Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH:8]=2)[CH:3]=1.C1(C)C=CC(S(O[CH2:29][C@H:30]([O:39][Si](C(C)(C)C)(C)C)[CH2:31][CH2:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)(=O)=O)=CC=1.[H-].[Na+].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O.O1CCCC1.O>[N:35]1[CH:36]=[CH:37][CH:38]=[C:33]([CH2:32][CH2:31][C@@H:30]([OH:39])[CH2:29][O:1][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14][C:15]([F:16])([F:17])[F:18])[CH:8]=3)[CH:3]=2)[CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](CCc2cccnc2)O[Si](C)(C)C(C)(C)C)cc1
Reactant: Oc1ccc2cc(OCCC(F)(F)F)ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O[C@H](CCc1cccnc1)COc1ccc2cc(OCCC(F)(F)F)ccc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
Prepared according to the method described in example 26e) from 2-hydroxy-6-(3,3,3-trifluoropropoxy)naphthalene (0.212 g), (2R)-2-(tert-butyldimethylsilyloxy)-4-(3-pyridyl)-1-butyl para-toluenesulfonate (0.30 g) and sodium hydride (60%, 33 mg) in dimethylformamide (3 ml) with heating at 60° C. for 2 hours. The adduct was dissolved in tetrahydrofuran (10 ml) and tetrabutylammonium fluoride hydrate (0.30 g) was added. After 2 hours, the mixture was diluted with water and extracted with ether. The organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with hexane:acetone (3:2) to give the title compound (0.18 g) which was recrystallised from ethyl acetate:hexane.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl[C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(O)C>CN(C)C=O>[CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=2)=[CH:7][CH:6]=1
Reactant: CNCCc1ccc(O)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CNCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Temperature: 85 °C
Yield: 22.7 %

Procedure:
Combine 4-(2-methylamino-ethyl)-phenol (1.0 g, 6.6 mmol), 6-chloronicotinamide (1.0 g, 6.6 mmol), and cesium carbonate (4.3 g, 13.2 mmol) in N,N-dimethylformamide (30 mL), stir and heat at 85° C. for 18 hours. Cool to room temperature and evaporate on a rotary evaporator to yield the crude product (1.3 g). The crude product is purified by flash column chromatography on silica gel eluting with 1% conc. ammonium hydroxide/10% ethanol in chloroform then ethanol to yield 6-[4-(2-Methylamino-ethyl)-phenoxy]-nicotinamide (0.4 g, 1.5 mmol): 1H NMR (DMSO-d6, 300.00 MHz): 8.58 (d, 1H); 8.22 (dd, 1H); 7.26-7.23 (m, 2H); 7.05-7.02 (m, 3H); 3.32 (br, 2H); 2.69 (m, 5H); 2.29 (m, 4H)m/z=271.87 (M+1); HPLC=99% (5/95 to 95/5 ACN/(0.1%TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH3:12].[C:14]([O-:17])(=[O:16])[CH3:15].[Na+].CN(C)C=O.CCCCCC>C(OCC)(=O)C>[C:14]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH3:12])(=[O:16])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: CCC/C=C/CCCCCCCBr
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCC/C=C/CCCCCCCOC(C)=O
Temperature: 110 °C
Yield: 72.3 %

Procedure:
Z/E-8-dodecenyl bromide (520 mg, 2.2 mmol), prepared as described above, was weighed into a 50 mL round bottom flask with a magnetic stir bar. Sodium acetate (540 mg, 6.6 mmol), freshly fused, was added in a single portion, followed by dimethyl formamide (5 mL). The flask was equipped with a condenser and was placed in a preheated oil bath (55° C.). The oil bath was further heated to 110° C. over 3 hours. The progress of the reaction was monitored by thin layer chromatography (TLC) using hexane:ethyl acetate in a ratio of 9:1 as the eluant. After 5 hours the reaction mixture was removed from the heat and allowed to cool to ambient temperature. Water (10 mL) was added to dilute the reaction mixture, and the resulting aqueous phase was extracted with hexane (3×15 mL). The combined hexane extracts were washed with water (2×10 mL) and brine (10 mL). The resulting organic phase was dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure to yield the Z/E-8-dodecenyl acetate product as a clear liquid (360 mg, 73%). The Z/E ratio was determined to be 92:8 by gas chromatography (GC) using a DB-XLB column.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>>[NH:10]([C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1)[NH2:11]
Reactant: Cc1cccnc1Br
Reactant: NN
Solvent: O
Product: Cc1cccnc1NN
Temperature: 110 °C
Yield: 67.7 %

