Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.O[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([C@:21]1([CH3:27])[CH2:25][O:24][C:23](=[O:26])[NH:22]1)[CH:15]=[CH:14]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CC(=O)OCC>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH:5]([O:8][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([C@:21]2([CH3:27])[CH2:25][O:24][C:23](=[O:26])[NH:22]2)[CH:15]=[CH:14]3)[CH2:4][CH2:3]1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Reactant: CC1(C)CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4,4-Dimethylcyclohexanol (63.2 mg, 0.000493 mol), (R)-4-(6-hydroxynaphthalen-2-yl)-4-methyl-oxazolidin-2-one (100 mg, 0.0004 mol), triphenylphosphine (129 mg, 0.000493 mol), and tetrahydrofuran (4 mL, 0.05 mol), diisopropyl azodicarboxylate (0.0971 mL, 0.000493 mol) was added dropwise and was stirred at room temperature overnight. The mixture was diluted with EA and washed with 5% citric acid and brine then dried with magnesium sulfate and concentrated. The crude was taken up into DCM and subjected to ISCO combiflash purification with EtOAc/hexane (0-70) to give product.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:26]=[CH:25][C:8]2[C:9]3[N:10]=[C:11]([C:17]4[N:21]([CH:22]([CH3:24])[CH3:23])[CH:20]=[N:19][N:18]=4)[S:12][C:13]=3[CH2:14][CH2:15][O:16][C:7]=2[CH:6]=1)=[O:4].[OH-].[Li+].Cl>C1COCC1.O>[CH:22]([N:21]1[CH:20]=[N:19][N:18]=[C:17]1[C:11]1[S:12][C:13]2[CH2:14][CH2:15][O:16][C:7]3[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:26]=[CH:25][C:8]=3[C:9]=2[N:10]=1)([CH3:24])[CH3:23]
Reactant: COC(=O)c1ccc2c(c1)OCCc1sc(-c3nncn3C(C)C)nc1-2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)n1cnnc1-c1nc2c(s1)CCOc1cc(C(=O)O)ccc1-2
Reaction time: 65 h
Yield: 95 %

Procedure:
To a suspension of 2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylic acid methyl ester in THF (6 mL) and water (1.5 mL) was added an aqueous 1N lithium hydroxide solution (1.0 mL, 1.0 mmol). The reaction mixture was stirred for 65 hours then an aqueous 1N HCl solution (2 mL) was added and the mixture was concentrated in vacuo to remove THF. A small quantity of MeOH was added to the resultant mixture and the solid was collected by filtration to give the title compound as an off-white solid (226 mg, 95%). LCMS: RT=3.88 min, [M+H]+=357
Reaction SMILES: CC([N:5]([C@H:9]([CH3:30])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[C:25]3[C:26]([CH3:29])=[N:27][O:28][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:29][C:26]1[C:25]2[C:20]([O:19][C:16]3[CH:17]=[CH:18][C:13]([NH:12][C:10](=[O:11])[C@@H:9]([CH3:30])[NH2:5])=[CH:14][CH:15]=3)=[CH:21][CH:22]=[CH:23][C:24]=2[O:28][N:27]=1
Reactant: Cc1noc2cccc(Oc3ccc(NC(=O)[C@@H](C)N(C(=O)[O-])C(C)(C)C)cc3)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc2cccc(Oc3ccc(NC(=O)[C@@H](C)N)cc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
