Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[C:17](OC)=[O:18])=[C:7]([N+:21]([O-])=O)[CH:6]=1)=[O:4].Cl>CCOC(C)=O.[Zn]>[O:18]=[C:17]1[NH:21][C:7]2[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:10]=[CH:9][C:8]=2[N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]12
Reactant: COC(=O)c1ccc(N2CCCCC2C(=O)OC)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)NC(=O)C1CCCCN21
Temperature: 25 °C
Yield: 88.4 %

Procedure:
Methyl 1-(4-(methoxycarbonyl)-2-nitrophenyl)piperidine-2-carboxylate (1.3 g, 4.0 mmole) was dissolved in EtOAc (20 mL) and 1N HCl (20 mL) and to the solution was added Zinc (0.80 g). The reaction mixture was reflux overnight then cooled to room temperature. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed to give Methyl 6,6a,7,8,9,10-hexahydro-6-oxo-5H-pyrido[1,2-a]quinoxaline-3-carboxylate (0.92 g, 88%).
Reaction SMILES: [CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]([CH3:20])([O:16][CH2:17][C:18]#[CH:19])[CH3:15])=[CH:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH:28](I)([CH3:30])[CH3:29]>C(C(C)=O)C>[CH:28]([O:5][C:4](=[O:6])[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:8][CH2:9][CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]([CH3:20])([O:16][CH2:17][C:18]#[CH:19])[CH3:15])([CH3:30])[CH3:29]
Reactant: C#CCOC(C)(C)CCCC(C)CC=CC(C)=CC(=O)O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C#CCOC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C
Temperature: 0 °C

Procedure:
2.63 g. of 3,7,11-trimethyl-11-(2-propynyloxy)-2,4-dodecadienoic acid are dissolved in 40 ml. of methyl ethyl ketone and then treated with 2.45 g. of potassium carbonate and 6.1 g. of isopropyl iodide. The mixture is heated at reflux under a nitrogen atmosphere for 6 hours, then poured on to ice-water and extracted with ether. The extracts are washed with water and saturated sodium chloride solution, dried and evaporated. By chromatography on silica gel, there is obtained pure 3,7,11-trimethyl-11-(2-propynyloxy)-2,4-dodecadienoic acid isopropyl ester; boiling point (bulb-tube) = 122°C/0.023 mmHg; nD25 = 1.4940.
Reaction SMILES: Cl[CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[S:4]1(=[O:6])=[O:5].C1([N:21]2[C:25]([SH:26])=[N:24][N:23]=[N:22]2)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH:7]1([CH:2]([S:26][C:25]2[NH:24][N:23]=[N:22][N:21]=2)[N:3]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:4]2(=[O:6])=[O:5])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Sc1nnnn1C1CCCCC1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C1c2ccccc2S(=O)(=O)N1C(Sc1nnn[nH]1)C1CCCCC1
Yield: 81.7 %

Procedure:
A mixture of 2-(chloromethyl) saccharin (3 g, 12.9 mmol) , 1-cyclohexyl-5-mercapto-1H-tetrazole (2.37 g, 12.9 mmol) and potassium carbonate (4.45 g, 32.2 mmol) was heated under reflux in methyl ethyl ketone (50 ml) for 1 hour. The reaction mixture was cooled, poured into dilute sodium bicarbonate/ice solution and extracted twice with ethyl acetate. The combined organic extracts were washed with water, dried (Na2SO4) and freed of solvent under vacuum. Chromatography (silica gel; MDC) afforded 2 g of 2-(1-cyclohexyl-1H-tetrazol-5-ylthiomethyl) saccharin as a white foam that was crystallized from hot cyclohexane, mp 103°-105° C. 1H nmr (90 MHz, CDCl3):5.65 (2H, s). FDMS: m/e 379 (M+).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[N:13]=[C:12](Cl)[N:11]=[C:10]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=2)[CH:3]=1.[SH:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:32])[CH2:30][CH3:31])=[CH:24][CH:23]=1.C(OCC)(=O)C>C(O)(C)(C)C>[CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[N:13]=[C:12]([S:21][C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:32])[CH2:30][CH3:31])=[CH:26][CH:27]=3)[N:11]=[C:10]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=2)[CH:3]=1
Reactant: CCC(=O)Nc1ccc(S)cc1
Reactant: CCOC(=O)Cc1cc(Nc2cc(C)[nH]n2)nc(Cl)n1
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cc(Nc2cc(C)[nH]n2)nc(Sc2ccc(NC(=O)CC)cc2)n1
Temperature: 25 °C
Yield: 42.1 %

