as eluent, and then further purified by recrystallization from Solmix A-11 to obtain 27.2 g of 1-bromo-4-(4-propylcyclohexa-1-enyl)benzene (16).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:28][CH:5]2[CH:6]([C:18]3[CH:23]=[CH:22][C:21]([O:24]COC)=[CH:20][CH:19]=3)[O:7][C:8]3[CH:9]=[CH:10][C:11]([O:14]COC)=[CH:12][C:13]=3[CH:4]2[CH2:3]1>C1COCC1.Cl.CCOC(C)=O>[F:29][C:2]1([F:1])[CH2:28][C@@H:5]2[C@H:6]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[O:7][C:8]3[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][C:13]=3[C@@H:4]2[CH2:3]1
Reactant: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(F)(F)CC32)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Oc1ccc([C@@H]2Oc3ccc(O)cc3[C@@H]3CC(F)(F)C[C@@H]32)cc1
Reaction time: 8 h
Yield: 100 %

Procedure:
Stir a solution of difluorocyclopentane 29 (196 mg, 0.480 mmol) in 7 mL of THF and 3 mL of 3 M HCl overnight. Add 1 mL of 5 M HCl and let stir overnight. Dilute the solution with EtOAc. Separate the aqueous solution and extract 2× with EtOAc. The combined organic solutions were washed with saturated aqueous sodium bicarbonate, brine, dried over Na2SO4, filtered, and concentrated. Absorb to 2 g of silica gel and purify by silica gel chromatography (10 g silica gel, 10 to 60% EtOAc/Hexanes over 30 min at 35 mL/min) to give 155 mg (0.48 mmol, 100%) of difluorocyclopentane 30. The enantiomers were separated by preparative chiral chromatography (Chiralpak AD, 65/35 heptane/ethanol).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([O:41][CH:42]([CH2:45][CH3:46])[CH2:43][CH3:44])[CH2:14][C@@H:15]([OH:40])[C@@H:16]([NH:32]C(=O)OC(C)(C)C)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[NH2:32][C@@H:16]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:23]=1)[C@H:15]([OH:40])[CH2:14][N:13]([O:41][CH:42]([CH2:43][CH3:44])[CH2:45][CH3:46])[S:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)(=[O:11])=[O:12]
Reactant: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)ON(C[C@@H](O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 5 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
To an ice cold solution of tert-Butyl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(1-ethylpropoxy)amino]-1-[4-(benzyloxy)benzyl]-2-hydroxypropylcarbamate (1.5 g, 2.3 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (10 mL). After stirring at 5° C. for 3 h, the reaction was concentrated in vacuo, taken up in ethyl acetate (80 mL), washed with saturated sodium bicarbonate (2×50 mL), dried (magnesium sulfate) and concentrated in vacuo to afford the title compound (1.27 g, quant.) as an off-white foam. 1H NMR (DMSO-d6): δ 0.77 (6H, dt), 1.07-1.72 (4H, m), 1.82 (2H, br), 2.28 (1H, t), 2.58-3.05 (4H, m), 3.43-3.53 (1H, m), 3.95-4.03 (1H, m), 4.86 (1H, br s), 5.01 (2H, s), 6.16 (2H, s), 6,86 (2H, d), 7.03 (2H, d), 7.12-7.40 (8H, m);
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH3:18])[CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:18][CH:15]([CH2:16][CH3:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: CCC(C)CCCCCBr
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)CCCCCOc1ccc(O)cc1
Reaction time: 9.5 h