1,1-dimethylethyl[(1R)-1-methyl-2-({4-[(3-methyl-1,2-benzisoxazol-4-yl)oxy]phenyl}amino)-2-oxoethyl]carbamate (Intermediate 13, 587 mg) was dissolved in 10.0 ml of DCM and then TFA (5.0 ml) was added. The reaction mixture was stirred at room temperature for 1 hour. After the removal of the volatiles, the residue was purified with an SCX cartridge and eluted with DCM/MeOH/NH3 (2.0 M solution in MeOH). Evaporation afforded 337 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:3]=1[CH2:4][N:5]1[C:10]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[C:20]([O:22][CH2:23][CH3:24])[N:19]=[C:18]([S:25][CH3:26])[N:17]=3)=[CH:14][CH:15]=2)=[CH:9][C:8]([C:27]([F:30])([F:29])[F:28])=[C:7]([C:31]#[N:32])[C:6]1=[O:33].[OH2:39].[OH2:40].O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O.[Mg+2].C1C=C(C([O-])=O)C(C(O[O-])=O)=CC=1.[Mg+2]>ClCCl.CO>[F:1][C:2]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:3]=1[CH2:4][N:5]1[C:10]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[C:20]([O:22][CH2:23][CH3:24])[N:19]=[C:18]([S:25]([CH3:26])(=[O:40])=[O:39])[N:17]=3)=[CH:14][CH:15]=2)=[CH:9][C:8]([C:27]([F:29])([F:30])[F:28])=[C:7]([C:31]#[N:32])[C:6]1=[O:33]
Reactant: O
Reactant: CCOc1cc(-c2ccc(-c3cc(C(F)(F)F)c(C#N)c(=O)n3Cc3ccc(F)cc3F)s2)nc(SC)n1
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: CCOc1cc(-c2ccc(-c3cc(C(F)(F)F)c(C#N)c(=O)n3Cc3ccc(F)cc3F)s2)nc(S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
1-(2,4-Difluoro-benzyl)-6-[5-(6-ethoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydropyridine-3-carbonitrile (49 mg, 0.087 mmol) was dissolved in a mixture of dichloromethane (2 mL) and methanol (0.4 mL). To this solution was added magnesium monoperoxyphthalate hexahydrate, MMPP, (108 mg, 0.218 mmol, 80% tech.) and the mixture was stirred at ambient temperature for overnight. After this period the reaction mixture was combined with dichloromethene (20 mL) and was washed with 1M NaHCO3 (2×10 mL), and brine (10 mL). The resulting organic layer was separated and dried over anhydrous Na2SO4 and evaporated in vacuo to yield crude product. The crude product was purified using flash silica chromatography (25-50% EtOAc/Hexane) to yield 1-(2,4-difluorobenzyl)-6-[5-(6-ethoxy-2-methanesulfonyl-pyrimidin-4-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile (42 mg, 80%) as a yellow solid. 1H-NMR (CDCl3): δ 7.72 (m, 1 H), 7.14 (m, 1 H), 7.13 (m, 1 H), 7.07 (s, 1 H), 6.88 (m, 1 H), 6.78 (m, 1 H), 6.63 (s, 1 H), 5.40 (s, 2 H), 4.61 (q, J=7.1 Hz, 2 H), 3.36 (s, 3 H), 1.46 (t, J=7.1 Hz, 3 H). MS(ES+): 597.2 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[CH:9]=[N:10][C:11]([CH3:17])=[C:12]([N+:14]([O-])=O)[CH:13]=2)[C:4]([CH3:19])([CH3:18])[CH2:3]1>CO.[OH-].[Pd+2].[OH-]>[CH3:17][C:11]1[C:12]([NH2:14])=[CH:13][C:8]([CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][C:4]2([CH3:19])[CH3:18])=[CH:9][N:10]=1
Reactant: Cc1ncc(C2=CCN(C)CC2(C)C)cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1ncc(C2CCN(C)CC2(C)C)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 1′,3′,3′,6-tetramethyl-5-nitro-1′,2′,3′,6′-tetrahydro-3,4′-bipyridine (0.912 g, 3.49 mmol) in MeOH (70 mL) was added palladium hydroxide (20 wt. % Pd (dry basis) on carbon, 808 mg). The reaction mixture was flushed with hydrogen gas and allowed to stir at rt overnight under an atmosphere of hydrogen. The reaction mixture was filtered through a Celite® pad and washed with MeOH. The filtrate was concentrated to give 2-methyl-5-(1,3,3-trimethylpiperidin-4-yl)pyridine-3-amine (0.814 g, 100%). LCMS (FA): Rt=0.24 min, m/z=234.4 (M+H).