Procedure:
2-Bromo-3-methylpyridine (5.16 g, 30.00 mmol) and hydrazine hydrate (10.92 mL, 224.97 mmol) were mixed. The reaction was heated to 110° C. for 20 hours with stirring. The mixture was cooled to ambient temperature during which a white solid precipitated. This was then collected filtration, washed with ether (3×10 mL), slurried in DCM (50 mL), stirred for 10 minutes and then passed through a phase separation cartridge to remove water. The organic liquors were evaporated and dried under high vacuum to give 2-hydrazinyl-3-methylpyridine (2.5 g, 68%). 1H NMR (400 MHz, CDCl3) δ 2.08 (3H, s), 4.02 (2H, s), 5.50 (1H, s), 6.64 (1H, dd), 7.20-7.30 (1H, m), 8.08 (1H, dd). MP=119° C. (Lit 122° C.).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C:8]1([CH2:21][OH:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.C(N(CC)CC)C.O>ClCCl>[OH:6][CH2:7][C:8]1([CH2:21][O:22][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CO)(COS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.1 %

Procedure:
Methanesulfonyl chloride (44 μL, 0.56 mmol) in dichloromethane (10 mL) was added slowly to a stirred, cooled (0° C.) solution of 1,1-dimethylethyl 4,4-bis(hydroxymethyl)-1-piperidinecarboxylate (Description 67, 140 mg, 0.56 mmol) and triethylamine (95 μL, 0.68 mmol) in dichloromethane (50 mL). The mixture was allowed to warm to room temperature and stirred for 16 hours. Water (10 mL) was added and the layers were separated. The aqueous layer was extracted with dichloromethane (2×40 mL), the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (80:20 increasing to 0:100), to give the title compound (98 mg, 54%). m/z (ES+) 324 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[N:17]3[CH:18]=[N:19][CH:20]=[C:16]3[CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[OH:3][CH2:4][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[N:17]3[CH:18]=[N:19][CH:20]=[C:16]3[CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1ccc(C2CCCc3cncn32)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: OCc1ccc(C2CCCc3cncn32)cc1
Temperature: 25 °C

Procedure:
A solution of 0.40 g of 5-(p-ethoxycarbonylphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine in 20 ml of methylene chloride is cooled to -70° under nitrogen and 4.0 ml of a 1.53M diisobutylaluminium hydride solution in toluene is added dropwise. The reaction mixture is allowed to warm to room temperature, quenched with 3.2 ml of methanol and 15 ml of water and filtered through Celite®. The layers are separated, the organic one is dried over sodium sulfate and evaporated to yield the title compound, m.p. 142°-145°.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1>CO.[Pd]>[NH2:15][C:14]1[C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NC1CC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(N)c1NC1CC1
Reaction time: 6 h

Procedure:
To a solution of methyl 2-(cyclopropylamino)-3-nitrobenzoate (1.1 g, 4.5 mmol) in MeOH (4 mL) was added palladium 10 wt % on carbon (0.24 g, 0.23 mmol) under N2. After flushing the flask with N2 several times, the solution was stirred under a H2 balloon for 6 h. LCMS showed the reaction was complete. After filtration of the reaction mixture and rinsing with MeOH, the filtrate was collected and concentrated in vacuo. Purification of the residue by flash chromatography over silica gel column using 0-20% gradient of DCM-MeOH—NH4OH (9:1:0.05) in DCM as eluent gave methyl 3-amino-2-(cyclopropylamino)benzoate: LC-MS (ESI) m/z 207.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH:26]1[C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]2[C:35]([O:37][C:38](=O)[C:28]=2[CH:27]=1)=[O:36]>>[CH3:9][O:8][C:5]1[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]([N:1]2[C:35](=[O:36])[C:29]3[C:28](=[CH:27][CH:26]=[C:31]([C:32]([OH:34])=[O:33])[CH:30]=3)[C:38]2=[O:37])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: COc1ccc(N)cc1-c1nc2cc(-c3ccc(Cl)cc3)ccc2o1
Product: COc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccc(Cl)cc3)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-methoxyphenyl)-5-(4-chlorophenyl)benzoxazole (75 mg, 0.21 mmol) and 1,2,4-benzenetricarboxylic anhydride (41 mg, 0.21 mmol) the title compound was obtained (105 mg, 45%). 1H NMR (DMSO) δ 13.72(s, 1H), 8.42(dd, 1H), 8.32(s, 1H), 8.20(d, 1H), 8.09(m, 2H), 7.87(d, 1H), 7.78(d, 2H), 7.72(m, 2H), 7.54(d, 2H), 7.48(d, 1H), 4.04(s, 3H). MS 525.3 m/z (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:33]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:32])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:31])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]2)[N:6]=1.[F:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[C:43]=1B(O)O>>[NH2:33][C:4]1[S:3][C:2]([C:43]2[C:44]([C:48]([F:50])([F:51])[F:49])=[CH:45][CH:46]=[CH:47][C:42]=2[F:41])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:31])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]1)=[O:32]
Reactant: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Reactant: OB(O)c1c(F)cccc1C(F)(F)F
Product: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(-c4c(F)cccc4C(F)(F)F)sc3N)cnn2C)CC[C@H]1N

