Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([C:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])[CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:4].CO.O.[OH-].[Li+]>C1COCC1>[CH3:30][C:29]([CH3:31])([CH3:32])[C:28]#[C:27][C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([C:18]([C@H:20]2[CH2:21][CH2:22][C@H:23]([CH3:26])[CH2:24][CH2:25]2)=[O:19])[CH:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)[CH:8]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)C2CCC(=O)CC2)c(C(=O)O)s1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (519 mg, 1.13 mmol) was dissolved in a mixture of 3:2:1 THF:MeOH:H2O (25 mL). Lithium hydroxide (5 mL, 1.0N aqueous solution) was added and the reaction mixture was stirred at 60° C. for 1 hour. The reaction mixture was then partitioned between ethyl acetate and water. The aqueous phase was neutralized with 5% citric acid(aq), and thrice extracted with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated to afford 505 mg of 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid which was carried on without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@H:6]1[CH2:10][C@H:9]([OH:11])[CH2:8][NH:7]1)=[O:5].C([O-])([O-])=O.[Na+].[Na+].[N:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:23][CH:22]=1)=[C:19]=[O:20]>C1COCC1>[CH3:2][O:3][C:4]([C@H:6]1[CH2:10][C@H:9]([OH:11])[CH2:8][N:7]1[C:19](=[O:20])[NH:18][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([F:31])([F:30])[F:32])=[CH:23][CH:22]=1)=[O:5]
Reactant: COC(=O)[C@H]1C[C@H](O)CN1
Reactant: O=C=Nc1ccc(OCC(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@H](O)CN1C(=O)Nc1ccc(OCC(F)(F)F)cc1
Reaction time: 0.25 h
Yield: 45 %

Procedure:
To a solution of (2R,4S)-4-Hydroxy-pyrrolidine-2-carboxylic acid methyl ester, hydrochloride (3 g, 16.57 mmol) in THF (15 mL) was added solid Na2CO3 (2.10 g, 19.88 mmol) and stirred for 15 min. To this mixture, freshly prepared 1-Isocyanato-4-(2,2,2-trifluoro-ethoxy)-benzene (4.3 g, 19.88 mmol) in THF (10 mL) was added and stirred for 2 h at room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was taken up in DCM and washed with water and brine, dried over Na2SO4 and concentrated to dryness. The residue was purified by column chromatography over silica (5% MeOH in DCM) to yield 2.7 g (50%) of the title compound as a white solid. LC-MS: 363.2 [M+1]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[O:13][C:12](=[O:14])[NH:11][C:10]1=[O:15].[C:16]([O-])(=[O:18])[CH3:17].[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:16]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[O:13][C:12](=[O:14])[NH:11][C:10]1=[O:15])(=[O:18])[CH3:17]
Reactant: CC(=O)[O-]
Reactant: Nc1ccccc1C1OC(=O)NC1=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccccc1C1OC(=O)NC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-(2-Aminophenyl)oxazolidine-2,4-dione hydrochloride (1 g., 4.37 mmoles) were taken into 15 ml. of glacial acetic acid. Sodium acetate (358 mg., 4.37 mmoles) were added and then, in a dropwise manner, acetic anhydride (449 mg., 0.41 ml., 4.37 mmoles). The reaction mixture was stirred at room temperature for 16 hours, poured into 50 ml. of water and extracted with three portions of ethyl acetate. The combined extracts were washed with two portions of water and then one of brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo solids (0.72 g.). Recrystallization from ethyl acetate gave purified 5-(2-acetamidophenyl)oazolidine-2,4-dione in two crops (0.26 g., m.p. 197°-198° C.; m/e 234].