Reaction SMILES: C(OC([N:8]=[C:9]([NH:32]C(=O)OC(C)(C)C)[N:10]1[CH2:17][CH:16]2[CH:12]([CH2:13][N:14]([C:18](=[O:31])[C:19]3[C:24]([N:25]4[N:29]=[CH:28][CH:27]=[N:26]4)=[CH:23][CH:22]=[CH:21][C:20]=3[F:30])[CH2:15]2)[CH2:11]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>O1C=COC=C1>[F:30][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([N:25]2[N:29]=[CH:28][CH:27]=[N:26]2)[C:19]=1[C:18]([N:14]1[CH2:15][CH:16]2[CH2:17][N:10]([C:9](=[NH:8])[NH2:32])[CH2:11][CH:12]2[CH2:13]1)=[O:31]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CC2CN(C(=O)c3c(F)cccc3-n3nccn3)CC2C1
Agent: C1=COC=CO1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)N1CC2CN(C(=O)c3c(F)cccc3-n3nccn3)CC2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude tert-butyl (((tert-butoxycarbonyl)imino)(5-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)carbamate was dissolved in dioxin (8 mL) and TFA (3 mL) was added and the reaction was stirred at room temperature overnight to form crude 5-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboximidamide (214 mg) as a TFA salt which was used directly in Step C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]#[N:10])=[CH:3][CH:2]=1.C([O-])=O.[NH4+]>C(O)C.O.[C].[Pd]>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]#[N:10])=[CH:3][CH:2]=1
Reactant: N#CC=Cc1ccncc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: N#CCCc1ccncc1
Yield: 66.6 %

Procedure:
3-(4-Pyridyl)acrylonitrile (1.3 g, 10.0 mmol) was dissolved in ethanol (10 ml), and 10% palladium-carbon (0.13 g) and a solution of ammonium formate (2.5 g, 40.0 mmol) in water (3 ml) were added thereto. The reaction mixture was refluxed for 2.5 hrs. Palladium-carbon was filtered off, and the reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The reaction mixture was subjected to a silica gel (25 g) column chromatography. The fractions eluted with hexane-ethyl acetate (1:1, v/v) were collected and concentrated to give the titled compound (0.88 g, 67%)
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH:14][C@H:15]([C:21]1[S:22][C:23]2[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:24]=2[N:25]=1)[CH2:16][CH2:17][C:18]([NH2:20])=O.N1C=CC=CC=1.O>O1CCCC1>[OH:14][C@H:15]([C:21]1[S:22][C:23]2[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:24]=2[N:25]=1)[CH2:16][CH2:17][C:18]#[N:20]
Reactant: NC(=O)CC[C@H](O)c1nc2ccc(I)cc2s1
Solvent: c1ccncc1
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#CCC[C@H](O)c1nc2ccc(I)cc2s1
Reaction time: 2 h
Yield: 73.8 %

Procedure:
0.33 mL trifluoroacetic anhydride was added to a solution of 556 mg of (4S)-4-hydroxy-4-(6-iodo-1,3-benzothiazol-2-yl)butane amide obtained in Production Example 299 and 0.25 mL pyridine in tetrahydrofuran under ice-cooling, and the mixture was stirred for 2 hours. Water was added thereto, the reaction solution was then extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate and purified by NH silica gel chromatography. The product was recrystallized from ethanol/ethyl acetate/hexane, to give 390 mg of the title compound as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][CH:10]1CC([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:44].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(OC(C)C)(C)C>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@@H:10]1[Br:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br
Reactant: O=C([O-])CC1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Product: Br[C@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