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-methoxy-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 98), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-fluoro-6-(trifluoromethyl)phenyl)boronic acid gave 279. 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 7.90 (s, 1H), 7.84-7.68 (m, 3H), 7.47 (s, 2H), 5.03 (t, J=5.2 Hz, 1H), 3.71-3.52 (m, 5H), 3.29-3.13 (m, 2H), 2.72 (s, 3H), 2.48-2.40 (m, 1H), 1.63-1.47 (m, 5H). LCMS (ES+) m/z 529 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CI.[H-].[Na+].[CH3:23]COC(C)=O>C1COCC1.O>[C:1]([O:5][C:6](=[O:18])[N:7]([C:8]1([C:11]2[CH:12]=[CH:13][C:14]([I:17])=[CH:15][CH:16]=2)[CH2:9][CH2:10]1)[CH3:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(I)cc2)CC1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Part A. 1-(4-Iodophenyl)cyclopropyl-carbamic acid tert-butyl ester (2.14 g, 5.85 mmol) was stirred in THF (20 mL) at 0° C. under N2. MeI (3 mL) was added followed by portionwise addition of NaH (2.34 g, 5 eq). The reaction was stirred at rt overnight. Several drops of H2O and EtOAc (20 mL) were added to quench the reaction. The organic solvent was evaporated, and H2O was added. It was extracted with Et2O (2×), washed with brine, dried over MgSO4, and concentrated to dryness. The residue was purified by FCC (silica gel, CH2Cl2:hexanes=0:1 to 1:1 to 1:0) to give pure [1-(4-iodophenyl)cyclopropyl]-methyl-carbamic acid tert-butyl ester as a white solid (2.07 g, yield 95%). LC/MS (ESI+) 373.8 (M+H), tR=2.95 min (10–90% CH3CN in H2O in a 4-min run).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]4[O:24]CCO4)[CH:15]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:26][CH2:27][OH:28].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH2:26][CH2:27][OH:28])[N:12]=[C:11]([C:14]3[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=3)[CH:20]=[O:24])[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(-c2nc(-c3cccc(C4OCCO4)c3)n[nH]2)cc1Cl
Reactant: OCCBr
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CC#N
Product: O=Cc1cccc(-c2nc(-c3ccc(Cl)c(Cl)c3)n(CCO)n2)c1
Temperature: 25 °C
Yield: 11 %