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].S(=O)(=O)(O)O.[CH:10]([CH:12]([CH2:18][CH3:19])[C:13](OCC)=O)=[O:11]>>[CH2:18]([C:12]1[C:10](=[O:11])[NH:1][C:2](=[O:3])[NH:4][CH:13]=1)[CH3:19]
Reactant: NC(N)=O
Reactant: CCOC(=O)C(C=O)CC
Agent: O=S(=O)(O)O
Product: CCc1c[nH]c(=O)[nH]c1=O
Temperature: 11.5 °C
Reaction time: 0.5 h

Procedure:
Urea (19.39 g, 0.32 mol) (J. T. Baker) was added over 20 minutes to fuming sulfuric acid (26–29.5% free SO3, 135 mL, 2.65 mol) (Aldrich) with cooling in an ice water bath maintaining the reaction temperature between 8 to 15° C. After stirring for an additional 30 minutes, ethyl 2-formylbutyrate (46.55 g, 0.32 mol) (from Example 1c, supra) was added over 18 minutes keeping the reaction at the same temperature. After stirring for another 30 minutes, a second portion of urea (15.07 g, 0.25 mol) was added over 10 minutes at the same temperature. The reaction mixture was then stirred at room temperature for 65 hours, and at 90–100° C. for 2 hours (gas evolution was observed, and reaction was exothermic, with reaction temperature rising to 110° C.). The mixture was cooled to 30° C. with an ice-water bath. Ice (270 g) was added slowly keeping the reaction below 35° C. The mixture was then cooled to 5° C. and stirred for 20 minutes. The solid formed was collected by filtration, washed with cold water, hexanes, and diethyl ether and dried by suction to give 5-ethyl uracil. (Yield 38.85 g, 85.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(CO)cc(Cl)n1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CO[Si](C)(C)C(C)(C)C)cc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A solution of [2-chloro-6-(methyloxy)-4-pyridinyl]methanol (for a synthesis see Adamczyk, M.; Akireddy, S. R.; Reddy, Rajarathnam E. Tetrahedron 2002, 58(34), 6951)(8.02 g, 46.22 mmol) in dry DMF (100 ml) was treated with tert-butyldimethylsilyl chloride (8.36 g, 55.46 mmol) and imidazole (3.77 g, 55.46 mmol) and stirred at rt for 2 h. The reaction mixture was treated with water extracted three times with dichloromethane, dried (magnesium sulphate), evaporated and chromatographed on silica gel (100 g), eluting with 1:4 ethyl acetate-hexane to give the desired product (12.38 g, 93%).
Reaction SMILES: C(O)C.O.[Si:5]([O:22][CH2:23][CH2:24][C@H:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:39]=[CH:38][C:37]([C:40]([O:42]C)=[O:41])=[C:36]([Cl:44])[CH:35]=1)[CH3:26])([C:18]([CH3:21])([CH3:20])[CH3:19])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+]>O1CCCC1>[Si:5]([O:22][CH2:23][CH2:24][C@H:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:39]=[CH:38][C:37]([C:40]([OH:42])=[O:41])=[C:36]([Cl:44])[CH:35]=1)[CH3:26])([C:18]([CH3:20])([CH3:21])[CH3:19])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(-c2ccccc2O[C@H](C)CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ccccc1-c1ccc(C(=O)O)c(Cl)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution in tetrahydrofuran (5.0 ml), ethanol (5.0 ml) and water (5.0 ml) of methyl 2′-{[(1R)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-methylpropyl]oxy}-3-chlorobiphenyl-4-carboxylate (565 mg) was added 1 N aqueous sodium hydroxide solution (1.48 ml), followed by stirring at 60° C. for 8 hours. After the reaction solution was concentrated under reduced pressure, a 10% aqueous citric acid solution and dichloromethane were added to the residue, and the solution was separated. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 2′-{[(1R)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-methylpropyl]oxy}-3-chlorobiphenyl-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:33])=[C:5]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8].[Li+].[OH-].Cl>C1COCC1.CO>[CH3:1][C:2]1[S:3][C:4]([CH3:33])=[C:5]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:28]=2)[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2c(C)sc(C)c2Cc2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1sc(C)c(C(=O)N[C@@H](C)c2ccc(C(=O)O)cc2)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of methyl 4-{(1S)-1-[({2,5-dimethyl-4-[4-(trifluoromethyl)benzyl]-3-thienyl}carbonyl)amino]ethyl}benzoate from Example 11, Step 5 (5.68 g, 11.9 mmol) in THF (305 mL) and MeOH (152 mL) was treated with LiOH (1N in water, 35.8 mL, 35.8 mmol) at r.t. for 44 h and at 50° C. for 3.5 h. The solution was allowed to cool to r.t., and 1N HCl was added (38.2 mL, 3.2 eq). 350 mL of volatiles were removed in vacuo, 800 mL of water was added to the residue and the resulting suspension was stirred for 19 h. The solid was collected by filtration, rinsed with water and dried. The desired product was obtained as a white solid. MS (−APCI): m/z 460 (M−1)−.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:41][CH2:42][N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[CH:36][CH:37]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: O=C(CCl)N1CCCC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCCC2)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 48.8 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (8.0 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.8 mg) was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10](Br)[CH:11]=1)[C:6]([OH:8])=[O:7])=[O:2].[CH2:13]([Zn]CC)[CH3:14]>O1CCOCC1.C1(C)C=CC=CC=1>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:13][CH3:14])[CH:11]=1)[C:6]([OH:8])=[O:7])=[O:2]
Reactant: O=Cc1cc(Br)cc(C(=O)O)c1
Reactant: CC[Zn]CC
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCc1cc(C=O)cc(C(=O)O)c1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
Under nitrogen, Pd(dppf) (97 mg, 0.119 mmol) was added to a stirred solution of 3-formyl-5-bromo-benzoic acid (3.00 g, 11.92 mmol) in dioxane (100 mL). Diethyl zinc (14.7 g, 17.9 mmol, as a 15% solution in toluene) was added and the mixture was stirred at 75° C. for 1 h. The reaction was quenched by adding water (5 mL) and the solvent was evaporated to a volume of about 50 mL. The mixture was basified by adding sat. aq. ammonia (1 mL). The mixture was filtered and the filtrate was acidified by adding formic acid (4 mL) before it was separated by prep. HPLC to give the title compound as a colourless resin (1.17 g). LC-MS*: tR=0.44 min, [M−H]−=177.26; 1H NMR (D6-DMSO): δ 1.24 (t, J=7.8 Hz, 3H), 2.77 (q, J=7.5 Hz, 2H), 7.92 (t, J=1.8 Hz), 8.08 (t, J=1.8 Hz, 1H), 8.26 (t, J=1.5 Hz, 1H), 10.06 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[C:8]([NH:9][C:10](=[O:29])[C@@H:11]([NH:19][C:20]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:22][CH2:21]2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[CH:5][N:4]=1.Cl>O1CCOCC1>[O:2]=[C:3]1[C:8]([NH:9][C:10](=[O:29])[C@@H:11]([NH:19][C:20]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:22][CH2:21]2)[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][C:6]([C:30]2[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=2)=[CH:5][NH:4]1