2,3,4,6-tetra-O-benzyl-D-galactopyranosylacetate (79.8 g) was dissolved in a mixture of toluene (160 ml) and isopropyl ether (520 ml), and the solution was cooled to −10 to 0° C. To this solution, an isopropyl ether solution (2.8 mmol/ml, about 100 ml) containing 2.0 equivalent volumes of HBr was added. After stirring for about 90 minutes at −10° C. to 0° C., an aqueous 5% sodium hydrogencarbonate solution was poured into the reaction solution, and excessive HBr was neutralized by stirring. The whole volume was transferred into a separation funnel for separation, then the water layer was discarded and washing was carried 2 times with an aqueous 10% sodium chloride solution. After concentration under vacuum, 2,3,4,6-tetra-O-benzyl-α-D-galactopyranosyl bromide (GalBr) was obtained as a syrup.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]([OH:14])=O.Cl.[C:16]1([C:22]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[C:32]1([C:22]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:30]3[CH:26]([CH2:27][N:28]([C:12](=[O:14])[CH2:11][C:4]4[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1ccc(OC)c(CC(=O)O)c1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(OC)c(CC(=O)N2CC3C(=O)CCC(c4ccccc4)(c4ccccc4)C3C2)c1
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
N,N'-Carbonyldiimidazole (1.14 g) is added to a solution of 2,5-dimethoxyphenylacetic acid (1.34 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 30 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.28 g) and triethylamine (1.96 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×200 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The meringue obtained is crystallized from a mixture of acetonitrile (20 cc) and isopropyl ether (80 cc). The crystals are drained, washed with isopropyl ether (25 cc) and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(2,5-dimethoxyphenyl)acetyl]-4-perhydroisoindolone (1.5 g) is obtained in the form of white crystals melting at 209° C.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[CH:27]1[C:40]2[CH:39]([C:41](O)=[O:42])[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:32][C:31]=2[CH:30]=[CH:29][CH:28]=1>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:41]([CH:39]1[C:40]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[O:32][C:33]2[C:38]1=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:42])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)C1c2ccccc2Oc2ccccc21
Product: CC(C)CN([C@@H](CCCCNC(=O)C1c2ccccc2Oc2ccccc21)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with xanthene-9-carboxylic acid under the conditions described in example 86 to yield the desired product.
Reaction SMILES: [CH3:1][C:2]([S:24]([CH3:27])(=[O:26])=[O:25])([CH2:8][CH2:9][N:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([CH3:22])[C:11]1=[O:23])[C:3]([O:5]CC)=[O:4].O.[OH-].[Li+]>O1CCCC1.CO.O.Cl>[CH3:1][C:2]([S:24]([CH3:27])(=[O:25])=[O:26])([CH2:8][CH2:9][N:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([CH3:22])[C:11]1=[O:23])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(CCn1ccc(-c2ccccc2)c(C)c1=O)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(-c2ccccc2)ccn(CCC(C)(C(=O)O)S(C)(=O)=O)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-methyl-4-(3-methyl-2-oxo-4-phenylpyridin-1(2H)-yl)-2-(methylsulfonyl)butanoate (118.3 mg, 0.313 mmol) in tetrahydrofuran/methanol/water (4:1:1, 3.13 mL) was added lithium hydroxide monohydrate (26.3 mg, 0.626 mmol). The mixture was stirred at ambient temperature overnight. The mixture was diluted with aqueous HCl (1 N in water) and extracted with ethyl acetate 2×. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to dryness to afford 2-methyl-4-(3-methyl-2-oxo-4-phenylpyridin-1(2H)-yl)-2-(methylsulfonyl)butanoic acid as a solid. 109.4 mg.