Procedure:
To a solution of 5-(3,4-Dichloro-phenyl)-3-(3-[1,3]dioxolan-2-yl-phenyl)-1H-[1,2,4]triazole mixture of tautomers) (400 mg, 0.31 mmol) in acetonitrile (5 ml) was added 2-bromoethanol (156 μl, 2.21 mmol) and BEMP on poystyrene resin support (2.3 mmol/g, 960 mg). This mixture was shaken at r.t. until the starting material had been consumed (5 d), then aminomethyl polystyrene (1.1 mmol/g, 147 mg) was added and the mixture shaken for a further 2 h at r.t. The mixture was then filtered, washed with acetonitrile and evaporated to afford an isomeric mixture of alkylated acetals which were chromatographically separated over SiO2 (Merck 230-400 Mesh) eluting with EiOAc/nHexane (1:4). The purified isomer was dissolved in THF (3 ml) and treated with 4N HCl (0.3 ml) at r.t. for 3 h, then the mixture was adjusted to pH 9 with NaHCO3, and the aqueous phase extracted twice with EtOAc. The organic phases were combined, dried, filtered and evaporated to afford the title aldehyde as a light yellow solid (45 mg, 11% yield), MS: m/e=362.2 (M+H+). The position of alkylation on the triazole ring was assigned by 1H-NMR, nOe spectroscopy.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[OH-].[Na+].[Cl:11][C:12]([Cl:17])([CH3:16])[C:13](Cl)=[O:14]>C(Cl)Cl>[Cl:11][C:12]([Cl:17])([CH3:16])[C:13]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:14]
Reactant: CC(Cl)(Cl)C(=O)Cl
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(Cl)(Cl)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
To a dry reaction vessel were added L-proline (115 g., 1.0 moles, 1.0 eq.), 144 mL of 6 N sodium hydroxide and 20 g. solid sodium hydroxide. The clear, colorless solution (pH=11.5) was cooled to +10° C. in an ice bath with stirring. All of the above 2,2-dichloropropionyl chloride was diluted with 50 mL methylene chloride and added to the L-proline solution over 2 hours, keeping the solution temperature below +10 ° C. and the pH at 11.5 by simultaneous addition of 290 mL of 6N sodium hydroxide to yield 2,2-dichloropropionyl-L-proline. The pH was adjusted to 3 by the addition of 216 mL of 6N hydrochloric acid. The solid which formed was collected by filtration using 300 mL of 6N hydrochloric acid as a wash to yield white crystalline 2,2-dichloropropionyl-L-proline which was dried under vacuum (30 Torr) for 18 hours to give 216 g. (90% yield based on L-proline). HPLC at 23 minutes showed ≥96% purity. The recrystallization from ethyl acetate or ethyl acetate-hexane removes 0.5 mole of water but does not significantly improve purity. m.p. 61°-62° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[C:10]([O-:16])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13].[H][H]>[Ni].C(OC(=O)C)C>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH:13][CH:12]([CH3:14])[CH2:11][C:10]([O-:16])=[O:15]
Reactant: [H][H]
Reactant: CC(=O)CC(=O)[O-]
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CC1(C)OCC(CO)O1
Product: CC(O)CC(=O)[O-]
Temperature: 60 °C
Reaction time: 7 h
Yield: 91.8 %

Procedure:
A Zipperclave Autoclave (Autoclave Engineers) was charged with ethylacetate (2.4 L), solketal acetoacetate from Example 1 (609.5 g, 2.82 mole) and Raney Nickel (25 g, W-2 grade, PM-77, water wet) under an inert atmosphere of nitrogen. The nitrogen was displaced with hydrogen to a pressure of approximately 1100 psi. The reaction mixture was then heated with vigorous stirring (1500 rpm) at 60° C. for approximately seven hours. A small (ca. 5 ml) sample of the reaction mixture was removed from the reactor, filtered through celite and concentrated in vacuo. Proton NMR analysis revealed that roughly 2 mole % of unreduced acetoacetate remained. The crude reaction mixture was then heated at 60° C. and 1000 psi hydrogen with vigorous stirring for an additional 5 hours. The autoclave was cooled to room temperature and the hydrogen atmosphere was displaced with nitrogen. The crude reaction mixture was filtered through celite. The resulting solution was extracted in a separatory funnel with saturated aqueous sodium chloride. The organic phase was isolated, filtered through magnesium sulfate and sodium sulfate. The resulting filtrate was concentrated in vacuo to provide an oil (565.11 g, 2.59 mole, approximately 92%). This oil was not purified further but was shown by NMR to be of high purity. Small amounts, <15 total mole %, of ethyl acetate and acetone were also detected.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=1.Cl.[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH2:19])[CH3:15].C(N(CC)CC)C>C(O)C>[CH3:12][C:4]1[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[N:7]=[C:2]([NH:19][CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:20])[N:3]=1
Reactant: CCOC(=O)CN
Reactant: Cc1nc(Cl)nc(C)c1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1nc(C)c([N+](=O)[O-])c(C)n1
Yield: 87.7 %