Reactant: COc1ncc(-c2ccncc2)cc1NC(=O)[C@H](Cc1ccccc1)NC1(c2ccccn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1cc(-c2ccncc2)c[nH]c1=O)[C@H](Cc1ccccc1)NC1(c2ccccn2)CC1
Temperature: 50 °C
Yield: 88.1 %

Procedure:
(S)—N-(2-methoxy-5-(pyridin-4-yl)pyridin-3-yl)-3-phenyl-2-(1-(pyridin-2-yl)cyclopropylamino)propanamide 11.1 (38.5 mg, 83 μmol) was dissolved in 4.5 mL dioxane. Concentrated HCl (0.5 ml, 16456 μmol) was added. The reaction was heated to 50° C. for 2.5 h. LC/MS showed the completion of the reaction. The reaction was concentrated, neutralized with saturated NaHCO3, then extracted with 30% IPA/CHCl3 once. The organic layer was concentrated and purified by silica gel chromatography to afford 33 mg (89%) of (S)—N-(2-oxo-5-(pyridin-4-yl)-1,2-dihydropyridin-3-yl)-3-phenyl-2-(1-(pyridin-2-yl)cyclopropylamino)propanamide (35.1). 1H NMR (400 MHz, MeOH) δ ppm 8.82 (d, J=2.74 Hz, 1H) 8.48-8.63 (m, 2H) 8.19-8.36 (m, 1H) 7.68 (d, J=2.74 Hz, 1H) 7.61-7.65 (m, 2H) 7.52-7.59 (m, 1H) 7.20-7.26 (m, 3H) 7.08-7.16 (m, 4H) 3.58 (dd, J=8.61, 4.70 Hz, 1H) 3.04 (dd, J=13.69, 4.69 Hz, 1H) 2.83 (dd, J=13.69, 9.00 Hz, 1H) 1.06-1.21 (m, 3H) 0.82-0.91 (m, 1H).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:10]1[N:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13]>CN(C=O)C>[Cl:19][C:17]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:18]=1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Reactant: OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Cl)nc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a solution of cyclopentanol (1.42 mL, 15.70 mmol) in DMF (5 mL) at 0° C. was added sodium hydride (95% in mineral oil, 0.39 g, 15.70 mmol) in portions and stirred for 1 h at room temperature. This mixture was slowly added to a solution of 2,6-dichloro-nicotinamide (2.0 g, 10.47 mmol) in DMF (10 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. DMF was removed under reduced pressure, and the resulting mixture was diluted with EtOAc (100 mL), washed with water (2×25 mL) and brine (2×25 mL) solution, dried over anhyd. Na2SO4, filtered, and concentrated to give yellow oil, which was purified by flash chromatography on silica gel using 10-25% EtOAc/hexanes as eluent to yield the title compound (1.94 g, 51%) as a transparent oil. 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J=7.8 Hz, 1 H), 7.65 (br. s., 1 H), 7.03 (d, J=8.2 Hz, 1 H), 5.74 (br. s., 1 H), 5.70-5.57 (m, 1 H), 2.25-1.95 (m, 2 H), 1.90-1.66 (m, 6 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13](N(OC)C)=[O:14])=[CH:11][N:10]=[C:9]2[SH:19])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]=[O:14])=[CH:11][N:10]=[C:9]2[SH:19])=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1cnc(S)n1-c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1cnc(S)n1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(4-fluorophenyl)-2-mercapto-N-methoxy-N-methyl-1H-imidazole-5-carboxamide (8) (1 g, 3.55 mmol) in anhydrous THF (71 mL) at 0° C. was added lithium aluminum hydride (2M in THF, 5.3 mL, 10.65 mmol). The reaction was stirred at 0° C. for 1 h and for an additional 3 h at room temperature. The reaction was quenched at 0° C. with 15% sodium bicarbonate (40 mL) and water (40 mL) and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-100% EtOAc in hexanes) to afford 1-(4-fluorophenyl)-2-mercapto-1H-imidazole-5-carbaldehyde (12).