Procedure:
A suspension of Ethyl 2-(6-(5-methyl-1H-pyrazol-3-ylamino)-2-chloropyrimidin-4-yl)acetate (0.676 g, 2.29 mmol) and N-(4-mercaptophenyl)propionamide (0.415 g, 2.29 mmol) in t-butanol (10 ml) was heated under reflux overnight. Reaction mixture was then cooled to room temperature, ethyl acetate (20 ml) added causing precipitation of product. Solid was collected by filtration, washed with sat. sodium hydrogen carbonate solution, water, diethyl ether then dried by suction to leave title compound as a yellow solid (0.425 g, 43%). 1H NMR (DMSO) 1.12 (3H, t), 1.20 (3H, t), 2.00 (3H, s), 2.40 (2H, q), 3.66 (2′H, s), 4.11 (2H, q), 5.05 (1H, br s), 5.30 (1H, br s), 7.53 (2H, d), 7.79 (2H, d), 10.20 (1H, s); ES+441.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13](Cl)=[O:14].[CH3:22][NH2:23].O>CCOCC>[CH3:22][NH:23][C:13](=[O:14])[C:12]1[CH:16]=[CH:17][C:18]([N+:19]([O-:21])=[O:20])=[C:10]([S:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH:11]=1
Reactant: CN
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Solvent: CCOCC
Solvent: O
Product: CNC(=O)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-(2,4-difluorophenylthio)-4-nitrobenzoyl chloride (1.2 g) in ether (8 ml) was added to a stirred mixture of 40% methylamine (2 ml), water (8 ml) and ether (5 ml) at 0° to 5° C. The mixture was stirred at the same temperature for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, dried and concentrated. The oily residue was crystallized from a mixture of ethyl acetate and hexane to give crystals of N-methyl-3-(2,4-difluorophenylthio)-4-nitrobenzamide (0.7 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]#[C:21][CH3:22])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].Cl.Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3](=[O:23])[CH:4]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]#[C:21][CH3:22])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[CH:5]([CH3:7])[CH3:6]
Reactant: ClCCN1CCOCC1
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)C(C)C)cc1
Agent: Cl
Product: CC#CCOc1ccc(S(=O)(=O)N(CCN2CCOCC2)C(C(=O)OC)C(C)C)cc1
Yield: 90.5 %

Procedure:
According to the procedure of Example 21, 0.419 g (1.236 mmol) of 2-(4-but-2-ynyloxy-benzenesulfonylamino)-3-methyl-butyric acid methyl ester and 0.408 g (2.20 mmol) of 4-(2-chloroethyl)morpholine hydrochloride provided 0.506 g of 2-[(4-but-2-ynyloxy-benzenesulfonyl)-(2-morpholin-4-yl-ethyl)-amino]-3-methyl-butyric acid methyl ester as a colorless oil. Electrospray Mass Spec 453.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:12]1[S:11][CH2:17][C:15](=[O:16])[N:14]=1
Reactant: NCc1ccc(F)cc1Cl
Reactant: O=C1CSC(=S)N1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSC(NCc2ccc(F)cc2Cl)=N1
Temperature: 0 °C
Reaction time: 72 h
Yield: 16.5 %

