Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[CH:10]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16](B(O)O)[CH:17]=1)=[O:11].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(COC)OC>[CH3:22][O:21][C:15]1[C:16]([C:2]2[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=2[CH3:9])=[CH:17][C:12]([CH:10]=[O:11])=[CH:13][CH:14]=1
Reactant: Cc1cccc(C)c1Br
Reactant: COc1ccc(C=O)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COc1ccc(C=O)cc1-c1c(C)cccc1C
Temperature: 80 °C
Reaction time: 25 h

Procedure:
In an atmosphere of nitrogen, tetrakis(triphenylphosphine)palladium was added to a mixture of 2-bromo-1,3-dimethylbenzene, (5-formyl-2-methoxyphenyl)boronic acid, a 1 M sodium carbonate aqueous solution, ethanol and dimethoxyethane, followed by stirring at 80° C. for 25 hours to obtain 6-methoxy-2′,6′-dimethylbiphenyl-3-carbaldehyde.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[CH3:7][P:8]([CH3:25])([CH2:10][CH2:11][NH:12][CH2:13][C:14]([S:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:16])[CH3:15])=[S:9].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:18]([S:17][C:14]([CH3:16])([CH3:15])[CH2:13][N:12]([CH2:11][CH2:10][P:8]([CH3:25])([CH3:7])=[S:9])[C:4](=[O:5])[CH2:3][O:2][CH3:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COCC(=O)Cl
Reactant: CC(C)(CNCCP(C)(C)=S)SCc1ccccc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COCC(=O)N(CCP(C)(C)=S)CC(C)(C)SCc1ccccc1
Reaction time: 1 h
Yield: 65.3 %

Procedure:
Methoxyacetyl chloride (1.03 g) in dry toluene (10 cm3) was added dropwise to a stirred solution of N-(2-dimethylphosphinothioylethyl)-2-benzylthio-2-methylpropylamine (3 g) and pyridine (1.2 cm3) in dry toluene (70 cm3) at 0° C. After stirring for 1 h the mixture was filtered and the volatile components removed under reduced pressure (40° C. at 0.05 mmHg) to give the amide (2.4 g, 65%) as a yellow oil which solidified on standing. An analytically pure sample of the amide (m.p. 91°-92° C.) was obtained by recrystallisation from ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:28][O:29][CH2:30][C:31](Cl)=[O:32]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:31](=[O:32])[CH2:30][O:29][CH3:28])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: COCC(=O)Cl
Product: COCC(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and methoxyacetyl chloride (16 mg, 150 μmol). Yield 18 mg (86%).
Reaction SMILES: C(#N)C.[F:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[OH:13])[CH:8]=[O:9].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:16]([O:13][C:12]1[C:11]([O:14][CH3:15])=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[F:4])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(C=O)cc(F)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(F)c1OCc1ccccc1
Yield: 67.2 %

Procedure:
To 40 ml of acetonitrile were added 7.3 g of 3-fluoro-4-hydroxy-5-methoxybenzaldehyde, 8.8 g of benzyl bromide, 16.8 g of cesium carbonate and 10 ml of DMF, and the mixture obtained was heated under reflux for 10 hours. The reaction mixture was concentrated under reduced pressure. Hydrochloric acid was added to the residue and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 7.5 g of 4-benzyloxy-3-fluoro-5-methoxybenzaldehyde represented by the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([OH:20])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].O.[CH2:28](O)[CH2:29][OH:30]>S(=O)(=O)(O)O>[OH:30][CH2:29][CH2:28][O:19][C:18](=[O:20])[C@H:17]([CH3:21])[N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: OCCO
Reactant: C[C@@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: C[C@@H](C(=O)OCCO)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 56 %