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].C(O)(=O)[CH:11]([CH2:13][C:14](O)=O)[OH:12]>S(=O)(=O)(O)O>[OH:4][C:3]1[C:2]([CH3:1])=[C:8]2[C:7]([CH:14]=[CH:13][C:11](=[O:12])[O:9]2)=[CH:6][CH:5]=1
Reactant: O=C(O)CC(O)C(=O)O
Reactant: Cc1c(O)cccc1O
Agent: O=S(=O)(O)O
Product: Cc1c(O)ccc2ccc(=O)oc12
Temperature: 80 °C
Reaction time: 24 h
Yield: 20.64 %

Procedure:
2-methyl resorcinol (0.161 mmol, 20.024 g) and malic acid (0.165 mmol, 22.129 g) were dissolved in concentrated sulfuric acid. The reaction mixture was stirred at 80° C. for 24h. The resulting solution was then poured over crushed ice, and the precipitate was collected by vacuum filtration. The precipitate was then washed with 5% NaHCO3 and again collected by vacuum filtration yielding an orange-yellow solid in a 20.64% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][CH2:6][N+:7]([O-:9])=[O:8])[CH3:2].[Na].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[C:15]=1[CH:22]=O.Cl>CCO>[CH2:1]([O:3][C:4]([C:5]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:20][C:16]2[C:15](=[C:14]([O:13][CH3:12])[CH:19]=[CH:18][CH:17]=2)[CH:22]=1)=[O:10])[CH3:2]
Reactant: COc1cccc(C=O)c1C=O
Reactant: CCOC(=O)CC[N+](=O)[O-]
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cc2c(OC)cccc2cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-nitro-propionic acid ethyl ester (16.25 g, 110.45 mmol, 4.0 equiv) in EtOH (150 ml) was added at 0° C. under an atmosphere of argon to a freshly prepared solution of sodium (2.54 g, 110.45 mmol, 4.0 equiv) in EtOH (110 ml). After 15 minutes, a solution of 3-methoxy-benzene-1,2-dicarbaldehyde (4.53 g, 27.61 mmol) in EtOH (150 ml) was added at 0° C. The reaction mixture was warmed to room temperature, and after 40 minutes, TLC analysis indicated complete conversion. 2 N aqueous HCl (55 ml, 4 equiv) was carefully added at 0° C., and the mixture was extracted with EtOAc (1.5 liter in total). The combined organic layers were washed with concentrated aqueous NH4Cl solution (200 ml), brine (400 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography (gradient of toluene/hexane 5:5 to 10:0) to afford the title compound (0.942 g, 12%, inseparable 1:1.15 mixture of regioisomers A:B) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ=8.87 (s, 1H isomer A), 8.69 (s, 1H isomer B), 8.33 (s, 1H isomer B), 8.15 (s, 1H isomer A), 7.64-7.59 (m, 1H isomer A+1H isomer B), 7.53 (d, J=8.1 Hz, 1H isomer B), 7.51 (d, J=8.3 Hz, 1H isomer A), 7.02 (d, J=6.5 Hz, 1H isomer B), 7.00 (d, J=7.8 Hz, 1H isomer A), 4.42 (q, J=7.3 Hz, 2H isomer A), 4.41 (q, J=7.1 Hz, 2H isomer B), 4.04 (s, 3H isomer A), 4.03 (s, 3H isomer B), 1.38 (t, J=6.3 Hz, 3H isomer A+3H isomer B). MS (ES+): 276 (M+H)+.