Procedure:
To a solution of 2-chloro-4-fluoro-benzylamine (4.5 g, 28.19 mmol) and Rhodanine (3.75 g, 28.2 mmol) in acetonitrile (170 mL) was added DIPEA (9.82 mL, 56.4 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (8.42 g, 31.02 mmol) was added in two portions within 10 min. After addition, the suspension was allowed to warm to room temperature and stirred for 3 days. The resulting black solids were filtered through a plug of celite and washed with acetonitrile (1.0 L) and ethyl acetate (500 mL). The combined filtrates were removed under the vacuum and the crude residue was dissolved in ethyl acetate (150 mL) and washed with water and brine solution. After drying over magnesium sulfate, the filtrate was removed under the vacuum and the residue was dissolved in ethyl acetate (50 mL) at hot condition. After cooling in the refrigerator overnight, the solids were collected by filtration and washed with hexanes. After drying in air, 1.2 g (16.5% yield) of 2-(2-chloro-4-fluoro-benzylamino)-thiazol-4-one was isolated as a white amorphous solid: EI-HRMS m/e calcd for C10H8FN2OS2 (M+) 258.0030, found 258.0027.
Reaction SMILES: [F:1][C:2]([F:15])([C:8]1(O)[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>>[F:15][C:2]([F:1])([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)(F)C1(O)CCCCO1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(F)(F)C1CCCCO1
Temperature: 60 °C
Yield: 78.1 %

Procedure:
Neat 1,2-dibromoethane (0.094 g, 0.500 mmol) was added to a suspension of zinc (1.308 g, 20.00 mmol) in THF (7 mL). The reaction mixture was sonicated for 3 h and cooled to rt and was added with titanocene dichloride (0.062 g, 0.250 mmol) and stirred for 10-15 min. A solution of tetrahydro-2H-pyran-2-one (0.501 g, 5 mmol) in THF (3 ml) was added, then followed by addition of a solution of ethyl 2-bromo-2,2-difluoroacetate (1.218 g, 6.0 mmol) in THF (3 mL) and the mixture was stirred at rt overnight. The reaction was cooled (0° C.) and diluted with ether and washed with 1 N HCl, water, brine and dried (MgSO4). Evaporation of solvents afforded an oil which was purified by silica gel FCC (5-10% EtOAc in DCM) to afford ethyl 2,2-difluoro-2-(2-hydroxytetrahydro-2H-pyran-2-yl)acetate as a clear oil (365 mg, 32.5%). A neat mixture of ethyl 2,2-difluoro-2-(2-hydroxytetrahydro-2H-pyran-2-yl)acetate (˜200 mg), triethylsilane (0.799 mL, 5.00 mmol) and TFA (0.385 mL, 5.00 mmol) was heated at 60° C. for 3 h and evaporated to dryness to afford an oil which was purified by silica gel FCC (DCM0 to yield ethyl 2,2-difluoro-2-(tetrahydro-2H-pyran-2-yl)acetate as a clear oil (145 mg, 78%) which was saponified (1 N NaOH, THF-MeOH, rt) to provide Cap P-35 as a white solid (75 mg, 83%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.35-7.13 (m, 1H), 4.14-4.05 (m, J=11.2, 4.3 Hz, 1H), 3.95-3.82 (m, 1H), 3.57-3.47 (m, J=11.7, 11.7, 2.3 Hz, 1H), 2.05-1.94 (m, 1H), 1.86-1.76 (m, 1H), 1.73-1.50 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:38])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH3:37])=[CH:30][CH:29]=1)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:38])[C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH3:37])=[CH:30][CH:29]=3)[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: CCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Product: CCCCc1ccc(C(=O)NCCn2cc(CCCCCc3cn(C(=O)OC(C)(C)C)c(N)n3)nn2)cc1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.123 g, 0.443 mmol) was reacted with N-(2-azidoethyl)-4-butylbenzamide (0.109 g, 0.443 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(4-butylbenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H), δ 7.67 (d, J=7.5 Hz, 2H), δ 7.29 (s, 1H), δ 7.11 (d, J=7.5 Hz, 2H), δ 6.42 (s, 1H), δ 6.25 (s, 2H), δ 4.48 (s, 2H), δ 3.83 (s, 2H), δ 2.56 (t, J=7.2 Hz, 4H), δ 2.21 (s, 2H), 1.47 (m, 13H), δ 1.21 (m, 4H), δ 0.83 (t, J=7.2 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ168.3, 140.6, 149.5, 148.2, 147.1, 138.4, 131.5, 128.7, 127.4, 122.2, 106.4, 84.9, 49.4, 40.2, 35.7, 33.5, 29.2, 28.9, 28.3, 28.1, 27.9, 25.5, 22.4, 14.1 ppm; HRMS (ESI) calcd for C28H41N7O3 (M+) 523.3271. found 523.3261, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-4-butylbenzamide hydrochloride (0.191 g, 94% yield). 1H NMR (300 MHz, CD3OD) δ 8.43 (s, 1H), δ 7.69 (s, 2H), δ 7.22 (s, 2H), δ 6.44 (s, 1H), δ 4.73 (s, 2H), δ 3.89 (s, 2H), δ 3.34 (s, 2H), δ 2.59 (s, 4H), δ 2.41 (s, 2H), δ 1.54 (s, 4H), δ 1.29 (s, 4H), δ 0.88 (t, J=6.9 Hz, 3H) ppm; 13C NMR (75 MHz, CD3OD) δ 169.2, 165.1, 160.3, 158.1, 147.4, 141.4, 131.2, 128.5, 127.7, 127.3, 126.9, 92.9, 39.6, 36.3, 33.4, 30.9, 28.0, 27.7, 24.1, 22.2, 13.2, 12.1, 10.9, 8.9, 6.2, 2.5 ppm; HRMS (ESI) calcd for C23H33N7O (M+) 423.2747. found 423.2738.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([CH2:18][C:19]([OH:21])=[O:20])[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])=[C:4]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:3]=1.[CH3:28]O>Cl.O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([CH2:18][C:19]([O:21][CH3:28])=[O:20])[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])=[C:4]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:3]=1
Reactant: CO
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1cc(CC(=O)O)ccc1OC
Agent: Cl
Solvent: C1COCCO1
Product: CCCCCNc1nc(N)nc(C)c1Cc1cc(CC(=O)OC)ccc1OC