Procedure:
A solution of (S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.0 g, 0.00995 mole) was concentrated sulfuric acid (4 drops) in ethylene glycol (50 ml) was refluxed under nitrogen for three hours, and then poured into a saturated sodium bicarbonate solution (200 ml). Water (50 ml) was added and the product was extracted into two portions of ethyl acetate. The combined organic layers were washed twice with water and once with a saturated sodium chloride solution, dried over magnesium sulfate, treated with charcoal and filtered. Evaporation of the solvents under reduced pressure gave 1.9 g (56% yield) of solid which was dissolved in hot isopropyl ether (with a little isopropyl alcohol added. The solution was stirred and cooled to room temperature to precipitate a solid. The mixture was cooled in the freezer, the solid was collected by filtration, rinsed with isopropyl ether and dried under high vacuum at room temperature overnight to give 1.44 g of title compound, mp 112°-113.5° C.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([C:12]1[N:13]=[CH:14][NH:15][C:16]=1[CH3:17])(=[O:11])[CH3:10]>CCOCC.O1CCCC1>[CH3:17][C:16]1[N:15]=[CH:14][NH:13][C:12]=1[C:9]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:11])[CH3:10]
Reactant: Br[Mg]c1ccccc1
Reactant: CC(=O)c1nc[nH]c1C
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1nc[nH]c1C(C)(O)c1ccccc1

Procedure:
A 3.0 M solution of phenyl-magnesium bromide (1.3 ml, 4 mmol) in ether was added to a solution of 0.25 g (2.0 mmol) 4-acetyl-5-methyl-imidazole in 20 ml dry tetrahydrofuran at ambient temperature. The mixture was refluxed for 2 h. The solvents are evaporated and the organics are extracted twice with ethyl acetate. The combined organic extracts are concentrated and the residue was purified by flash chromatography (silica gel, dichloromethane/methanol 95:5) to yield a product mainly containing 1-(5-methyl-3H-imidazol-4-yl)-1-phenyl-ethanol. This product was dissolved in 20 ml ethanol/ethyl acetate (1:1) and 0.5 ml of 10M hydrochloric acid was added. The mixture was hydrogenated (5% Pd/C, 0.07 g; 4 bar H2, 50° C.) for 4 h. Then the mixture was filtered through Celite®, and the solvent was evaporated. The residue was partitioned between an aqueous solution of potassium carbonate and ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated to yield a yellow oil that was purified by flash chromatography (silica gel, dichloromethane/methanol 95:5). To the amine an equimolar amount of hydrochloric acid in ethanol (5M) was added. By dilution with ether 4-methyl-5-(1-phenyl-ethyl)-1H-imidazole hydrochloride precipitated as a colourless solid that was filtered off (45 mg, 12%); MS (EI): 186.1 (M+.), 171.1 (((M-CH3)+.), 100%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][NH2:20])[CH3:16].[O:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>ClCCl.O>[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][NH:20][CH:27]1[CH2:28][CH2:29][O:24][CH2:25][CH2:26]1)[CH3:16]
Reactant: O=C1CCOCC1
Reactant: CCOC(CN)OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(CNC1CCOCC1)OCC
Reaction time: 18 h

Procedure:
Sodium triacetoxyborohydride (10.6 g) was added to a cooled (0° C.) solution of aminoacetaldehyde diethyl acetal (5.8 mL) and tetrahydro-4H-pyran-4-one (3.7 mL) in dichloromethane (100 mL). The reaction was stirred for 18 h, allowing the temperature to warm to ambient conditions. Water (100 mL) was added, followed by portionwise addition of sodium bicarbonate (16.8 g), causing effervescence. The mixture was stirred vigorously for 1 h, and then allowed to partition. The phases were then separated and the aqueous phase extracted with more dichloromethane (50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford the titled compound as a colourless oil. Yield 8.3 g.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=1.Cl.[NH2:25]O>>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:23][N:25]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(F)cc1
Reactant: NO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)on1
Reaction time: 24 h

