Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[O:13]=[C:14]1[NH:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:10][O:9][C:7]([C:6]1[CH:11]=[CH:12][C:3]([CH2:2][N:19]2[CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:15][C:14]2=[O:13])=[CH:4][CH:5]=1)=[O:8]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2=O)cc1

Procedure:
500 mg of methyl 4-(bromomethyl)benzoate was reacted with 480 mg of tert-butyl 3-oxopiperazine-1-carboxylate and 1 g of Cesium Carbonate in 9 mL of DMF at 45° C. Upon completion, the reaction was extracted in Ethyl Acetate 2 times saturated bicarbonate, dried over Magnesium Sulfate, filtered and concentrated to give tert-butyl 4-(4-(methoxycarbonyl)benzyl)-3-oxopiperazine-1-carboxylate. 613 mg of tert-butyl 4-(4-(methoxycarbonyl)benzyl)-3-oxopiperazine-1-carboxylate was hydrolyzed via Procedure M to give 4-((4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)methyl)benzoic acid. 200 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-((4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)methyl)benzoic acid via Procedure G. The crude product was extracted twice with saturated bicarbonate in Ethyl Acetate, dried over Magnesium Sulfate, filtered and concentrated to give crude tert-butyl 4-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)-3-oxopiperazine-1-carboxylate. 4N HCl was subsequently added to crude tert-butyl 4-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)-3-oxopiperazine-1-carboxylate and concentrated to give the HCl salt of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-oxopiperazin-1-yl)methyl)benzamide. The reaction was purified by reverse phase HPLC to give pure N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-oxopiperazin-1-yl)methyl)benzamide. MS (Q1) 421.3 (M)+.
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](OCCCl)=[O:4].[C:15]([O:19][CH:20]([CH3:22])[CH3:21])(=[O:18])[CH2:16][OH:17].C(C1C=CC=CC=1)(C)(C)C>C(OCC)C>[OH:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:17][CH2:16][C:15]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[O:4]
Reactant: CC(C)OC(=O)CO
Reactant: O=C(OCCCl)C(O)c1ccccc1
Solvent: CCOCC
Solvent: CC(C)(C)c1ccccc1
Product: CC(C)OC(=O)COC(=O)C(O)c1ccccc1

Procedure:
A 6 mL aliquot of an ethyl ether solution containing 0.25M 2-chloroethyl 2-hydroxy-2-phenylacetate, 0.25M isopropyl glycolate, and 1.0% tert-butylbenzene was added to 0.43 g Lipase P30. After mixing for 5 d at room temperature, the conversion of 2-chloroethyl 2-hydroxy-2-phenylacetate to the title compound was estimated (by GC, Method B) to be approximately 15%. The GC peak assigned to the title compound was confirmed by HRMS: calcd for C12H12O5Tms (M-CH3) 309.1158, obsd 309.1171. In identical reactions substituting Lipase G, Lipase AK, Lipase MAP10, Protease M, Lipase AP12, or porcine pancreatic lipase for Lipase P30, the relative values for conversions at 5 d (Lipase P30=100) were 17, 12, 12, 6, 4, and 2%, respectively.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[S:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][N:14]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[N+:15]([C:12]1[S:11][C:10]([NH:9][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])=[N:14][CH:13]=1)([O-:17])=[O:16]
Reactant: Nc1ncc([N+](=O)[O-])s1
Reactant: O=C1CCCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(O)CCCC(=O)Nc1ncc([N+](=O)[O-])s1
Reaction time: 18 h
Yield: 49.5 %