Procedure:
A solution of the product from step (iv) (135 mg) in MeOH (5 ml) and 4M HCl in dioxane (0.5 ml) was stirred at rt for 18 h. The solvent was evaporated and the residue purified by RPHPLC to give the title compound as a solid, 31 mg.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.[I:11]I.S([O-])([O-])=O.[Na+].[Na+]>CO.O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[C:3]=1[I:11]
Reactant: II
Reactant: Oc1ccc2ncsc2c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Oc1ccc2ncsc2c1I
Temperature: 25 °C
Reaction time: 48 h
Yield: 29.5 %

Procedure:
6-Hydroxy-benzothiazole (0.39 g) and iodine (1.32 g) were dissolved in methanol/water (15 ml/5 ml) to prepare a solution which was then stirred at room temperature for 2 days. An aqueous sodium sulfite solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give 6-hydroxy-7-iodo-benzothiazole (211 mg, yield 29%).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>CCOCC>[NH2:9][CH2:8][C:7]1[CH:10]=[CH:11][C:12]([C:14]([F:15])([F:16])[F:17])=[CH:13][C:6]=1[O:5][CH2:4][CH2:3][N:2]([CH3:18])[CH3:1]
Reactant: CN(C)CCOc1cc(C(F)(F)F)ccc1C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CN(C)CCOc1cc(C(F)(F)F)ccc1CN
Temperature: 0 °C
Yield: 67.7 %