Procedure:
In a further embodiment, an isoxazole cyclization reaction is provided in Scheme 15A. In this embodiment, 1-(4-fluorophenyl)ethanone is reacted with diethyl oxalate to provide ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate. In one embodiment, this reaction is performed in the presence of a base such as potassium tert-butoxide. In another embodiment, this reaction is performed at about room temperature for about 24 hours. The isoxazole ring is then generated by reaction of ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate with hydroxylamine hydrochloride to provide ethyl 5-(4-fluorophenyl)isoxazole-3-carboxylate. In one embodiment, this reaction is performed in at elevated temperatures. In another embodiment, this reaction is performed in ethanol for about 2 hours. Ethyl 5-(4-fluorophenyl)isoxazole-3-carboxylate is then reduced with lithium aluminum hydride to provide 5-(4-fluorophenyl)isoxazol-3-yl)methanol. In one embodiment, the reduction is performed in THF, at a temperature of about 0° C. to about room temperature overnight. 5-(4-Fluorophenyl)isoxazole-3-carbaldehyde is then formed by oxidizing (5-(4-fluorophenyl)isoxazol-3-yl)methanol. In one embodiment, the oxidation is performed using PCC. In another embodiment, the oxidation is performed in dichloromethane at about room temperature overnight. 5-(4-Fluorophenyl)isoxazole-3-carbaldehyde may then converted to a compound of Formula (I-A) using the methods described herein.
Reaction SMILES: CCC([O-])(C)C.[Na+].[C:8]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH2:9][C:10]([CH3:12])=[O:11].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22](F)[C:21]=1[F:30].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[F:30][C:21]1[C:20]([F:19])=[CH:25][CH:24]=[C:23]([N+:26]([O-:28])=[O:27])[C:22]=1[CH:9]([C:10](=[O:11])[CH3:12])[C:8]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: CCC(C)(C)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)C(C(=O)OC(C)(C)C)c1c([N+](=O)[O-])ccc(F)c1F
Temperature: 40 °C

Procedure:
To toluene (810 1) was charged sodium tert-pentoxide (91 kg, 2.3 eq). The mixture was heated to 40° C. and tert-butyl acetoacetate (124.3 kg, 2.2 eq) added. The mixture was heated to 70° C. and trifluoronitrobenzene (63.1 kg, 1.0 eq) added. The temperature was maintained at 70° C. for 3 hours. The mixture was cooled to 25° C. and 20% w/w sulphuric acid added to adjust the pH to 5. The lower aqueous layer was discarded and the organic layer washed twice with water (2×227 kg of water), with 2.3% w/w sodium bicarbonate (192 kg) and then water (192 kg). The organic layer was distilled under vacuum (50 mbar), removing 574 kg of distillate leaving a solution of tert-butyl 2-(2,3-difluoro-6-nitrophenyl)-3-oxobutanoate in toluene.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9]C(=O)OC(C)(C)C)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[NH2:9][CH2:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([OH:1])[CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC[C@H]1CC[C@H](O)CC1

Procedure:
Tert-butyl trans-(4-hydroxycyclohexyl)methylcarbamate (1 g) in dichloromethane (10 ml) was treated with trifluoroacetic acid (10 ml) at 0° C. for two hours. The reaction mixture was concentrated and the residue was dried under vacuum to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:16]([CH2:24][OH:25])[O:15][C:14]3=[O:26])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].IC.[C:33]([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:16]([CH2:24][O:25][CH3:33])[O:15][C:14]3=[O:26])=[CH:11][CH:12]=2)=[CH:27][CH:28]=1
Reactant: O=C([O-])O
Reactant: O=C1O[C@@H](CO)[C@H](c2ccccc2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC[C@@H]1OC(=O)N(c2ccc(Oc3ccc(Cl)cc3)cc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
To (4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(hydroxymethyl)-4-phenyloxazolidin-2-one (14 mg, 0.035 mmol) in THF (1 mL) was added NaH (˜5 mg) and the reaction was stirred for 10 min. at room temperature. Iodomethane (˜0.01 mL) was added and the reaction was stirred for an additional 2 h. NaHCO3 aqueous solution was added to quench, followed by dilution with water and ethyl acetate. The organic phase was washed with brine, dried (MgSO4), and concentrated. Flash chromatography (0-30% ethyl acetate/hexanes) yielded 8 mg (57%) of the title compound as a colorless oil. 1H NMR (CDCl3) δ (ppm) 7.23-7.32 (m, 7H), 7.16-7.19 (m, 2H), 6.78-6.82 (m, 4H), 5.16 (d, 1H, J=5.7 Hz), 4.36 (dd, 1H, J=9.3, 3.9 Hz), 3.63 (ddd, 2H, J=18.4, 11.0, 4.1), 3.41 (s, 3H). HPLC-MS calculated C23H20ClNO4 (M+H+): 410.1, found: 410.1.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@H:10]1[C:40]1[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[C:42]([Br:48])[CH:41]=1)C1C=CC=CC=1.Cl.[H][H]>C1COCC1.CO.[Pd]>[Br:48][C:42]1[CH:41]=[C:40]([C@@H:10]2[O:11][C@H:12]([CH2:31][OH:32])[C@@H:13]([OH:23])[C@H:14]([OH:15])[C@H:9]2[OH:8])[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=1
Reactant: COc1cc(Br)cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(Br)cc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1
Yield: 58.9 %