Reaction SMILES: NCC(C1C=NC(C(F)(F)F)=CC=1)O.C(N(CC)CC)C.ClCC(Cl)=O.C([O-])(O)=O.[Na+].Cl[CH2:33][C:34]([NH:36][CH2:37][CH:38]([OH:49])[C:39]1[CH:40]=[N:41][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:43][CH:44]=1)=[O:35].[OH-].[K+]>ClCCl.C(O)(C)C.CO>[F:46][C:45]([F:48])([F:47])[C:42]1[N:41]=[CH:40][C:39]([CH:38]2[CH2:37][NH:36][C:34](=[O:35])[CH2:33][O:49]2)=[CH:44][CH:43]=1
Reactant: O=C(CCl)NCC(O)c1ccc(C(F)(F)F)nc1
Agent: NCC(O)c1ccc(C(F)(F)F)nc1
Agent: O=C(Cl)CCl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC(C)O
Product: O=C1COC(c2ccc(C(F)(F)F)nc2)CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
2-amino-1-(6-(trifluoromethyl)pyridin-3-yl)ethanol (1.05 g, 5.09 mmol) and triethylamine (567 mg, 781 μl, 5.6 mmol) were combined with dichloromethane (50 ml) to give a yellow solution. To this chloroacetyl chloride (633 mg, 449 μl, 5.6 mmol) in 20 mL dichloromethane was added by dropwise addition at 0° C. After 1 h at 0° C. the reaction mixture was complete by LCMS. The reaction mixture was poured onto water. The pH adjusted to 8 with saturated NaHCO3. The resultant aqueous phase was extracted 4 times with dichloromethane. The combined organic extracts were washed with brine. Brine and aqueous phase were combined and further extracted with dichloromethane (2×). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The resulting residue, 2-chloro-N-(2-hydroxy-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)acetamide (1.5 g, 5.31 mmol) was combined with methanol (100 ml) to give a light yellow solution. KOH (357 mg, 6.37 mmol) was added. Reaction was checked by LCMS after and showed only starting material. A solvent exchange was done with isopropanol as follows: 50 mL of isopropanol was added to the reaction mixture and it was concentrated to ¼ volume under reduced pressure at 40° C. Another 50 mL of isopropanol was added and the mixture was concentrated under reduced pressure to 50 mL. Another 50 mL of isopropanol was added. LCMS showed a ratio of 81:19 starting material:product. The reaction mixture was stirred at room temperature overnight. LCMS showed a ratio of 15:52 starting material: product. Warming at 50° C. for 1 h did not lead to any more product formation, so reaction was stopped. The reaction mixture was concentrated to reduced volume (5 mL). The resultant solution was diluted with ethyl acetate and water and the aqueous phase adjusted to pH=6 (with 1N HCl). The layers were separated and the aqueous phase was extracted with ethyl acetate (2×). The aqueous phase was made basic with NaOH and extracted again with ethyl acetate (2×). The combined ethyl acetate extracts were washed with brine and dried over MgSO4, and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, 40 g, 0% to 2% MeOH in dichloromethane) to afford a white solid, which was triturated with ether to afford 6-(6-(trifluoromethyl)pyridin-3-yl)morpholin-3-one as an off-white powder (659 mg). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.45-3.69 (m, 2H) 4.25-4.61 (m, 2H) 4.93 (dd, J=10.01, 3.59 Hz, 1H) 6.62 (br. s., 1H) 7.74 (d, J=8.31 Hz, 1H) 7.96 (dd, J=8.31, 1.89 Hz, 1H) 8.75 (d, J=1.89 Hz, 1H).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])=[C:2]=[S:3].O1CCCC1.[CH3:18][CH:19]([NH:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:24][CH2:23]1)[CH3:20]>C(O)C>[CH3:20][CH:19]([N:21]([CH:22]1[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:27]1)[C:2]([NH:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])=[S:3])[CH3:18]
Reactant: O=[N+]([O-])c1ccccc1N=C=S
Reactant: CC(C)NC1CCN(CCc2ccccc2)CC1
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)N(C(=S)Nc1ccccc1[N+](=O)[O-])C1CCN(CCc2ccccc2)CC1
Yield: 84 %

Procedure:
A mixture of 21.6 parts of 1-isothiocyanato-2-nitrobenzene and 45 parts of tetrahydrofuran is stirred till all solid enters solution. Then there are added 29.5 parts of N-(1-methylethyl)-1-(2-phenylethyl)-4-piperidinamine and 160 parts of ethanol and the whole is stirred overnight at room temperature. The reaction mixture is evaporated and the residue is crystallized from 2-propanol. The product is filtered off and dried, yielding 43 parts (84%) of N-(1-methylethyl)-N'-(2-nitrophenyl)-N-[1-(2-phenylethyl)-4-piperidinyl]thiourea; mp. 100.6° C.