Procedure:
A 25 ml-flask was charged with 0.637 g of hydroquinone, 1 g of optically active 1-bromo-6-methyloctane, 0.667 g of anhydrous potassium carbonate and 4 ml of N,N-dimethylformamide, and reaction was carried out at 90° C. for 9.5 hours. After the reaction, insoluble substances were recovered by filtration and extracted with ether. The ether layer was washed with water and a saturated aqueous solution of sodium chloride and dried, and ether was removed by distillation under reduced pressure. The obtained crude product was purified by silica gel chromatography to obtain 0.32 g of optically active 4-(6'-methyloctyloxy)phenol.
Reaction SMILES: [CH:1]1([N:7]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.C([O:36][C:37](=[O:43])[CH:38](Br)[CH:39]([CH3:41])[CH3:40])C>>[CH:1]1([N:7]([C@H:19]2[CH2:20][CH2:21][C@H:22]([CH3:25])[CH2:23][CH2:24]2)[C:8](=[O:9])[NH:10][C:11]2[S:12][C:13]([S:16][CH:38]([CH:39]([CH3:40])[CH3:41])[C:37]([OH:36])=[O:43])=[CH:14][N:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)CC1
Reactant: CCOC(=O)C(Br)C(C)C
Agent: O[C@H](CS)[C@@H](O)CS
Product: CC(C)C(Sc1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
Prepared as described in general procedure (H) using 1-cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and ethyl-2-bromoisovalerate.
Reaction SMILES: [C:1]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]=1[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([O:26][CH2:27][C:28]([O:30]CC)=[O:29])[CH:20]=[CH:19]2)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+]>C(O)C.O>[C:1]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]=1[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([O:26][CH2:27][C:28]([OH:30])=[O:29])[CH:20]=[CH:19]2)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)c1c(-c2ccc3cc(OCC(=O)OCC)ccc3c2)oc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCC(=O)c1c(-c2ccc3cc(OCC(=O)O)ccc3c2)oc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.3 %

Procedure:
A mixture of ethyl 2-{[6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}acetate (0.743 g, 1.73 mmol) and 1N sodium hydroxide (2.7 mL, 2.7 mmol) in ethanol (15 mL) was stirred at room temperature for 1 hour, 10 minutes. The mixture was diluted with excess water and washed with diethyl ether. The aqueous phase was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with water and brine. It was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue crystallized from methanol and dried for 16 hours at 52° C. to afford 2-{[6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}acetic acid (0.343 g, 49%), mp 130-132° C. Mass spectrum (−APCl, [M−H]−) m/z 401; 1HNMR (400 MHz, DMSO-d6): δ13.0-13.1 (br s, 1H), 8.35 (d, 1H, J=1.5 Hz), 8.0-8.05 (m, 2H), 7.95 (d, 1H, J=8.8 Hz), 7.8 (dd, 1H, J=8.4 Hz and 1.9 Hz), 7.7 (m, 2H), 7.35-7.45 (m, 3H), 7.3 (dd, 1H, J=8.9 Hz and 2.5 Hz), 4.85 (s, 2H), 2.7 (t, 2H, J=7.4 Hz), 1.5-1.55 (m, 2H), 1.1-1.15 (m, 2H), and 0.7 ppm (t, 3H, J=7.4 Hz). Elemental Analysis for C25H22O5: Calculated: C, 74.61;H, 5.51; N, 0.00. Found: C, 74.29;H, 5.51; N, 0.05.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](O)=O)=[CH:11][C:10]=1[CH2:18][O:19][CH3:20])[CH3:2].[NH2:21][C:22](=[N:40][OH:41])[C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][CH:39]=1)[CH2:26][N:27]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH3:28]>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:41][N:40]=[C:22]([C:23]3[CH:24]=[C:25]([CH:37]=[CH:38][CH:39]=3)[CH2:26][N:27]([CH3:28])[CH2:29][C:30]([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31])[N:21]=2)=[CH:11][C:10]=1[CH2:18][O:19][CH3:20])[CH3:2]
Reactant: CN(CC(=O)OC(C)(C)C)Cc1cccc(C(N)=NO)c1
Reactant: CCc1ccccc1-c1ccc(C(=O)O)cc1COC
Product: CCc1ccccc1-c1ccc(-c2nc(-c3cccc(CN(C)CC(=O)OC(C)(C)C)c3)no2)cc1COC