Procedure:
5% palladium/carbon (1.0 g) was added to a solution of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-(3-bromo-5-methoxyphenyl)-D-glucitol (10.0 g) in THF-methanol (ratio: 1:1, 100 ml). Two drops of a 1 M aqueous solution of hydrochloric acid was further added to the mixture, followed by stirring for 30 minutes in a hydrogen atmosphere. After filtrating the reaction mixture, the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain (1S)-1,5-anhydro-1-(3-bromo-5-methoxyphenyl)-D-glucitol (2.9 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:14]([CH2:22][CH2:23][CH3:24])=[N:15][N:16]([CH3:21])[C:17]=1[C:18]([NH2:20])=[O:19].C(N(CC)CC)C>ClCCl>[C:18]([C:17]1[N:16]([CH3:21])[N:15]=[C:14]([CH2:22][CH2:23][CH3:24])[C:13]=1[NH:12][C:9](=[O:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:19])[NH2:20]
Reactant: CCCc1nn(C)c(C(N)=O)c1N
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1nn(C)c(C(N)=O)c1NC(=O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of this 4-bromophenylacetyl chloride in dry dichloromethane (5 ml) was then added dropwise to a solution of 4-amino-1-methyl-3-propyl-1H-5-pyrazolecarboxamide (6 g, 0.033 mol) and triethylamine (7 ml, 0.050 mol) in dichloromethane (250 ml), and the reaction stirred at room temperature for 18 hours.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH:26]([C:29]1[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[C:31]([CH:38]([CH3:40])[CH3:39])[C:30]=1[S:41](Cl)(=[O:43])=[O:42])([CH3:28])[CH3:27]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:41]([C:30]4[C:31]([CH:38]([CH3:39])[CH3:40])=[CH:32][C:33]([CH:35]([CH3:37])[CH3:36])=[CH:34][C:29]=4[CH:26]([CH3:28])[CH3:27])(=[O:43])=[O:42])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4c(C(C)C)cc(C(C)C)cc4C(C)C)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2,4,6-triisopropylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][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][C:21]([OH:23])=O)([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:44]([O:48][C:49]([CH2:51][CH2:52][NH:53][CH2:54][C:55]1[CH:63]=[CH:62][C:58]([C:59]([OH:61])=[O:60])=[CH:57][CH:56]=1)=[O:50])([CH3:47])([CH3:46])[CH3:45]>C(OCC)(=O)C>[C:44]([O:48][C:49]([CH2:51][CH2:52][N:53]([CH2:54][C:55]1[CH:63]=[CH:62][C:58]([C:59]([OH:61])=[O:60])=[CH:57][CH:56]=1)[C:21](=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:24])=[O:50])([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)O
Reactant: CC(C)(C)OC(=O)CCNCc1ccc(C(=O)O)cc1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)N(CCC(=O)OC(C)(C)C)Cc1ccc(C(=O)O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
Hexadecanedioic acid mono-tert-butyl ester (0.3 g, 0.88 mmol) was dissolved in ethyl acetate. N-Ethyl-N-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.167 g, 0.88 mmol) and 1-hydroxy-7-azabenzotriazole (0.119 g, 0.88 mmol) was added and the mixture was stirred at 50° C. for 1 hour. After cooling to room temperature, diisopropylethylamin (0.45 mL, 2.63 mmol) was added followed by 4-[(2-tert-Butoxycarbonylethylamino)methyl]benzoic acid (0.489 g, 1.75 mmol). The mixture was stirred overnight under nitrogen at room temperature. The mixture was separated between ethyl acetate (100 mL) and water (2×50 mL). The organic phase was dried (Na2SO4), solvent removed in vacuo. The crude product was purified by RP-HPLC on C18-column, buffer A: 0.1% TFA, buffer B: MeCN+0.1% TFA; gradient 80-100% B to yield the title compound (145 mg, 27%).
Reaction SMILES: CON(C)[C:4](=[O:17])[C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6][CH2:7][CH3:8].[C:19]1([Mg]Br)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[O:17]=[C:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH2:6][CH2:7][CH3:8]
Reactant: Br[Mg]c1ccccc1
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a 50 mL round-bottomed flask was (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopentan-2-ylcarbamate (91d, 250 mg, 0.96 mmol) dissolved in THF (9.6 ml). Phenylmagnesium bromide (2.88 ml, 2.88 mmol) 1.0 M in THF was added. The reaction was stirred at r.t. for 5 h. The reaction was poured into a mixture of saturated ammonium chloride and ethyl acetate. The mixture was shaken and the layers separated. The water layer was washed twice with ethyl acetate. The combined organic layers were washed once with a small portion of water and dried over sodium sulphate. The solvent was evaporated and the crude product was purified by flash chromatography.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([F:7])([F:6])[F:5].CS(C)=O.C([N:20](CC1C=CC=CC=1)[CH2:21][CH2:22][NH2:23])C1C=CC=CC=1.[BH4-].[Na+]>C(O)C>[F:5][C:4]([F:7])([F:6])[CH:3]1[CH2:2][NH:23][CH2:22][CH2:21][NH:20]1
Reactant: O=C(CBr)C(F)(F)F
Reactant: NCCN(Cc1ccccc1)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Product: FC(F)(F)C1CNCCN1
Reaction time: 21 h

