Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:20])[CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1.CC(C)=[O:23]>S(=O)(=O)(O)O.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:23])([CH3:20])[CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1
Reactant: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(O)(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
3.55 g. of 3-(2',4'-difluoro-4-biphenylyl)-3-bromobutyric acid, obtained by brominating 3-(2',4'-difluoro-4-biphenylyl)butyric acid, are dissolved in a mixture of 15 ml. of acetone and 15 ml. of water. One drop of sulfuric acid is added and the mixture is warmed to 45° for 4 hours and worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)-3-hydroxybutyric acid, m.p. 121°-123°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+].[C:16](OCC)(=[O:21])[CH2:17][C:18]([CH3:20])=O>C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:16](=[O:21])[CH2:17][C:18]([CH3:20])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(NN)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(N2N=C(C)CC2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The starting material is obtained as follows: To the suspension of 2,700 g of p-methoxyphenylhydrazine in 24,600 ml of 50% aqueous ethanol, the solution of 1,411 g of sodium acetate in 3,000 ml of water is added while stirring under nitrogen at room temperature for 15 minutes, followed by 2,148 g of ethyl acetoacetate during 30 minutes at 25°-30°. The mixture is refluxed for 45 minutes, slowly cooled to 10° and stirred overnight. The precipitate formed is filtered off, washed twice with 2,000 ml of cold 50% aqueous ethanol each, and dissolved in 2,000 ml of boiling anhydrous ethanol. The solution is stirred at room temperature overnight, the precipitate formed filtered off and washed twice with 500 ml of cold ethanol, to yield the 1-(p-methoxyphenyl)-3-methyl-2-pyrazolin-5-one melting at 125°-128°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[O:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:15])[O:10][C:11]=1[CH3:12]
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1oc(C(=O)O)cc1-c1c(Cl)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (244 mg, 0.95 mmol), 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (320 mg, 0.95 mmol) [prepared according to the procedure of Preparation 6, except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.0 g, 17.8 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (533 mg, 1.14 mmol) in chloroform (9 mL). DIEA (830 μL, 4.75 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (242 mg, 0.465 mmol, 49%): LC-MS (ES) m/z=521 (M+H)+.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5]([CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:6][N:7]=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>ClCCl.CCOC(C)=O>[C:25]1([O:24][C:22](=[O:23])[NH:2][C:3]2[S:4][C:5]([CH2:8][CH2:9][N:10]3[C:18](=[O:19])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]3=[O:20])=[CH:6][N:7]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ncc(CCN2C(=O)c3ccccc3C2=O)s1
Agent: Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1ncc(CCN2C(=O)c3ccccc3C2=O)s1)Oc1ccccc1
Reaction time: 2 h

Procedure:
To a suspension of a HBr salt of 2-[2-(2-amino-thiazol-5-yl)-ethyl]-isoindole-1,3-dione (compound 58.1; 1.42 mmol) in dichloromethane was added TEA (4.30 mmol) followed by the addition of phenyl chloroformate (1.43 mmol) at room temperature. After 2 hours, the reaction was concentrated to dryness to give a solid that was suspended in EtOAc, filtered, washed with additional EtOAc and dried under vacuum to provide {5-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-thiazol-2-yl}-carbamic acid phenyl ester (compound 58.2, which is contaminated with triethyl amine salts) which was used in the next reaction without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[O:7][CH2:8][C:9]([OH:11])=[O:10])([CH3:3])[CH3:2].[C:16]1([CH3:28])[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH2:26]O)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:16]1([CH3:28])[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH2:26][O:10][C:9](=[O:11])[CH2:8][O:7][C:6]2[CH:12]=[C:13]([CH3:15])[CH:14]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)CCO)cc1
Reactant: Cc1cc(OCC(=O)O)cc(C(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)CCOC(=O)COc2cc(C)cc(C(C)C)c2)cc1
Yield: 97.8 %

Procedure:
A mixture of 3-isopropyl-5-methylphenoxyacetic acid (prepared above, 6.0 g, 28.8 mmol), 2-(p-toluenesulfonyl)ethanol (5.77 g, 28.8 mmol), and p-toluenesulfonic acid hydrate (p-TsOH.H2O) (0.5 g) in 100 mL of toluene was refluxed with Dean-Stark trap for 3 h. Then water was added and the mixture was extracted with CH2Cl2. The combined organic layers were washed with saturated NaHCO3 solution (2×), dried over MgSO4, and concentrated to give 3-isopropyl-5-methylphenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 64, 11.0 g, 98%) as a light brown oil.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([C@H:9]([O:11][C:12]([C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20](=[O:55])[C@@H:21]([NH:37][C:38](=[O:54])[C@@H:39]([NH:43][C:44](=[O:53])[CH2:45][C@H:46]([O:51][CH3:52])[CH2:47][CH2:48][CH:49]=[CH2:50])[CH:40]([CH3:42])[CH3:41])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:24]=3)[NH:15]2)=[O:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1)=C>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.ClCCCl>[C:33]([Si:30]([CH3:31])([CH3:32])[O:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[CH2:22][C@@H:21]1[NH:37][C:38](=[O:54])[C@H:39]([CH:40]([CH3:42])[CH3:41])[NH:43][C:44](=[O:53])[CH2:45][C@H:46]([O:51][CH3:52])[CH2:47][CH2:48][CH:49]=[CH:50][C:7]2=[CH:6][C:5](=[CH:4][CH:3]=[CH:8]2)[C@@H:9]([CH3:10])[O:11][C:12](=[O:13])[C@H:14]2[NH:15][N:16]([CH2:17][CH2:18][CH2:19]2)[C:20]1=[O:55])([CH3:35])([CH3:36])[CH3:34]
Reactant: C=CCC[C@H](CC(=O)N[C@H](C(=O)N[C@@H](Cc1cccc(O[Si](C)(C)C(C)(C)C)c1)C(=O)N1CCC[C@@H](C(=O)O[C@H](C)c2cccc(C=C)c2)N1)C(C)C)OC
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: CO[C@@H]1CC/C=C/c2cccc(c2)[C@@H](C)OC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)NC(=O)[C@H](C(C)C)NC(=O)C1
Solvent: ClCCCl
Product: CO[C@@H]1CCC=Cc2cccc(c2)[C@@H](C)OC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)NC(=O)[C@H](C(C)C)NC(=O)C1

Procedure:
A stirred solution of (S)-1-{(S)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-[(S)-2-((R)-3-methoxy-hept-6-enoylamino)-3-methyl-butyrylamino]-propionyl}-hexahydro-pyridazine-3-carboxylic acid (R)-1-(3-vinyl-phenyl)-ethyl ester (123 mg, 0.158 mmol) and Hoveyda-Grubbs 2nd generation catalyst (10 mg, 0.0158 mmol) in 1,2-dichloroethane (60 mL) was heated at 80° C. for 1.5 hours. The reaction mixture was cooled before adding silica gel. The mixture was evaporated then purified by silica gel chromatography using ethyl acetate to give the title compound (54 mg, 46%) as a pale brown solid. 1H NMR (300 MHz, CDCl3) δ0.16 (s, 6H), 0.80-1.00 (m, 17H), 1.34-1.94 (m, 12H), 2.00-2.20 (m, 5H), 2.34-2.53 (m, 3H), 2.63-3.03 (m, 3H), 3.38 (s, 3H), 3.52-3.70 (m, 2H), 4.27-4.38 (m, 2H), 4.92-5.10 (m, 2H), 5.29 (d, J=10.9 Hz, 1H), 5.64-5.98 (m, 2H), 6.52-6.99 (m, 4H), 7.22-7.42 (m, 2H). LCMS (m/z) 749.3 [M+H] Tr=5.91 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([NH2:12])=[C:5]2[C:13]#[N:14].[N+:15]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br)([O-:17])=[O:16].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[N+:15]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([NH2:12])=[C:5]2[C:13]#[N:14])([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: Cn1c(N)c(C#N)c2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(N)c(C#N)c2cc(OCc3cccc([N+](=O)[O-])c3)ccc21
Reaction time: 2 h
Yield: 56.2 %

Procedure:
A solution of 5-hydroxy-2-amino-1-methyl-1H-indole-3-carbonitrile (100 mg; 0.53 mmol) and 3-nitrobenzyl bromide (130 mg; 0.6 mmol) in DMF (5 ml) was treated with Cs2CO3 (520 mg; 1.6 mmol) and the mixture was stirred for 2 hours. Water (80 ml) was added and the precipitate was filtered, taken up in methanol, filtered, washed and dried to give 5-(3-nitrobenzyloxy)-2-amino-1-methyl-1H-indole-3-carbonitrile (96 mg).
Reaction SMILES: N1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1C=CC=C[CH:12]=1>B(F)(F)F>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:12]=[CH:2][CH:3]=1
Reactant: c1ccncc1
Reactant: c1ccc2ncccc2c1
Agent: FB(F)F
Product: c1ccc2ccccc2c1

Procedure:
Naphthalene was polymerized at a temperature of from 200° to 400° C. in the presence of a HF.BF3 catalyst to obtain a pitch which has an optical anisotropy of 100 volume % as observed under a polarization microscope, an optically anisotropic structure of a "rough flow type", a glass transition temperature width (ΔTg) of 52° C., a quinoline-insoluble content of 18.5% by weight, a Mettler softening point of 250° C. and an elemental composition as analyzed of C: 94.8 wt % and H: 5.2 wt %. This pitch was finely pulverized. Then, 200 ml of pyridine was added to 5 g of this pitch, and extraction was conducted at 100° C., followed by filtration with a 0.05 μm membrane filter to remove the pyridine-insoluble matter. Then, from the soluble matter, pyridine was removed to obtain a pyridine-soluble pitch.
Reaction SMILES: O1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([O:28][CH3:29])=[C:8]([C:14]([CH2:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3C)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[C:9]([O:11][CH2:12]C)=[O:10])=C1.[C:30]1([S:36](CC2C(C(OC)=O)=C(OC)C(Br)=CC=2)(=O)=O)C=CC=CC=1.CC1(C)C(C)(C)OB(C2SC=CC=2)O1>>[C:21]1([S:18]([CH2:17][C:14]2[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:28][CH3:29])[C:6]([C:3]3[S:36][CH:30]=[CH:5][CH:4]=3)=[CH:16][CH:15]=2)(=[O:19])=[O:20])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2C)ccc(-c2ccoc2)c1OC
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Agent: CC1(C)OB(c2cccs2)OC1(C)C
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2cccs2)c1OC

Procedure:
Prepared by proceeding in a manner similar to Intermediate 28, starting from methyl 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 65) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene.
Reaction SMILES: CN.Cl.Cl.[CH2:5]([N:7]([CH2:30][CH3:31])[CH2:8][CH2:9][NH:10][C:11](=[O:29])[C:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O)[CH3:6].[C:32]([BH3-])#[N:33].[Na+]>CO>[ClH:20].[CH2:5]([N:7]([CH2:30][CH3:31])[CH2:8][CH2:9][NH:10][C:11]([C:12]1[N:33]([CH3:32])[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:15]2[C:14]=1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16]2)=[O:29])[CH3:6]
Reactant: [BH3-]C#N
Reactant: CCN(CC)CCNC(=O)C(=O)c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCN(CC)CCNC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 7.45 g. of methylamine in 120 ml. of methanol is treated with 12 ml. of 6.65-N methanolic hydrochloric acid. Thereafter, there are successively added under an atmosphere of argon at 20°-25° C. 17.0 g. of o-benzoyl-p-chlorophenylglyoxylic acid [2-(diethylamino)ethyl]amide hydrochloride and 1.6 g. of sodium cyanoborohydride and the mixture is stirred at room temperature for an additional 2 hours. The mixture is made acidic with concentrated hydrochloric acid while cooling with ice, stirred at room temperature for an additional 0.5 hour and evaporated to dryness under reduced pressure. The residue is made alkaline with 2-N ammonium hydroxide with the addition of ice and extracted with diethyl ether. After drying over sodium sulfate, the extract is concentrated to dryness and the oily residue triturated with hexane to crystallize the product. The product is removed by filtration, dissolved in 30 ml. of methanol and the solution treated with excess ethereal hydrochloric acid. After dilution with diethyl ether to a ten-fold volume, the hydrochloride which crystallizes out is removed by filtration and washed with diethyl ether. Recrystallization from methanol/diethyl ether yields 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid [2-(diethylamino)ethyl]amide hydrochloride in the form of almost colorless crystals having a melting point of 211°-214° C. (decomposition).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[O:12][C:11]([CH3:19])([CH3:18])[CH2:10][C:9]2=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[O:12][C:11]([CH3:19])([CH3:18])[CH:10]=[C:9]2[CH2:1][CH3:2]
Reactant: COc1cc2c(cc1Br)C(=O)CC(C)(C)O2
Reactant: CC[Mg]Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CCC1=CC(C)(C)Oc2cc(OC)c(Br)cc21

Procedure:
Following General Procedure C, ethylmagnesium bromide (2.0 M in THF, 4.7 mL, 14.08 mmol) was added to a solution of 6-bromo-7-methoxy-2,2-dimethyl-chroman-4-one (Compound 4, 800 mg, 2.81 mmol) in THF. The crude alcohol was treated with p-toluenesulfonic acid to afford the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](O)=[O:15])[C:9]2=[O:17])=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[OH:33])=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([C:40]2[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=2)([OH:33])[CH:34]2[CH2:35][CH2:36][N:37]([C:14](=[O:15])[CH2:13][N:10]3[CH2:11][CH2:12][C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)[C:9]3=[O:17])[CH2:38][CH2:39]2)=[CH:28][CH:27]=1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A mixture of the product of Example 58D (171 mg, 0.518 mmol), the product of Example 32A (157 mg, 0.518 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (197 mg, 0.518 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.361 mL, 2.07 mmol) in CH2Cl2 (5 mL) was stirred at ambient temperature for 36 hours. The reaction mixture was diluted by CH2Cl2, and the organic mixture was washed with 1 N aqueous HCl and saturated NaHCO3 solution and brine, dried with Na2SO4, filtered, and concentrated in vacuo. The crude product was chromatographed on silica gel (Analogix® Intelliflash™ 280; SF15-24 g column; 50% ethyl acetate/hexanes) to afford purified material that was taken up in a minimal amount of ether. Addition of hexanes caused formation of a solid that was collected by vacuum filtration and air-dried to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.59-7.47 (m, 4H), 7.40-7.29 (m, 4H), 7.18-7.04 (m, 8H), 5.48 (s, 1H), 4.41-4.29 (m, 1H), 4.19 (d, J=16.5, 1H), 4.09 (d, J=16.6, 1H), 3.86-3.75 (m, 1H), 3.38-3.30 (m, 2H), 3.05-2.89 (m, 1H), 2.85-2.63 (m, 3H), 2.63-2.51 (m, 1H), 1.40-1.17 (m, 4H); MS (DCI+) m/z 617 (M+H)+.
Reaction SMILES: [CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([OH:37])(=[O:36])[C@H:30]([CH2:32][C:33]([OH:35])=[O:34])[OH:31]>C(OCC)(=O)C.C(O)C>[CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([O-:37])(=[O:36])[C@H:30]([CH2:32][C:33]([O-:35])=[O:34])[OH:31]
Reactant: O=C(O)C[C@H](O)C(=O)O
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C([O-])C[C@H](O)C(=O)[O-]
Temperature: 60 °C

Procedure:
A 250 mL round flask was charged with Sitagliptin free base (5 g, 12 mmol) and a mixture of ethyl acetate:ethanol (5:0.8 v/v, 25 mL) was added. The mixture was mechanically stirred and heated to 60° C. until complete dissolution. The solution was then cooled to room temperature. In parallel, L-malic acid (1.65 g, 12 mmol) was completely dissolved in a mixture of ethyl acetate:ethanol (5:0.8 v/v, 10 mL) at 60° C. and then cooled to room temperature. The solution of the L-malic acid was then added dropwise to the solution of Sitagliptin free base over a period of 10 minutes while stirring at room temperature with the rotation speed of 310 rpm. The obtained white gel-paste reaction mixture was stirred at room temperature for about 69 hours. The obtained massive white precipitate was isolated by vacuum filtration, washed with cold mixture of ethyl acetate:ethanol (5:0.8 v/v, 2×10 mL) and dried in a vacuum oven at 40° C. for 23 hours to give Sitagliptin L-malate (5.99 g, 92% w/w yield).
Reaction SMILES: [C@H:1]1([NH:11][C:12]([C@H:14]2[NH:19][CH2:18][CH2:17][N:16]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:15]2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:30]([NH:37][C@H:38]([C:42](O)=[O:43])[CH:39]([CH3:41])[CH3:40])([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:33]([O:32][C:30]([NH:37][C@@H:38]([CH:39]([CH3:41])[CH3:40])[C:42]([N:19]1[CH2:18][CH2:17][N:16]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[CH2:15][C@H:14]1[C:12]([NH:11][C@H:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:13])=[O:43])=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(N[C@@H]1CCCc2ccccc21)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Yield: 63.5 %

Procedure:
The deprotected piperazine 3 (16.20 g, 41.2 mmol) is coupled with BOC-L-valine (8.95 g, 41.2 mmol) using DIEA (36.0 mL, 0.21 mol), HBTU (17.19 g, 45.3 mmol) and HOBt (6.12 g, 45.3 mmol) in DMF (700 mL) under the same conditions as in step 1 above. Purification is carried out by flash chromatography on silica gel (CH2Cl2 as eluent initially, followed by 10% Et2O/CH2Cl2 to elute the desired product). The desired coupled product 4 is isolated as a white foam (15.51 g, 64% yield): 1H NMR δ (CDCl3) 6.99-7.64 (m, 9H), 5.99-6.34 (br m, 1H), 2.68-5.26 (br m, 11H), 1.51-2.15 (br m, 6H), 1.42 (s, 9H), 1.15 (s, 3H), 0.64-1.02 (br m, 5H); LCMS (APCl+) 594.2 (MH+), 537.9 (MH+-tBu), 493.7 (MH+-BOC, 100%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]#[N:13])[CH:8]=[CH:9][CH:10]=1.Cl[CH2:15][CH2:16][N:17]([CH2:25][CH2:26]Cl)[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]>CS(C)=O.C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2([C:12]#[N:13])[CH2:26][CH2:25][N:17]([C:18]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:24])[CH2:16][CH2:15]2)[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc(CC#N)c1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1cccc(C2(C#N)CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 87.9 %

Procedure:
This compound is prepared by the procedure described in step A of preparation 1.8, from 16.3 g of sodium hydride at a concentration of 60% in oil in 400 ml of DMSO, 30 g of 3-methoxyphenylacetonitrile in 150 ml of THF and 47 g of tert-butyl bis(2-chloroethyl)carbamate in 100 ml of DMSO. This gives 54 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.[CH2:16]([CH:18]1[CH2:23][NH:22][CH:21]([CH3:24])[CH2:20][CH2:19]1)[CH3:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:22]1[CH2:23][CH:18]([CH2:16][CH3:17])[CH2:19][CH2:20][CH:21]1[CH3:24])=[O:15]
Reactant: CCC1CCC(C)NC1
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Product: CCC1CCC(C)N(C(=O)c2cnoc2-c2ccccc2Cl)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 5-ethyl-2-methylpiperidine (7.6 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (2.8 mg). Calcd for C18H21ClN2O2: 332.1292, found 332.1293.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[CH:5]=[CH:4][N:3]=1.Cl([O-])=[O:12].[Na+].S(=O)(=O)(O)N>C1COCC1.O.[OH-].[Na+]>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]([Cl:10])[C:7]=1[C:8]([OH:12])=[O:9]
Reactant: O=Cc1c(Cl)ccnc1Cl
Reactant: [O-][Cl+][O-]
Agent: NS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1c(Cl)ccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
A solution of 0.40 g of the aldehyde from Step B was dissolved in 6 mL of THF and then added to a solution of 0.27 g of sodium chlorite and 0.29 g of sulfamic acid in 6 mL of water. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with 1 N sodium hydroxide (10 mL) and extracted with diethyl ether (1×). The aqueous layer was then acidified with concentrated HCl, extracted with methylene chloride (2×), and the combine methylene chloride extracts were dried over magnesium sulfate. The methylene chloride was removed under vacuum to give 0.22 g of a solid. 1H NMR (CDCl3; 300 MHz) δ 7.38 (d, 1H J is 5.4 Hz), 8.40 (d, 1H, J is 5.5 Hz), 8.60 (bs, 1H).