Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][CH2:2]1.Cl[C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][N:27]=2)[N:24]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:30][C:28]([F:29])([F:31])[C:25]1[N:23]2[N:24]=[C:19]([N:1]3[CH2:6][CH2:5][CH:4]([C:7]4[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=4)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][CH2:2]3)[CH:20]=[CH:21][C:22]2=[N:27][N:26]=1
Reactant: CCOC(=O)c1cccc(C2CCNCC2)c1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1
Temperature: 125 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
Ethyl 3-(piperidin-4-yl)benzoate (1.195 g, 5.12 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (1 g, 4.49 mmol) and DIPEA (1.174 mL, 6.74 mmol) in DMA (10 mL). The resulting solution was stirred at 125° C. for 2 hours. The reaction mixture was evaporated to dryness, redissolved in DCM and purified by flash silica chromatography, eluting with 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to give a beige solid, which was triturated with ether to give ethyl 3-[1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl]benzoate (0.805 g, 42.7%) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1>[Pd].C1COCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1cccc(O)c1)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(CCc1cccc(O)c1)c1ccccc1

Procedure:
The title compound was prepared as described in General Method 3 from 3-(3-hydroxy-phenyl)-1-phenyl-prop-2-en-1-one (8.0 g, 35.7 mmol), 5% Pd on BaSO4 (0.4 g), and THF (100 mL) at a reaction time of 2 hours. The crude product was purified by silica gel chromatography, eluting with EtOAc:hexane (10:90 to 25:75) to give the title compound, m.p. 81°-83° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH2:12][CH2:13][CH3:14])[CH2:8][O:9]2)=[CH:4][C:3]=1[F:15].C([Li])CCC.[I:21]I>C1COCC1.CCCCCC>[F:15][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[I:21])[O:9][CH2:8][CH:7]([CH2:12][CH2:13][CH3:14])[CH2:6]2
Reactant: II
Reactant: CCCC1COc2cc(Br)c(F)cc2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC1COc2cc(I)c(F)cc2C1
Reaction time: 1.5 h

Procedure:
10.6 g (38.8 mmol) of 7-bromo-6-fluoro-3-propylchroman are initially introduced in 100 ml of THF, and 27 ml (43.0 mmol) of a 15 percent solution of n-butyllithium in hexane are added dropwise. After 90 min, 10.0 g (39.4 mmol) of iodine, dissolved in 50 ml of THF, are added, the mixture is stirred for 1 h, and the cooling is removed. The batch is diluted with MTB ether, washed with water and with sat. sodium hydrogensulfite soln. and dried over sodium sulfate. The solvent is removed in vacuo, and the crude product is filtered through silica gel with heptane/toluene (4:1), giving 6-fluoro-7-iodo-3-propylchroman as a colourless solid, which is sufficiently pure for further reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:14][NH2:15]>CO.[Pd]>[CH3:14][NH:15][CH2:5][C:4]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][O:11][C:10]=2[C:3]=1[O:2][CH3:1]
Reactant: CN
Reactant: COc1c(C=O)ccc2c1OCO2
Agent: [Pd]
Solvent: CO
Product: CNCc1ccc2c(c1OC)OCO2
Reaction time: 2 h
Yield: 100 %