Procedure:
A solution of Compound 2 (69 mg), glycine ethyl ester hydrochloride (102 mg) and triethylamine (103 μL) in ethanol was stirred for 3 hours under reflux. After the reaction was completed, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:3) to give 82 mg (86% yield) of the desired product as a pale yellow amorphous.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5](=[S:7])[S:4][N:3]=1.CC1C=CC(S(O[CH2:19][CH2:20][CH:21]=[C:22]([F:24])[F:23])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:23][C:22]([F:24])=[CH:21][CH2:20][CH2:19][S:7][C:5]1[S:4][N:3]=[C:2]([CH3:1])[N:6]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC=C(F)F)cc1
Reactant: Cc1nsc(=S)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1nsc(SCCC=C(F)F)n1
Yield: 32 %

Procedure:
To a solution of 3-methyl-1,2,4-thiadiazole-5(4H)-thione (1.2 g) in acetone (100 cm3) was added 4,4-difluorobut-3-enyl 4-methylbenzenesulfonate (2.4 g) and potassium carbonate (1.2 g) and the mixture was refluxed for 4 hours after which tlc indicated complete consumption of starting material. The reaction was poured into ethyl acetate and water and the layers separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried (MgSO4). The solution of product was then filtered and evaporated under reduced pressure to give a brown oil which was purified by flash chromatography (silica, 7% ethyl acetate in hexane) to give 5-((4,4-difluorobut-3-enylthio)-3-methyl-1,2,4-thiadiazole as a brown oil (0.645 g). M+ =222; 1H NMR: δ2.56(2H, br q); 2.63 (3H,s); 3.30(2H,t); 4.30(1H,m).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[F:21])[NH2:17].F[C:23]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:24]=1[C:25]([OH:27])=[O:26]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[F:21])[NH:17][C:23]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:24]=1[C:25]([OH:27])=[O:26]
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: Nc1ccc(F)c(Cl)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cc(F)c(F)cc1Nc1ccc(F)c(Cl)c1
Yield: 84.2 %

Procedure:
Using General Method 1, the reaction of 2.5 M solution of n-BuLi in hexanes (21 mL, 53 mmol), diisopropylamine (7.2 mL, 51 mmol), 3-chloro-4-fluoro-aniline (2.48 mL, 17 mmol), and 2,4,5-trifluorobenzoic acid (3.0 g, 17 mmol) provided 4.32 g of the crude title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]([OH:11])=O.[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:16]=[C:17]([CH:21]([NH2:23])[CH3:22])[CH:18]=[CH:19][CH:20]=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]([NH:23][CH:21]([C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][C:13]([F:12])([F:24])[F:25])[CH:16]=1)[CH3:22])=[O:11]
Reactant: O=C(O)C=Cc1ccccn1
Reactant: CC(N)c1cccc(OC(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)C=Cc1ccccn1)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3-(pyridin-2-yl)acrylic acid, Preparation 16 (50 mg) in CH2Cl2 (2 mL) at room temperature were added (±)-1-(3-trifluoromethoxy phenyl)ethylamine, Preparation 15 (76 mg), EDC hydrochloride (129 mg), DMAP (41 mg), and triethylamine (0.2 mL), and the resulting solution was stirred at room temperature for 12 hours. The crude product was purified by silica gel chromatography eluting with ethyl acetate to provide the title compound as the racemate (96 mg). This racemate was separated by HPLC using AD column eluting with hexanes/ethanol (9:1) to give the title compound as an enantiomer of undetermined chirality.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Cl[CH2:14][C:15]1[O:19][N:18]=[C:17]([CH:20]([CH3:22])[CH3:21])[N:16]=1.O>CN(C)C=O>[CH:20]([C:17]1[N:16]=[C:15]([CH2:14][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[O:19][N:18]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1noc(CCl)n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1noc(CN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C

Procedure:
To a solution of potassium phthalimide (72 g, 0.39 mol) in dry N,N-dimethylformamide (300 mL) was added 5-(chloromethyl)-3-isopropyl-1,2,4-oxadiazole (50 g, 0.31 mol) gradually with stirring. The reaction mixture was maintained at ambient temperature for 2 h and then poured into cold water (1.2 L). The resulting yellow precipitate was collected by filtration, washed with water, and dried in the air to yield the title compound.