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C([C:24]([O:26][CH2:27][CH3:28])=[O:25])#N.CCOC(C)=O>C1COCC1.O>[CH2:27]([O:26][C:24]([CH:8]1[C:7](=[O:10])[CH2:6][CH2:5][C:4]2([O:3][CH2:2][CH2:1][O:11]2)[CH2:9]1)=[O:25])[CH3:28]
Reactant: CCOC(=O)C#N
Reactant: O=C1CCC2(CC1)OCCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CC2(CCC1=O)OCCO2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1,4-Cyclohexanedione mono-ethylene ketal (25 g) was dissolved in THF and cooled to −78° C. 1M Lithium bis(trimethylsily)amide (160 mL) in THF was added dropwise. After 30 min, ethyl cyanoformate (15.9 mL) was added dropwise. After 60 min, the solution was poured into EtOAc and water containing ice. The organic layer was washed with water and brine before it was dried and concentrated. This crude was filtered through a plug of silica to give the 8-oxo-1,4-dioxa-spiro[4.5]decane-7-carboxylic acid ethyl ester (32.4 g). MS found: (M+H)+=228.9
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C@H:4]1[CH2:8][C:7](=[O:9])[CH2:6][N:5]1[C:10](=[O:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.COC(=O)[C@@H]1CC(=O)CN1C(=O)CC1C=CC=CC=1.CCCCCCCCCCCCCCCC>C([O-])(=O)C.[Na+].ClCCl>[CH3:1][O:2][C:3](=[O:19])[CH:4]1[CH2:8][C:7](=[O:9])[CH2:6][N:5]1[C:10](=[O:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)[C@H]1CC(=O)CN1C(=O)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: COC(=O)[C@@H]1CC(=O)CN1C(=O)Cc1ccccc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCCCCCCCCCCCC
Product: COC(=O)C1CC(=O)CN1C(=O)Cc1ccccc1
Reaction time: 28 h

Procedure:
An aqueous solution (1.0 mL) containing 19 mM of N-(2-phenylacetyl)-4-keto-D-proline methyl ester and 19 mM of N-(2-phenylacetyl)-4-keto-L-proline methyl ester in 0.200M sodium acetate (pH 5.0) and 25 mg/mL of Candida antartica lipase fraction B was mixed at 25° C. The reaction mixture was analyzed by mixing with an equivalent volume of 20 mM hexadecane in dichloromethane for 3 minutes, which resulted in the complete extraction of the unreacted D- and L-isomers. The dichloromethane extract was then analyzed by chiral gas chromatography on a Chiraldex G-TA column (Advanced Separation Technologies, Inc., 50 m×0.32 mm ID) to determine the relative amounts of the unreacted D- and L-isomers. After 28 h, 97% of the D-isomer and 28% of the L-isomer remained, yielding a 55% enantiomeric excess of the D-isomer at 38% conversion of the racemic mixture (E=28).
Reaction SMILES: O=[As:2]O[As]=O.C([O-])(=O)CS.[NH4+].[CH2:12]([C:14]([CH2:19][SH:20])([CH2:17][SH:18])[CH2:15][SH:16])[CH3:13]>C(O)C>[CH2:12]([C:14]12[CH2:19][S:20][As:2]([S:18][CH2:17]1)[S:16][CH2:15]2)[CH3:13]
Reactant: CCC(CS)(CS)CS
Reactant: O=[As]O[As]=O
Agent: O=C([O-])CS
Agent: [NH4+]
Solvent: CCO
Product: CCC12CS[As](SC1)SC2
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
Arsenic trioxide (0.101 g, 0.506 mmol) was dissolved in ethanol (95%, 20 mL) and ammonium thioglycolate (827.2 μL of 5.5 M aqueous solution, 4.55 mmol) were stirred vigorously while heating to 50° C. After 60 minutes 4 (0.184 g, 1.01 mmol) was added, stirring continued for 20 minutes, cooled, and then filtered to remove insoluble material. The filtrate was taken to dryness, washed with water (2×15 mL), dissolved in dichloromethane (10 mL), dried over anhydrous magnesium sulfate, filtered, and taken to dryness to yield light yellow crystals. X-ray quality crystals were grown by slow evaporation from chloroform. Yield: 0.135 g, 50.3%. 