Procedure:
5.0 g of 2-methoxy-3,4-methylenedioxybenzaldehyde was suspended in 30 ml of methanol, to which 4.31 g of 40% methylamine aqueous solution (2 equivalent) was added. 59 mg of 5% Pd/C catalyst (0.1 mol %) was added to the obtained reaction mixture and hydrogenation was carried out at ordinary temperature and atmospheric pressure. Absorption of hydrogen was completed in about 2 hours to quantitatively obtain N-methylbenzylamine derivative. The catalyst was filtered out and excessive methylamine, water formed and methanol solvent were distilled off to obtain an oily N-methyl-2-methoxy-3,4-methylenedioxybenzylamine. (Yield 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:35][CH3:36])=[C:19]([CH2:23][N:24]4[CH2:29][CH2:28][CH:27]([C:30]([O:32]CC)=[O:31])[CH2:26][CH2:25]4)[CH:20]=[CH:21][CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:35][CH3:36])=[C:19]([CH2:23][N:24]4[CH2:25][CH2:26][CH:27]([C:30]([OH:32])=[O:31])[CH2:28][CH2:29]4)[CH:20]=[CH:21][CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)C1CCN(Cc2cccc(-c3cnc(-c4ccc(OC(C)C)c(Cl)c4)s3)c2CC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCc1c(CN2CCC(C(=O)O)CC2)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To a solution of ethyl 1-{[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]methyl}-4-piperidinecarboxylate (D85) (160 mg) in isopropanol (40 mL) and water (10 mL) stirred under nitrogen at room temperature was added a solution of NaOH (24.3 mg) in water in one charge. The reaction mixture was stirred at room temperature overnight. Isopropanol was removed in vacuo. The residue was dissolved in water and acidified with 1N HCl to pH=5. The solvent was removed in vacuo, the residue was dissolved in THF, and filtered. The filtrate was purified by Mass Directed AutoPrep to give 1-{[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]methyl}-4-piperidinecarboxylic acid (E36) (73 mg) as a TFA salt (white solid). δH (DMSO-d6, 400 MHz): 1.02 (3H, t), 1.34 (6H, d), 1.78 (2H, m), 2.05 (2H, m), 2.54 (1H, m), 2.83 (2H, m), 3.18 (2H, m), 3.45 (2H, m), 4.42 (2H, m), 4.80 (1H, m), 7.32 (1H, d), 7.44 (2H, m), 7.63 (1H, d), 7.87 (2H, m), 7.99 (1H, d), 9.28 (1H, br s), 12.59 (1H, br s). δF (DMSO-d6, 376 MHz): −74.0. MS (ES): C27H31ClN2O3S requires 498. found 499.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])[C:5]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[O:9])=[N:6][CH:7]=1.Cl.O1CCOC[CH2:36]1>CO>[CH3:36][O:13][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[C:8]([C:5]1[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:21])=[O:22])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:9]
Reactant: O=C(O)c1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A mixture of 2-[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]benzoic acid (20 mg), 4N HCl/dioxane (1 mL) and 1.5 mL of methanol was refluxed overnight. After cooled to room temperature, the mixture was concentrated and the residue was diluted with ethyl acetate, washed with sodium bicarbonate and brine and dried. Removal of the solvents afforded the title compound as an off white solid: 1H NMR: (CDCl3, ppm) δ 11.20 (s, 1H), 8.22 (m, 2H), 8.04 (m, 2H), 7.94 (m, 1H), 7.62 (m, 2H), 7.54 (m, 1H), 7.31 (m, 1H), 3.54 (s, 3H); MS: (M+H)/z=533.0.
Reaction SMILES: [Br:1][C:2]1[CH2:6][C:5](/[C:7](=[CH:11]/[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)/[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[C:18](Cl)(=O)C(Cl)=O.CO>C1COCC1.CN(C=O)C>[CH3:18][O:9][C:8](=[O:10])/[C:7](/[C:5]1[CH2:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[CH:11]\[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(O)/C(=C\C1CCCCC1)C1=CC=C(Br)C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)/C(=C\C1CCCCC1)C1=CC=C(Br)C1
Yield: 111.1 %