Procedure:
The nitrile 26b (2.15 g, 8.33 mmol) solubilized in Et2O (20 mL) was added in small portion to a mixture of LiAlH4 (0.63 g, 2 mol eq) in Et2O (25 mL) stirred at 0° C. Then the mixture was stirred at room temperature overnight. The excess of LiAlH4 was decomposed by water addition at 0° C., the solid formed was filtered, washed with Et2O and the filtrate was separated. The organic phase was anhydrified over Na2SO4 and evaporated to dryness to obtain 27b as yellow oil (1.48 g, 5.64 mmol, 67% Yield) used without further purifications.
Reaction SMILES: C(OC([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[C:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)=O)C.[OH-].[Na+].Cl>CCO.C1COCC1>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[C:27]2[CH2:28][C:29]([CH3:36])([CH3:35])[CH2:30][C:31]([CH3:34])([CH3:33])[CH2:32]2)[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)C#Cc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(OC(=O)OCC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(C#CC(=O)O)cc2)CC(C)(C)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
To a solution of ethyl 3-{4-[(4-{[(ethyloxy)carbonyl]oxy}phenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propynoate (148) (88 mg, 0.18 mmol) in a mixture of EtOH (4 mL) and THF (4 mL) was added an aqueous solution of 1 N NaOH (5 mL). The mixture was stirred at 60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 1 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract was washed with water, brine and dried over Na2SO4. Upon concentration and trituration with hot 1:1 hexanes/ether (contained 1% of methanol), (35 mg (50%) of compound 149 was obtained as white solid. mp 172-174° C. (dec.). 1H NMR (400 MHz, DMSO-d6): δ 0.86 (s, 6H), 0.87 (s, 6H), 1.24 (s, 2H), 1.85 (s, 2H), 1.91 (s, 2H), 6.66 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.1 Hz, 2H), 7.52 (d, J=8.1 Hz, 2H), 9.31 (s, 1H), 13.73 (s, 1H). HRMS (EI) Calcd for C32H44O3Si2: 532.2829 (M+.); Found: 532.1591.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1I)[CH3:2].[CH3:15][O:16][CH2:17][C:18]#[CH:19].CCN(CC)CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(#N)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:19]#[C:18][CH2:17][O:16][CH3:15])[CH3:2]
Reactant: C#CCOC
Reactant: CCOC(=O)COc1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccccc1C#CCOC
Reaction time: 4 h

Procedure:
A three neck reaction flask was successively charged with 12.65 g (41.3 mmol) of the above prepared (2-iodo-phenoxy)-acetic acid ethyl ester, 128 ml of acetonitrile, 5.793 g (2 eq.) of 3-methoxy-1-propyne, 17.28 ml (3 eq.) of NEt3, 1.45 g (0.05 eq.) of (PPh3)2PdCl2, and 0.394 g (0.05 eq.) of CuI. After stirring for 4 h the bulk of the solvent was removed i. V. and the residue distributed between HCl and AcOEt. Washing of the organic layer with cold water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=8/2), yielded 9.54 g of the title compound as light brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22]1([CH2:28][C:29](O)=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:29](=[O:30])[CH2:28][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)CC1
Reactant: O=C(O)CC1CCCCC1
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2ccccc2)C(=O)CC2CCCCC2)CC1
Yield: 84.3 %

Procedure:
Using general procedure E, 4-benzylamino-piperidine-1-carboxylic acid tert-butyl ester (300 mg, 1.03 mmol) and cyclohexylacetic acid (161 mg, 1.13 mmol) afforded 4-[benzyl-(2-cyclohexyl-acetyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (360 mg, 85%).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[O:14][CH2:15][CH3:16])C>CCO>[CH2:15]([O:14][C:8]1[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=1[C:6]([OH:17])=[O:5])[CH3:16]
Reactant: CCOC(=O)c1ccc(F)cc1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cc(F)ccc1C(=O)O
Temperature: 40 °C
Reaction time: 18 h
Yield: 90.5 %