1H NMR (CDCl3; 500 MHz) δ ppm: 0.89 (t, 3H, CH3), 1.39 (q, 2H, CH2) 2.94 (s, 6H, SCH2). 13C NMR (CDCl3 d6; 125.8 MHz) δ ppm: 8.17 (CH3), 31.29 (C), 31.65 (SCH2), 37.39 (CCH2). ESI-MS (m/z) 254.69 (254.93 calcd for [M+H]+ of [C6H11S3As]). Elemental Anal. calc'd (found) for C6H11S3As: C, 28.34 (31.42); H, 4.36 (4.70).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=1.[Cl-].[Cl-].[NH3+:19][C@@H:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:24][NH+:23]=1)[CH3:21].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14]([NH:19][C@@H:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:31])[F:32])=[CH:24][N:23]=2)[CH3:21])=[O:16])=[CH:11][CH:12]=1
Reactant: C[C@@H]([NH3+])c1ccc(OCC(F)(F)F)c[nH+]1
Reactant: O=C(O)Cc1ccc(-c2cnccn2)cc1
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C[C@@H](NC(=O)Cc1ccc(-c2cnccn2)cc1)c1ccc(OCC(F)(F)F)cn1
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 0.10 g (0.48 mmol) (4-pyrazin-2-ylphenyl)acetic acid in 2.00 ml of CH2Cl2 was added 0.17 g (0.58 mmol) of 2-[(1R)-1-ammonioethyl]-5-(2,2,2-trifluoroethoxy)pyridinium dichloride, 0.085 g (0.63 mmol) of HOAt, 0.12 g (0.63 mmol) of EDC, and 0.25 mL (1.44 mmol) of DIEA. After 1 h at room temperature, the reaction mixture was diluted with CH2Cl2, washed three times with water, and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, linear gradient 50-100% EtOAc in hexanes) afforded 0.14 g (70%) of 2-(4-pyrazin-2-ylphenyl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide. 1H NMR (CD3OD, 400 MHz) 9.09 (d, J=1.46 Hz, 1H); 8.65 (t, J=1.74 Hz, 1H); 8.51 (d, J=2.57 Hz, 1H); 8.26 (d, J=3.02 Hz, 1H); 8.03 (d, J=8.15 Hz, 2H); 7.46 (d, J=8.15 Hz, 2H); 7.43 (dd, J=3.02, 8.70 Hz, 1H); 7.30 (d, J=8.70 Hz, 1H); 5.03 (quintet, J=6.96 Hz, 1H); 4.62 (q, J=8.34 Hz, 2H); 3.64 (s, 2H); 1.46 (d, 3H, J=6.96 Hz). HRMS (ES) [M+1]+calcd for C21H20F3N4O2: 417.1538, Found: 417.1523. FLIPR alpha1I IP=30 nM.
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:10]([CH2:16][CH2:17][CH2:18][CH3:19])[C:11]([O:13][CH2:14][CH3:15])=[O:12].O.CCOC(C)=O>C(O)C>[CH2:17]([C:16]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[NH:7][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:18][CH3:19]
Reactant: NNc1ccccc1
Reactant: CCCCC(=O)C(=O)OCC
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCc1c(C(=O)OCC)[nH]c2ccccc12
Reaction time: 18 h
Yield: 58.1 %

Procedure:
A solution of phenylhydrazine (1.0 g, 6.92 mmol) in absolute ethanol (50 mL) was placed in an oil bath at 60° C. and a reflux condenser attached. Ethyl 2-oxohexanoate (1.0 g, 6.33 mmol) (prepared according to Singh, J; Kissick, T. P.; Mueller, R. H. Organic Preparations and Procedures International (1989), 21(4), 501-4.) was added dropwise. The reaction mixture was heated to reflux and stirred for 18 h. Water (25 mL) and EtOAc (25 mL) were added and the layers separated. The aqueous layer was extracted with EtOAc (2×25 mL), the organic layers combined, dried over sodium sulfate, filtered and concentrated. Trituration of the crude material (9:1 hexanes/EtOAc) afforded ethyl 3-propyl-1H-indole-2-carboxylate (0.850 g, 58%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.46 (s, 1H) 7.65 (d, 1H) 7.40 (d, 1H) 7.25 (d, 1H) 7.04 (t, 1H) 4.33 (q, 2H) 3.02 (t, 2H) 1.56-1.67 (m, 2H) 1.35 (t, 3H) 0.91 (t, 3H). MS: m/z 232.0 (M+1).