Procedure:
Dissolve (Z)-2-(4-bromo-cyclopenta-1,3-dienyl)-3-cyclohexyl-acrylic acid (124 g, max. 0.338 mol) in dry THF (500 mL) and DMF (2 mL) and cool with an ice bath. Add oxalylchloride (51.5 g, 0.406 mol) slowly and stir 1 h 30 min after addition at 0-10° C. Add MeOH (500 mL) and stir 1 h at ambient temperature. Concentrate the reaction mixture and dilute residue with ethylacetate (600 mL) and add water (400 mL). Extract aqueous phase with ethylacetate and wash combined organic layers with saturated sodium chloride, dry over sodium sulfate and remove-solvents under vacuum to get 116.9 g crude product. MS (m/e): 329.0/331.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[N:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:29]([C:31]1[CH:32]=[C:33]([S:38](Cl)(=[O:40])=[O:39])[CH:34]=[CH:35][C:36]=1[F:37])#[N:30].[NH4+].[Cl-]>C1COCC1>[C:29]([C:31]1[CH:32]=[C:33]([S:38]([N:6]([CH2:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]=2[O:2][CH3:1])[C:7]2[N:8]=[N:9][CH:10]=[CH:11][CH:12]=2)(=[O:40])=[O:39])[CH:34]=[CH:35][C:36]=1[F:37])#[N:30]
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Reactant: COc1ccc(CNc2cccnn2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2cccnn2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a suspension of N-(2,4-dimethoxybenzyl)pyridazin-3-amine (Preparation 19, 1.0 g, 4.00 mmol) in THF (15 mL) at −20° C. was slowly added LiHMDS (1M, 4.0 mL, 4.00 mmol). The reaction mixture was left to stir at −20° C. for 30 minutes and then cooled to −78° C. To the reaction mixture was slowly added 3-cyano-4-fluorobenzene-1-sulfonyl chloride (0.8 g, 3.64 mmol) suspended in THF (15 mL). The reaction mixture was slowly warmed to room temperature and left at room temperature for 18 hours. To the vessel was added saturated aqueous NH4Cl solution (30 mL) and the product was extracted with EtOAc (25 mL). The organic layer was washed with saturated brine (40 mL), dried over MgSO4, and the solvent removed under vacuum. The residue was purified using silica gel column chromatography eluting with 70% EtOAc in heptanes to afford the title compound as an orange oil (561 mg, 36%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH2:23][NH2:24])[N:9]=1.[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([CH2:43][C:44](O)=[O:45])=[CH:35]1.CN(C)CCCN=C=NCC.Cl.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:27]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH2:23][NH:24][C:44](=[O:45])[CH2:43][C:36]2[C:37]3[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=3)[NH:34][CH:35]=2)[N:9]=1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: NCCCn1nc(CCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n(Cc2ccccc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1c[nH]c2ccccc12)NCCCn1nc(CCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n(Cc2ccccc2)c1=O
Reaction time: 16 h
Yield: 79.4 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenethyl)-4-benzyl-1-(3-aminopropyl)-5-oxo-1,2,4-triazole (Example 2, 0.500 g, 0.0010 mol) was dissolved in dichloromethane (20 ml) and indole-3-acetic acid (0.222 g, 0.00127 mol), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide.HCl (0.244 g, 0.00127 mol), hydroxybenzotriazole (0.171 g, 0.00127 mol) and triethylamine (0.7 ml, 0.005 mol) added. The reaction was stirred for 16 hours, diluted with ethyl acetate (50 ml), washed with 10% citric acid solution, saturated sodium bicarbonate solution and brine. The organic layer was dried (MgSO4) and solvent evaporated. The residue was chromatographed on silica eluting with ethyl acetate then 1% methanol/ethyl acetate, to give the title compound as a pale yellow solid (0.500 g 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[CH:12]=[CH:13][C:14](=[O:16])[CH3:15].[BH4-].[Na+].O>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[CH:12]=[CH:13][CH:14]([OH:16])[CH3:15]
Reactant: COc1cc([N+](=O)[O-])ccc1C=CC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc([N+](=O)[O-])ccc1C=CC(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a suspension of 4-(2-methoxy-4-nitrophenyl)but-3-en-2-one (12.2 g; 55.2 mmol) in 150 mL of ethanol at rt was added NaBH4 (2.30 g; 60.7 mmol) over 5 minutes. The suspension was stirred at rt for 1 h, diluted with 1M NaHPO4 (˜60 mL) followed by water (100 mL) and concentrated under reduced pressure to remove ethanol. After extracting the aqueous residue with CH2Cl2, the organic layer was washed with water and brine, dried over anhydrous MgSO4, filtered. Concentration of the filtrate under reduced pressure afforded 12.3 g (100%) of the title compound as a dark, red gum. HPLC (Method #1) 3.68 min retention time, (50%); MS (ES): m/z 206 [M−OH]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@@H:10]([C:28](=[O:42])[NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=2)[CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[F:41][C:38]([F:39])([F:40])[O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][NH:29][C:28]([C@H:10]2[CH2:9][NH:8][CH2:13][CH2:12][N:11]2[S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:26])[F:27])=[CH:19][CH:18]=2)(=[O:15])=[O:16])=[O:42])=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)[C@@H](C(=O)NCc2ccc(OC(F)(F)F)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CNCCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.9 %

Procedure:
4N Hydrogen chloride/1,4-dioxane solution (40 ml) was added to the compound (2.20 g) obtained in Step 3, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned by adding chloroform and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium carbonate, filtrated, and concentrated under reduced pressure. The residue was crystallized from a mixed solvent of diisopropyl ether and n-hexane, collected by filtration and dried to give the title compound (1.57 g).
Reaction SMILES: [N:1]([CH2:4][CH:5]([CH2:24][CH:25]([O:27][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:26])[CH2:6][S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[N+]=[N-].C(OC(C)CC(COC(=O)NCCCCCCCCCCCCCCCCCC)CN)(=O)C1C=CC=CC=1>[Pd].CO>[C:28]([O:27][CH:25]([CH3:26])[CH2:24][CH:5]([CH2:6][S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:4][NH2:1])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCCCCCCCCCCCCCCCSCC(CN=[N+]=[N-])CC(C)OC(=O)c1ccccc1
Agent: [Pd]
Agent: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)CC(C)OC(=O)c1ccccc1
Solvent: CO
Product: CCCCCCCCCCCCCCCCSCC(CN)CC(C)OC(=O)c1ccccc1

Procedure:
A mixture is 1.291 g (2.56 mM) of 1-azido-2-(2-benzoyloxypropan-1-yl)-3-n-hexadecylthiopropane m12b, 130 mg of 10% palladium on charcoal in 130 ml of methanol is hydrogenated by the same procedure as described in (129) and crude product of the titled compound m13 is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[NH:14][N:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:28][CH2:29][CH2:30][F:31])(=O)=O>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:28][CH2:29][CH2:30][F:31])[N:13]=[N:12]1
Reactant: CS(=O)(=O)OCCCF
Reactant: O=c1[nH]nnn1-c1ccc([N+](=O)[O-])cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(CCCF)nnn1-c1ccc([N+](=O)[O-])cc1F
Temperature: 60 °C
Yield: 60.8 %

Procedure:
A stirred mixture of 28.0 g (0.124 mole) of 1-(2-fluoro-4-nitrophenyl)-1,4-dihydro-5H-tetrazol-5-one, 19.3 g (0.140 mole) of potassium carbonate, and 21.8 g (0.140 mole) of 3-fluoropropyl methanesulfonate in 100 mL of dimethylformamide was heated at 60° C. for approximately 18 hours. The reaction mixture was poured into icewater, and the resultant fixture was extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure leaving a residue. This residue was purified by column chromatography on silica gel, eluting with methylene chloride, to yield 21.5 g of 1-(2-fluoro-4-nitrophenyl)-4-(3-fluoropropyl)-1,4-dihydro-5H-tetrazol-5-one as a solid, m.p. 86°-89° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:18]([O-:20])=[O:19])=[C:7]([N:9](S(C)(=O)=O)[S:10]([CH3:13])(=[O:12])=[O:11])[CH:8]=1.O1CCCC1.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:18]([O-:20])=[O:19])=[C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:8]=1
Reactant: COc1ccc([N+](=O)[O-])c(N(S(C)(=O)=O)S(C)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])c(NS(C)(=O)=O)c1
Reaction time: 18 h

Procedure:
To a solution of N-(5-Methoxy-2-nitro-phenyl)-N-(methylsulfonyl) methanesulfonamide (7.70 g) in Tetrahydrofuran (200 mL, 2 mol) was added 1 M of Sodium hydroxide in Water (50 mL). The mixture was stirred for 18 hours. The mixture was poured into a separatory funnel and the aqueous layer (bottom layer) was separated. The aqueous layer was washed with Ethyl Acetate (100 mL). The organic layers were combined, dried over magnesium sulfate, filtered and evaporated. N-(5-Methoxy-2-nitro-phenyl)-methanesulfonamide isolated as an orange solid (5.59 g, 76%).
Reaction SMILES: Cl.[C:2]([C:4]([CH3:24])([CH3:23])[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19]COC)[CH:13]=1)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:3]>CO.C(OCC)(=O)C.O>[C:2]([C:4]([CH3:23])([CH3:24])[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][OH:19])[CH:13]=1)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:3]
Reactant: CCOC(=O)CC(c1cccc(COCOC)c1)C(C)(C)C#N
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CC(c1cccc(CO)c1)C(C)(C)C#N
Temperature: 60 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
Conc. hydrochloric acid (1.10 mL) was added to a solution of ethyl 4-cyano-3-(3-((methoxymethoxy)methyl)phenyl)-4-methylpentanoate (210 mg) in methanol (2 mL) at room temperature, and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was diluted with ethyl acetate, water was added at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a mixture (147 mg) of the title compound and methyl ester thereof. This compound was used for the next step without further purification.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].ClCCCl.[S:13](=O)(=[O:16])([OH:15])[OH:14].C(C(CCCC)C([O-])=O)C.[K+:28]>C(OCC)(=O)C>[K+:28].[OH:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[S:13]([O-:16])(=[O:15])=[O:14]
Reactant: O=S(=O)(O)O
Reactant: Oc1ccc(O)cc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: O=S(=O)([O-])c1cc(O)ccc1O
Temperature: 12.5 °C
Reaction time: 0.21 h
Yield: 87.6 %

Procedure:
Hydroquinone (10 g, 0.09 mol) and 1,2-dichloroethane (30 mL) was taken in a round bottom flask, after cooling the flask to about 10-15° C., sulfuric acid (36 N, 8.9 g) was added dropwise at the same temperature and stirring continued further for about 10-15 min. Temperature was slowly raised to 40° C. then stirred for 3-8 h. The reaction mass was then cooled to 25-35° C. and ethyl acetate (100 mL) added to dissolve the solid formed. A solution of potassium 2-ethylhexanoate (18.2 g, 0.099 mol) in ethyl acetate (100 mL) was added slowly. The reaction was further stirred for an hour. The precipitated crude solid was filtered, washed with ethyl acetate to give 18 g of 2,5-dihydroxybenzenesulfonic acid potassium salt.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[I-:16].CN[C@@H]1CCCC[C@H]1NC.[I-].[Na+]>O1CCOCC1>[I:16][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: [I-]
Reactant: CC1(c2cccc(Br)c2)COCC(=O)N1
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(c2cccc(I)c2)COCC(=O)N1
Temperature: 110 °C

Procedure:
A mixture of (RS)-5-(3-bromo-phenyl)-5-methyl-morpholin-3-one (X-1) (2.0 g), cupper(I) iodide (72 mg), trans-N,N′-dimethyl-1,2-cyclohexandiamine (105 mg), and sodium iodide (2.22 g) in dioxane (20 ml) was heated at 110° C. over the weekend. The reaction mixture was evaporated at reduced pressure and the residue directly transferred to column chromatography on silica using a gradient of dichloromethane/methanol=100/0 to 75/25 as the eluent. The (RS)-5-(3-iodo-phenyl)-5-methyl-morpholin-3-one was obtained as a light green solid (2.26 g, 96% of theory). MS (ISP): m/z=318.2 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCN(CC)CC.[NH:23]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:24]([C:28](ON1C(=O)CCC1=O)=[O:29])[CH:25]([CH3:27])[CH3:26].C(O)(=O)C>CN(C=O)C.C(Cl)(Cl)Cl>[NH:23]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[C@H:24]([C:28]([NH:1][C@H:2]([C:13]([OH:15])=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:29])[CH:25]([CH3:26])[CH3:27]
Reactant: C[C@@H](OCc1ccccc1)[C@H](N)C(=O)O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)O)[C@@H](C)OCc1ccccc1
Reaction time: 24 h

Procedure:
A suspension of H-Thr(Bzl)-OH (3.0 g, 14.34 mmol) in DMF (60 ml) was mixed with Et3N (2 ml) and Boc-Val-OSu (4.96 g, 15.78 mmol) at 0° C for 2 hours and then at 25° C for 24 hours. Acetic acid was added to about pH 3 and the solvents removed under reduced pressure. The product was extracted into EtOAc, washed with 5% AcOH and water, dried (MgSO4) and evaporated to clear oil which crystallized from EtOAc with petroleum ether to yield 4.9 g (83.1%); mp 132°-135° C; [α]D25 +21.5° (c, 1, CHCl3). Anal. Calcd for C21H32N2O6 (408.49): C, 61.74; H, 7.89; N, 6.85. Found: C, 61.61; H, 7.76; N, 6.80.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][CH:8]=1)[CH2:5][CH3:6].[OH-].[Na+].Cl>CCO.O>[CH2:14]([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH:4]([CH2:5][CH3:6])[C:3]([OH:18])=[O:2])=[CH:12][CH:11]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCOc1ccc(C(CC)C(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCOc1ccc(C(CC)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
(Scheme 2, Compound F) To a solution of 2-(4-butoxy-phenyl)-butyric acid methyl ester (2.0 g, 8.0 mmol) in EtOH (30 mL) was added NaOH (10 N, 6 mL, 60 mmol). The resulting mixture was stirred at rt for 3 hours, diluted with H2O (30 mL), acidified to pH˜1.0 using HCl (6N). The precipitates were filtered off by filter paper, washed by H2O and hexanes. This compound was obtained as a white solid. (1.4 g, 5.9 mmol, 74% yield). 1H NMR (DMSO-d6) δ 12.20 (br. s, 1H), 7.16 (d, 2H, J=7.0 Hz), 6.87 (d, 2H, J=8.5 Hz), 3.92 (t, 2H, J=6.5 Hz), 3.31 (t, 2H, J=6.9 Hz), 1.93 (m, 1H), 1.63 (m, 3H), 1.42 (m, 2H), 0.97 (t, 3H, J=7.2 Hz), 0.79 (t, 3H, J=4.0 Hz).