Procedure:
A 5M solution of sodium hydroxide (6.5 mL; 32.5 mmol; 3 eq.) was added to a solution of 2-ethoxy-4-fluoro-benzoic acid ethyl ester (2.3 g; 10.8 mmol; 1 eq.) in EtOH (46 mL) and the resulting mixture was stirred at 40° C. for 18 hours then concentrated in vacuo. The residue was taken up in water and the pH made acidic with 5M HCl. The precipitate was filtered off, washed with water and dried to afford the title compound (1.8 g, 90%) as a white solid. 1H NMR (DMSO-d6) δ 12.56 (s, 1H), 7.71 (dd, J=7.0, 8.6 Hz, 1H), 7.01 (dd, J=2.4, 11.7 Hz, 1H), 6.80 (dt, J=2.4, 8.5 Hz, 1H), 4.09 (q, J=7.0 Hz, 2H), 1.32 (t, J=7.0 Hz, 3H). HPLC (max plot) 99.3%; Rt 2.71 min. UPLC/MS: (MS+) 185.2 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH2:19][NH2:20])[CH:16]=[N:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:20][CH2:19][C:15]1[CH:16]=[N:17][CH:18]=[C:13]([F:12])[CH:14]=1
Reactant: NCc1cncc(F)c1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Br)cc1NCc1cncc(F)c1
Temperature: 80 °C

Procedure:
A mixture of 4-bromo-2-fluoro-1-nitrobenzene (1.20 g, 5.45 mmol), (5-fluoropyridin-3-yl)methanamine (757 mg, 6.0 mmol) and potassium carbonate (3.015 g, 21.82 mmol) in N,N-dimethylformamide (8 mL) was heated at 80° C. for 1 hour. After cooling, the mixture was diluted with ethyl acetate and the mixture was washed with water and brine, dried over magnesium sulfate, filtered and concentrated to give the crude title compound which was used without further purification. MS (ESI) m/z 327 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11].Br[C:20]1[CH:24]=[C:23]([C:25]([OH:27])=[O:26])[O:22][N:21]=1>>[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:20]2[CH:24]=[C:23]([C:25]([OH:27])=[O:26])[O:22][N:21]=2)[CH2:15][CH2:14]1)=[O:11]
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Reactant: O=C(O)c1cc(Br)no1
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)on3)CC2)c(Cl)c1Cl
Yield: 33.6 %

Procedure:
The title compound was prepared via the procedure described in Example 1 from 182 mg (0.5 mmol) of 3,4-dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 1) and 103 mg (0.54 mmol) of 3-bromoisoxazole-5-carboxylic acid (Intermediate 120), to afford the title compound as a white solid, (65 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[C@H:6]([CH2:7][OH:8])[C:5]1([CH3:23])[C:9]1[CH:18]=[CH:17][C:16]2[C:15]([CH3:20])([CH3:19])[CH2:14][CH2:13][C:12]([CH3:22])([CH3:21])[C:11]=2[CH:10]=1.[CH2:24](I)C>>[CH2:1]([O:2][CH2:3][CH:4]1[C@H:6]([CH2:7][OH:8])[C:5]1([CH3:23])[C:9]1[CH:18]=[CH:17][C:16]2[C:15]([CH3:20])([CH3:19])[CH2:14][CH2:13][C:12]([CH3:22])([CH3:21])[C:11]=2[CH:10]=1)[CH3:24]
Reactant: COCC1[C@H](CO)C1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCI
Product: CCOCC1[C@H](CO)C1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 78 %

Procedure:
Following a procedure similar to that for the preparation of Intermediate 6a using Intermediate 4 as the starting material and ethyl iodide as alkylating reagent yielded the title compound as a colorless oil (69 mg, 78% yield):
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[C:3]([O:5][CH3:6])=[O:4].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].CCN(CC)CC.OS([O-])(=O)=O.[Na+]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[C:2]([CH3:9])([CH3:1])[CH2:7][O:8][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)C(C)(C)CO
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.5 %

Procedure:
Methyl 2,2-dimethyl-3-hydroxypropionate (1.32 g), tert-butyldimethylsilyl chloride (1.8 g), 4-dimethylaminopyridine (122 mg) and NEt3 (1.67 ml) were dissolved in DCM (100 ml) and stirred for 16 h at RT. A NaHSO4 solution was added, and the org. phase was further washed with water, dried (Na2SO4) and evaporated off. Column chromatography (EA/Hept 1/4) afforded 800 mg of the desired compound.