Procedure:
A 12.3 g portion of bromo-3,3,3-trifluoropropanone was slowly added to 50 ml of dimethyl sulfoxide and stirred under a dry atmosphere for 21 hours and then diluted to 100 ml with ethanol. A solution of 31 g of N,N-dibenzylethylenediamine in 100 ml of ethanol was added dropwise and the mixture was stirred for 8 hours. A 2.43 g portion of sodium borohydride was added over 30 minutes, this mixture was stirred overnight then the ethanol was removed. The dimethyl sulfoxide residue was dissolved in water and extracted with dichloromethane. The extracts were combined, washed with water and brine and then subjected to flash chromatography on a silica gel column, eluting with ether:hexane (3:7). The 2-(trifluoromethyl)dibenzylpiperazine was dissolved in 25 ml of ethanol in an argon flushed Parr bottle. A 0.63 g portion of 10% palladium on carbon was added and the mixture was shaken under 47 lbs. of hydrogen pressure overnight at 40° C. Filtration and evaporation of the solvent gave 0.55 g of 2-(trifluoromethyl)piperazine as a semi-solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([NH2:17])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=1[CH3:11])=[O:5])[CH3:2].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([NH:17][C:18](=[O:20])[CH3:19])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1sc(N)c(C(=O)OCC)c1C
Product: CCOC(=O)c1sc(NC(C)=O)c(C(=O)OCC)c1C

Procedure:
A solution of 23.0 g. (0.09 mol) of 2,4-diethoxycarbonyl-3-methyl-5-aminothiophene in 250 ml. of acetic anhydride was heated to 100° C. for 1.5 hrs. The resulting mixture was cooled in an ice bath and the precipitated crystals were filtered to yield 2,4-diethoxycarbonyl-3-methyl-5-acetylamino-thiophene, m.p. 130°-131° C.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])=[C:2]=[O:3].[N:11]1[C:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]=12.CCN(C(C)C)C(C)C>CN(C=O)C>[C:5]1([CH3:10])[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH:1][C:2]([N:17]1[CH2:18][CH2:19][N:14]2[CH:13]=[C:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:11]=[C:15]2[CH2:16]1)=[O:3]
Reactant: CCOC(=O)c1cn2c(n1)CNCC2
Reactant: Cc1ccccc1N=C=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn2c(n1)CN(C(=O)Nc1ccccc1C)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a vial containing 1-isocyanato-2-methylbenzene (0.0166 g, 0.125 mmol) was added ethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (0.024 g, 0.125 mmol), DIPEA (0.0762 mL, 0.438 mmol), and DMF (1.5 mL). The solution was shaken at room temperature for 16 h, then concentrated to give crude ethyl 7-(o-tolylcarbamoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate.