Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])C)[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].[CH:13]([Cl:16])(Cl)[Cl:14].ClCl.[CH2:19](O)C>>[Cl:14][C:13]([Cl:16])([CH3:19])[C:10]([C:4]1[CH:5]=[C:6]([Cl:9])[C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=1)=[O:12]
Reactant: CC(=O)c1cc(Cl)c(O)c(Cl)c1
Reactant: ClC(Cl)Cl
Reactant: CCO
Agent: ClCl
Product: CC(Cl)(Cl)C(=O)c1cc(Cl)c(O)c(Cl)c1

Procedure:
A 500-milliliter reaction flask was charged with 21.9 grams (0.1 mole) of the 3',5'-dichloro-4'-hydroxyacetophenone, 250 grams of chloroform, and 10 grams of ethanol. The compound was chlorinated with 17.8 grams (0.25 mole) of chlorine gas added at 50°-55° C. over a period of 2.5 hours. The solution was evaporated under reduced pressure, and 27.1 grams of crude, white 2,2,3',5'-tetrachloro-4'-hydroxpropiophenone was obtained. Analysis calcd.: Hydrolyzable Cl, 24.6. Found: Hydrolyzable Cl, 22.3.
Reaction SMILES: [Br-].[F:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].O=[C:36]1[CH2:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]1>C1COCC1.O>[F:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:40]2[CH2:41][CH2:36][CH2:37][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:39]2)[CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: Fc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(=Cc2cccc(F)c2)C1
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
(3-Fluorobenzyltriphenylphosphonium bromide (Intermediate 228, 5.3 g) was added in portions to a solution of sodium tert-butoxide (1.06 g) in anhydrous THF (20 mL) at room temperature and the mixture was stirred for 30 minutes. A solution of tert-butyl 3-oxopiperidine-1-carboxylate (2 g) in anhydrous THF (10 mL) was added dropwise at room temperature and the mixture was stirred for 24 hours. The mixture was diluted with water (100 mL) and extracted with ether (100 mL), washed with brine, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexxane with a gradient of 0-20% to give tert-butyl 3-[1-(3-fluorophenyl)-methylidene]piperidine-1-carboxylate (1.42 g).
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](NC)=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].CN(C)C=O.IC1C=CC(C(O)=O)=CC=1OC.S(Cl)([Cl:34])(=O)=O>>[I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([Cl:34])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: O=S(=O)(Cl)Cl
Reactant: CNC(=O)c1ccc(I)c(OC)c1
Agent: COc1cc(C(=O)O)ccc1I
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Cl)ccc1I

Procedure:
4-Iodo-3-methoxy-N-methylbenzamide. N,N-Dimethylformamide (0.1 mL) was added to a solution of 4-iodo-3-methoxybenzoic acid (2.0 g, 7.2 mmol) in sulfuryl dichloride (20 mL), and the mixture was heated to reflux for 2 h. The excess sulfuryl dichloride was removed under reduced pressure to give the crude product 4-iodo-3-methoxy-benzoyl chloride. To a solution of methyl amine (0.72 g, 10.8 mmol) and triethylamine (2.18 g, 21.6 mmol) in dichloromethane (20 mL) was added dropwise a solution of the above 4-iodo-3-methoxy-benzoyl chloride in dichloromethane (15 mL) at 0° C. After the reaction was completed, water was added, the organic layer was separated, dried over sodium sulfate evaporated to give the crude product, which was purified on silica gel column (eluting with 10-17% ethyl acetate in petroleum ether) to give 4-iodo-3-methoxy-N-methylbenzamide (0.92 g, 46% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.92 (d, J=8.0 Hz, 1H), 7.42 (d, J=5.6 Hz, 1H), 7.31 (dd, J1=8.0 Hz, J2=2.0 Hz, 1H), 3.88 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18][C:19]2[N:28]=[C:27]([N:29]([CH3:31])[CH3:30])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.[Br:42][C:43]1[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[C:45]([O:53][C:54]([F:57])([F:56])[F:55])[CH:44]=1>CO.C(Cl)Cl.[Pd]>[Br:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18][C:19]3[N:28]=[C:27]([N:29]([CH3:31])[CH3:30])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[CH2:13][CH2:12]2)(=[O:51])=[O:50])=[C:45]([O:53][C:54]([F:57])([F:56])[F:55])[CH:44]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: CN(C)c1nc(NC[C@H]2CC[C@H](NC(=O)OCc3ccccc3)CC2)nc2ccccc12
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1nc(NC[C@H]2CC[C@H](NS(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a suspension of trans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-carbamic acid benzyl ester (500 mg, 1.15 mmol) in MeOH (5 mL) was added 5% Pd/C (50 mg). The mixture was stirred at ambient temperature under hydrogen atmosphere for 2 hr, at 50° C. for 8 hr, and at ambient temperature for 10.5 hr, filtered, and concentrated to give a colorless oil. To a solution of the above oil in CH2Cl2 (5 mL) was added diisopropylethylamine (420 μL, 2.41 mmol). The mixture was cooled to 4° C. and a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (431 mg, 1.27 mmol) in CH2Cl2 (2 mL) was added below 5° C. The reaction mixture was stirred at 4° C. for 1.5 hr. The reaction was quenched with saturated aqueous NaHCO3 The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 33% to 50% EtOAc in hexane) to give trans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-2-trifluoromethoxy-benzenesulfonamide (560 mg, 81%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[CH:19]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([CH3:21])[CH3:20]>>[ClH:1].[ClH:1].[CH:19]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[CH:4][N:3]=2)[CH2:24][CH2:23]1)([CH3:21])[CH3:20]
Reactant: CC(C)N1CCNCC1
Reactant: FC(F)(F)Oc1ccc(-c2ccc(Cl)nc2)cc1
Product: CC(C)N1CCN(c2ccc(-c3ccc(OC(F)(F)F)cc3)cn2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 2-chloro-5-(4-trifluoromethoxyphenyl)pyridine and 1-isopropylpiperazine.
Reaction SMILES: N[C:2]1[CH:7]=[C:6](NCCCC2C=CC=CC=2)[CH:5]=[C:4](N)[N+:3]=1[O-:19].Cl[S:21]([OH:24])(=[O:23])=[O:22].C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[OH-:19].[S:21]([O:19][N+:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)([OH:24])(=[O:23])=[O:22]
Reactant: O=S(=O)(O)Cl
Reactant: Nc1cc(NCCCc2ccccc2)cc(N)[n+]1[O-]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(O)O[n+]1ccccc1
Product: [OH-]
Reaction time: 8 h

Procedure:
A mixture of 1.00 grams of 2,6-diamino-4-((3-phenyl-1-propyl)amino)-pyridine-1-oxide, 1.50 grams of chlorosulfonic acid, and 2.5 grams of di-isopropylethylamine in 25 ml of chloroform is stirred overnight. The mixture is concentrated in vacuo. The residue is stirred with aqueous sodium bicarbonate, filtered and washed with ether to give the crude product. This is recrystallized from DMF and ethyl acetate to yield the purified 2,6-diamino-4-((3-phenyl)-1-propyl)amino)-1-(sulfooxy)-pyridinium hydroxide, inner salt.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[O:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)[Cl:19].[NH2:22][C:23]1[S:24][C:25]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1>N1C=CC=CC=1>[ClH:19].[NH2:22][C:23]1[S:24][C:25]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[C:26]([C:28](=[O:29])[NH:14][CH2:13][CH2:12][CH2:11][O:10][C:9]2[CH:15]=[CH:16][CH:17]=[C:7]([CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)[N:27]=1
Reactant: NCCCOc1cccc(CN2CCCC2)c1
Reactant: Nc1nc(C(=O)O)c(-c2ccncc2)s1
Reactant: ClP(Cl)Cl
Solvent: c1ccncc1
Product: Cl
Product: Nc1nc(C(=O)NCCCOc2cccc(CN3CCCC3)c2)c(-c2ccncc2)s1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-[3-(pyrrolidin-1-ylmethyl)phenoxy]propylamine (2.33 g) and phosphorus trichloride (0.44 ml) in pyridine (20 ml) was added 2-amino-5-(4-pyridyl)-4-thiazolecarboxylic acid (1.1 g) and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of ethyl acetate and water. The resultant mixture was adjusted to pH 1.0 with 10% hydrochloric acid. The separated aqueous layer was adjusted to pH 8 with saturated potassium carbonate and extracted with chloroform. The solvent was dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to column chromatography on alumina eluting with a mixture of ethyl acetate and tetrahydrofuran (3:7). The fractions containing the desired compound were combined and evaporated in vacuo. To the oily residue was added a solution of ethyl acetate and hydrochloric acid. The precipitate was collected by filtration and dried over phosphorus pentoxide in vacuo to afford 2-amino-5-(4-pyridyl)-4-[ 3-[3-(pyrrolidin-1-yl-methyl)phenoxy]propylcarbamoyl]thiazole hydrochloride (0.34 g).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH:9]([O:11][C:12]2[C:21]3[C:16](=[C:17]([CH3:24])[C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[N:15]=[C:14]([C:25]3[S:26][CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=3)[N:13]=2)[CH2:8][CH2:7][N:6]1C)=[O:4].COC(C1CC(OC2C3C(=C(C)C(OC)=CC=3)N=C(C3SC=C(C(F)(F)F)N=3)C=2)CCN1)=O>>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH:9]([O:11][C:12]2[C:21]3[C:16](=[C:17]([CH3:24])[C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[N:15]=[C:14]([C:25]3[S:26][CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[N:29]=3)[N:13]=2)[CH2:8][CH2:7][NH:6]1)=[O:4]
Reactant: COC(=O)C1CC(Oc2nc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)CCN1C
Agent: COC(=O)C1CC(Oc2cc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)CCN1
Product: COC(=O)C1CC(Oc2nc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)CCN1
Yield: 55 %

Procedure:
Compound 23 was synthesized from compound 22 as a pale yellow powder in 55% yield according to the procedure as described for compound 14. MS (ESI, EI+) m/z=483 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH3:12])[C:4](=[O:13])[CH:3]=1.O.[SH-:15].[Na+]>C(O)C>[SH:15][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH3:12])[C:4](=[O:13])[CH:3]=1
Reactant: CCCn1c(Cl)cc(=O)n(C)c1=O
Reactant: [SH-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCn1c(S)cc(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 6-chloro-3-methyl-1-propyl-pyrimidine-2,4(1H,3H)-dione (3.76 g), sodium hydrosulphide hydrate (6.0 g) and ethanol (100 ml) was stirred at room temperature for 48 h then concentrated under reduced pressure. The residue was dissolved in water (500 ml) and washed with ethyl acetate (2×100 ml). The aqueous phase was acidified with dilute hydrochloric acid, then extracted with ethyl acetate (3×100 ml). The combined organic phase was dried (MgSO4) and concentrated in vacuo to give a pale yellow solid which was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][C@H:13]([CH3:17])[CH2:14][O:15][CH3:16])[CH:11]=1)[N:8]=[C:7]([CH3:18])[CH:6]=[CH:5]2.[Se](=O)=[O:20]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][C@H:13]([CH3:17])[CH2:14][O:15][CH3:16])[CH:11]=1)[N:8]=[C:7]([CH:18]=[O:20])[CH:6]=[CH:5]2
Reactant: COC[C@@H](C)Oc1cc(F)cc2ccc(C)nc12
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: COC[C@@H](C)Oc1cc(F)cc2ccc(C=O)nc12
Yield: 89.5 %

Procedure:
To a solution of (R)-6-fluoro-8-(1-methoxypropan-2-yloxy)-2-methylquinoline (0.70 g, 2.8 mmol) in dioxane (55 mL) and water (0.55 mL) was added selenium dioxide (0.38 g, 3.4 mmol) and the resultant mixture heated at reflux for 2 hours. The cooled reaction mixture was filtered through a plug of Celite® to remove solids, rinsing with dichloromethane. The filtrate was concentrated under reduced pressure and purified by normal phase chromatography on silica gel (10-30% ethyl acetate/hexanes) to afford the title compound (0.66 g, 89%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11]/[C:10](=[CH:26]\N(C(C)C)C(C)C)/[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].[OH-].[Na+].C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:11][C@@H:10]([CH3:26])[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:2])[CH3:3].[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:11][C@H:10]([CH3:26])[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)N(/C=C1\C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O)C(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Product: C[C@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C

Procedure:
1.3 g (R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) is added to ethyl acetate (40 ml) at ambient temperature. 0.3 g of 10% Palladium on Carbon (Engelhard 4505) and one drop of aqueous sodium hydroxide solution are added to the mixture. The mixture is then pressurised under a hydrogen atmosphere to 4 bar. The mixture is stirred at ambient temperature and 4 bar hydrogen pressure for 4 days. The mixture is then filtered to remove the catalyst and concentrated under reduced pressure. The residue is then purified by column chromatography (ethyl acetate/hexane, 70:30) to afford (3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3-a, R1=Boc) and (3S,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3-b, R1=Boc). Diastereomer ratio 76:24 (3-a, R1=Boc: 3-b, R1=Boc) as determined by hplc.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[O:11][CH3:12].[Br:14]N1C(=O)CCC1=O>C1C=CC=CC=1>[Br:14][CH2:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH3:12])=[C:4]([CH:9]=1)[C:3]([O:2][CH3:1])=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(C)ccc1OC
Solvent: c1ccccc1
Product: COC(=O)c1cc(CBr)ccc1OC

Procedure:
A mixture of 2-methoxy-5-methylbenzoic acid methyl ester (J.Chem.Soc.Perkin Trans.1, 1994, 1125) (1.47 g) and N-bromosuccinimide (1.45 g) in benzene (15 ml) was irradiated under a 500 W halogen lamp for 3 hours. The solvent was evaporated and the residue triturated with diethyl ether. The succinimide was filtered off and the filtrate evaporated.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:19]=[C:20]([O:22]CC3C=CC=CC=3)[CH:21]=2)[C:10]([NH:12][C:13]2[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=2)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:19]=[C:20]([OH:22])[CH:21]=2)[C:10]([NH:12][C:13]2[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=2)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OC3CCCC3)c2)n1
Agent: [Pd]
Solvent: CCO
Product: Cn1ccc(NC(=O)c2cc(O)cc(OC3CCCC3)c2)n1
Reaction time: 86 h

Procedure:
3-(Cyclopentyloxy)-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide (1.87 g, 4.78 mmol) was dissolved in ethanol (40 mL) and 10% palladium on charcoal (102 mg) catalyst added under argon. The reaction was stirred under an atmosphere of hydrogen for 86 hours, then filtered through Celite® and concentrated in vacuo to a light brown solid (1.31 g). 1H NMR δ (d6-DMSO): 1.54 (m, 2H), 1.76 (m, 4H), 1.96 (m, 2H), 2.75 (s, 1H), 3.83 (s, 3H), 4.91 (m, 1H), 6.49 (m, 1H), 6.61 (m, 1H), 6.98 (m, 1H), 7.06 (m, 1H), 7.65 (s, 1H), 9.73 (br s, 1H); m/z 302 (M+H)+
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=[O:10].[CH2:14](O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:8]([O:13][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])(=[O:12])[C:9]([CH3:11])=[O:10]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: CC(=O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOC(=O)C(C)=O
Temperature: 25 °C
Yield: 60.1 %

Procedure:
A toluene solution (1 L) containing pyruvic acid (220 g, 2.5 mol), stearyl alcohol (675 g, 2.5 mol) and p-toluenesulfonic acid monohydrate (1.2 g) was heated and refluxed for 16 hours under nitrogen flow. The reaction led to generation of water in the system. However, the water was removed using Dean-Stark trap. The resultant reaction solution was cooled down to room temperature, followed by removal of toluene using an evaporator under a reduced pressure. The residual was then purified using reduced pressure distillation (1 mmHg, 110 to 120° C.) to give stearyl pyruvate (512 g, yield: 80%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[Cl:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](=[N:15]O)[NH2:14])=[C:11]([CH3:19])[CH:10]=1>N1CCCCC1>[Cl:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]2[NH:15][CH:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[O:7][N:14]=2)=[C:11]([CH3:19])[CH:10]=1
Reactant: O=Cc1ccco1
Reactant: Cc1cc(Cl)ccc1C(N)=NO
Solvent: C1CCNCC1
Product: Cc1cc(Cl)ccc1C1=NOC(c2ccco2)N1
Temperature: 10 °C
Yield: 18.1 %

Procedure:
A mixture of 2-furancarboxaldehyde (166 mL, 192 mg, 2.0 mmol), 4-chloro-N′-hydroxy-2-methylbenzimidamide (368 mg, 2.0 mmol) and one drop of piperidine was heated to 10° C. for 4 h. The mixture was cooled to room temperature and purified by automated column chromatography on the ISCO COMPANION (SiO2, gradient heptanes/ethyl acetate) to give the 3-(4-chloro-2-methylphenyl)-5-(furan-2-yl)-4,5-dihydro-1,2,4-oxadiazole product (95 mg) with a yield of 18%. LC-MS [M+H] 263 (C13H11ClN2O2+H, expected 263.05)
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[C:21](=[O:39])[N:22]([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29]([C:35]([F:38])([F:37])[F:36])[CH:28]=2)[C:23](=[O:26])[C:24]=1[CH3:25]>O1CCCC1.C(OCC)(=O)C>[C:31]([C:30]1[CH:33]=[CH:34][C:27]([N:22]2[C:23](=[O:26])[C:24]([CH3:25])=[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]3)[C:21]2=[O:39])=[CH:28][C:29]=1[C:35]([F:38])([F:37])[F:36])#[N:32]
Reactant: CC1=C(CCCCCI)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1=C(CCCCCN2CCN(C(=O)OC(C)(C)C)CC2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 25 °C
Reaction time: 168 h
Yield: 98 %

Procedure:
1.56 g of 1,1-dimethylethyl piperazine-1-carboxylate was added under a nitrogen atmosphere to a solution of 2.0 g of 4-[2,5-dihydro-3-(5-iodopentyl)-4-methyl-2,5-dioxo-1H-pyrrol-1-yl]-2-(trifluoromethyl)benzonitrile in 53 ml of tetrahydrofuran, and this mixture was stirred for 7 days at room temperature. For working-up, it was diluted with ethyl acetate and washed with semi-saturated sodium bicarbonate solution. After drying on sodium sulfate and concentration by evaporation, it was chromatographed with methanol/dichloromethane on silica gel, and thus 2.2 g of the title compound was obtained as a yellowish oil.
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[OH-].[NH4+]>O>[C:1]([O:4][CH:5]=[CH2:6])(=[O:3])[CH3:2].[CH:1]([OH:3])=[CH2:2]
Reactant: CCOC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: C=CO
Product: C=COC(C)=O
Reaction time: 48 h

Procedure:
To 100 g of the same copolymer was added 1500 ml of ethyl acetate, 40 ml of concentrated ammonium hydroxide and 40 ml of water. After two days with stirring, the polymer dissolved to give a gel. During the next three weeks at room temperature, a progressive decrease in viscosity of the solution was noted. At this time the solution was heated to remove ammonia, giving a partially saponified polymer of composition 32.4 wt % vinyl acetate, 16.4 wt % vinyl alcohol, 38 wt % TFE, and 13.2 wt % HFP in a 27.4 wt % solids solution in ethyl acetate.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:23]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C@H:30]2[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:32]([C:42](O)=[O:43])[CH2:31]2)[CH:24]=1.[NH2:51][CH2:52][CH2:53][NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58]>ClCCl.C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:57]([O:56][C:55]([NH:54][CH2:53][CH2:52][NH:51][C:42](=[O:43])[C@@H:32]1[CH2:31][C@@H:30]([O:29][C:25]2[CH:24]=[C:23]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH:28]=[CH:27][CH:26]=2)[CH2:34][N:33]1[C:35]([O:37][C:38]([CH3:40])([CH3:41])[CH3:39])=[O:36])=[O:61])([CH3:60])([CH3:59])[CH3:58]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CC(C)(C)OC(=O)N1C[C@H](Oc2cccc(-c3ccccc3)c2)C[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCNC(=O)[C@@H]1C[C@@H](Oc2cccc(-c3ccccc3)c2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
Triethylamine (56 μL), 1-hydroxybenzotriazole (25 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (78 mg) were added to a solution of trans-4-(3-biphenyloxy)-N-tert-butoxycarbonyl-L-proline (B), (141 mg) and tert-butyl N-(2-aminoethyl)carbamate (65 mg) in dichloromethane (3 mL). After stirring at room temperature overnight, the reaction mixture was diluted with chloroform and washed with saturated sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography chloroform:methanol=100:1, v/v to give the titled compound (175 mg) as a colorless foam: 1H NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 2.37 (m, 1H), 2.59 (m, 1H), 3.28 (m, 1H), 3.29 (s, 2H), 3.40 (m, 1H), 3.73 (m, 2H), 4.41 (m, 1H), 5.01 (m, 1H), 5.18 (m, 1H), 6.86 (m, 2H), 7.08 (s, 1H), 7.20 (d, J=7.3 Hz, 1H), 7.35 (t, J=7.3 E4z, 2H), 7.43 (t, J=7.3 Hz, 2H), and 7.56 (d, J=7.3 Hz,2H).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3]([NH2:5])=[O:4].[C:7]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][C:12]=1[NH:20][C:21](=[O:38])[CH2:22][CH:23]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])[CH2:24][CH2:25][CH2:26][CH3:27])([CH3:10])([CH3:9])[CH3:8]>>[C:7]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([NH:5][C:3](=[O:4])[CH:2]([CH3:6])[CH3:1])=[O:19])=[CH:13][C:12]=1[NH:20][C:21](=[O:38])[CH2:22][CH:23]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])[CH2:24][CH2:25][CH2:26][CH3:27])([CH3:8])([CH3:9])[CH3:10].[CH:31]([O:34][CH:2]([CH3:3])[CH3:6])([CH3:32])[CH3:30]
Reactant: CCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Reactant: CC(C)C(N)=O
Product: CC(C)OC(C)C
Product: CCCCC(CC(=O)Nc1cc(C(=O)NC(=O)C(C)C)ccc1C(C)(C)C)c1ccc(OC)cc1OC

Procedure:
Following a similar procedure to that described in Example 139, but using 2-methylpropanamide and N-(2-t-butyl-5-carboxyphenyl)-3-(2,4-dimethoxyphenyl)heptanamide (prepared as described in Preparation 31B), the title compound was obtained as crystals, melting at 139-140° C. (from diisopropyl ether).