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 36 and Intermediate 51. The reaction mixture was filtered through a SPE NH2 column (10 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1), affording the title compound as a pale yellow oil. 1H NMR (CDCl3) δ 8.43 (d, J=1.3 Hz, 1H), 8.19-8.16 (m, 2H), 8.11 (d, J=7.5 Hz, 1H), 7.61-7.47 (m, 2H), 7.41-7.34 (m, 3H), 7.29-7.23 (m, 1H), 7.13-7.10 (m, 1H), 4.27-4.18 (m, 2H), 3.80 (s, 2H), 3.33 (s, 3H), 3.24 (s, 2H), 2.48-2.29 (m, 5H), 1.50 (s, 9H), 1.05 (t, J=7.6 Hz, 3H). LC/MS (Method B): 528.3 (M+H)+. HPLC (Method A) Rt 5.05 min (Purity: 98.4%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH:32]([CH3:34])[CH3:33])[CH3:31])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH:32]([CH3:33])[CH3:34])[CH3:31])(=[O:28])=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)N(C)C(C)C)cc1Br
Product: Cc1ccc(S(=O)(=O)N(C)C(C)C)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 3-bromo-N-isopropyl-N,4-dimethylbenzenesulfonamide (Intermediate 103), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:21])[NH:6][C@@H:7]1[CH2:20][C:10]2[NH:11][C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][C@H:31]([OH:34])[C@H:30]1[CH2:35]OS(C)(=O)=O)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][C@H:31]([OH:34])[C@H:30]1[CH2:35][N:11]1[C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=2[C:9]2[CH2:8][C@H:7]([NH:6][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:21])[CH2:20][C:10]1=2)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1COS(C)(=O)=O
Reactant: CC(C)OC(=O)N[C@@H]1Cc2[nH]c3ccc(C#N)cc3c2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(C[C@@H]3[C@@H](O)CCN3C(=O)OC(C)(C)C)c3ccc(C#N)cc23)C1
Temperature: 60 °C
Yield: 62.3 %

Procedure:
A mixture of ((S)-7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester (1.50 g, 5.29 mmol), (2R,3S)-3-hydroxy-2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (3.13 g, 10.59 mmol), cesium carbonate (3.45 g, 10.59 mmol), and potassium iodide (88 mg, 529 μmol) in dimethylformamide (50 mL) is heated in a 60° C. oil bath for two days. After cooling to ambient temperature, the reaction is diluted with ethyl acetate (120 mL) and washed with water (3×100 mL) and brine. The organic portion is dried over sodium sulfate, filtered, and concentrated to dryness. The resulting residue is purified by medium pressure liquid chromatography, eluting with ethyl acetate:chloroform (2:8). Fractions containing pure product are combined and concentrated to afford 1.59 g (62%) of the title compound. LC-ES/MS m/z 505.2 [M+Na]+, TR=3.97 min.
Reaction SMILES: [C:1]([C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11]C2C=CC=C3C(NC(=O)C=23)=O)[CH2:5][CH2:4]1)#[N:2].[NH2:29]N>CO>[C:1]([C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][NH2:29])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(c2ccccc2)CCN(CCCc2cccc3c2C(=O)NC3=O)CC1
Reactant: NN
Solvent: CO
Product: N#CC1(c2ccccc2)CCN(CCCN)CC1
Yield: 96 %

Procedure:
To a solution of 3-(4-cyano-4-phenylpiperidin-1-yl)propylphthalimide (112 g, 0.3 mol) in methanol (1.5 L), hydrazine (30 mL) was added and the mixture was stirred and refluxed for 20 hours. It was cooled, the white solid formed was filtered and washed with more methanol (200 mL). Solvent was evaporated from the filtrate and residue was dried under vacuum for 4 hours. Chloroform (500 mL) was added to this, stirred for 1 hour and filtered. The white solid was washed with more chloroform (200 mL), the solvent was evaporated from the combined filtrates to leave the product as an oil (70 g, 96%).