Procedure:
Glutaric anhydride (1.0 g, 8.8 mmol), TEA (1.35 ml, 9.6 mmol) and cat. DMAP were dissolved in CH2Cl2 (7 mL). 2-Amino-5-nitrothiazole (1.4 g, 9.64 mmol) was then added and the solution was held at ambient temperature. After 18 hours, the solution was diluted with EtOAc (50 mL) and extracted with 1M NaOH (3×30 mL). The combined aqueous layers were washed with EtOAc (20 mL) then acidified with 12M HCl and subsequently extracted with EtOAc (5×20 mL). The combined organics were washed with brine (2×20 mL), dried (MgSO4), filtered and concentrated to dryness to yield 5-(5-nitrothiazol-2-ylamino)-5-oxopentanoic acid (1.13 g, 54%) as an orange solid. 1H NMR (300 MHz, DMSO-d6) δ 12.59 (bs, 1H), 8.59 (s, 1H), 2.57 (t, J=7.4 Hz, 2H), 2.28 (t, J=7.3 Hz, 2H), 1.82 (quint., J=7.3 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 174.0, 172.8, 161.8, 142.8, 141.7, 34.1, 32.7, 19.6; HRMS (ESI) calcd for [C8H9N3O5S+H]+260.0336. found 260.0344. Method B with 5-(5-nitrothiazol-2-ylamino)-5-oxopentanoic acid (30 mg, 0.12 mmol) afforded the title compound VPC161276 (23 mg, 46%) as an orange solid. 1H NMR (300 MHz, DMSO-d6) δ 8.61 (s, 2H), 2.61 (t, J=7.2 Hz, 4H), 1.97 (quint., J=7.0 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 172.8, 162.0, 142.8, 141.5, 34.0, 19.3; HRMS (ESI) calcd for [C11H10N6O6S2+H]+387.0176. found 387.0185.
Reaction SMILES: Cl[C:2]1[S:6][CH:5]=[CH:4][C:3]=1[CH2:7]Br.[Cl-].C[N+](C(=O)CCCCCCC)(C(=O)CCCCCCC)[C:12](=O)[CH2:13][CH2:14]CCCCC.C(Cl)(Cl)Cl>O1CCCC1.[OH-].[Na+]>[S:6]1[CH:5]=[CH:4][C:3]2[CH:7]=[CH:12][CH:13]=[CH:14][C:2]1=2
Reactant: Clc1sccc1CBr
Reactant: CCCCCCCC(=O)[N+](C)(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: c1ccc2sccc2c1

Procedure:
Stir cis-6-chloro-2,3-dihydro-3-hydroxy-2-[(1', 2', 4'-triazolyl)-1'-methyl]benzo(b)thiophene (1.17 gms., 4.37 mmols), 2-chloro-3-thenylbromide (1.06 gms., 5.0 mmol) and methyl tricaprylyl ammonium chloride (0.1 gm.) in tetrahydrofuran (25 ml) and 50% sodium hydroxide (10 ml) at room temperature for one hour. Pour the reaction mixture into chloroform (500 ml.) and extract with two 500 ml. portions of water. Dry the chloroform solution over anhydrous magnesium sulfate, filter and evaporate in vacuo. Chromatograph the resultant residue on silica gel eluting with chloroform. Combine the like eluates as determined by thin layer chromatography and evaporate in vacuo to obtain cis-6-chloro-3-(2'-chloro-3'-thenyloxy)-2,3-dihydro-2-[(1", 2", 4"-triazolyl)-1"-methyl]benzo(b)thiophene, a gum.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)C#N)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(=O)([O-])[O-:23].[K+].[K+]>CS(C)=O.O>[Cl:1][C:2]1[C:3]([C:12](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: N#CC(c1ccc(Cl)cc1)c1ncc(C(F)(F)F)cc1Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(c1ccc(Cl)cc1)c1ncc(C(F)(F)F)cc1Cl
Temperature: 23 °C
Reaction time: 72 h

Procedure:
A solution of 2.0 g of 3-chloro-2-[1-(4-chlorophenyl)-1-cyanomethyl]-5-trifluoromethylpyridine (prepared by the method of Example 1) in 20 ml of dimethyl sulfoxide was admixed with a solution of 2.0 g of potassium carbonate in 3 ml of water, and the mixture was then stirred at 23° C. for 3 days under air. For work-up, the reaction mixture was poured into 200 ml of water. The product of value was then extracted with tert-butyl methyl ether (three times 80 ml). The combined organic phases were washed with water (two times 50 ml each), dried over sodium sulfate and finally concentrated. The resulting black oil was purified by Kugelrohr distillation under reduced pressure. Yield: 1.2 g (62%) of a light-yellow oil; boiling range: 110-120° C. (0.3 mbar); 1H NMR see Ex. 7.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1.[C:11]1([CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:7]([N:5]1[N:4]=[N:3][C:2]([NH:1][C:18](=[O:19])[CH:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:6]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)n1nnc(N)n1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CC(C)(C)n1nnc(NC(=O)C(c2ccccc2)c2ccccc2)n1

Procedure:
The title compound, white solid, m.p. 191-192° and MS: (neg. ions): m/e=334.3 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-tert-butyl-2H-tetrazole and diphenylacetyl chloride.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]([CH2:10][O:11][C:12](=[O:32])[NH:13][CH2:14][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])[CH2:8]O)[N:5]=[N:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:52]=[N+]=[N-].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.[C].[Pd].C1C=CC=CC=1>[CH3:1][C:2]1[N:6]([CH:7]([CH2:10][O:11][C:12](=[O:32])[NH:13][CH2:14][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])[CH2:8][NH2:52])[N:5]=[N:4][N:3]=1
Reactant: [N-]=[N+]=N
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)n1nnnc1C
Agent: [Pd]
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)n1nnnc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a stirred solution of 1.02 g (2.25 mM) of 2-(5-methyl-1H-tetrazol-1-yl)-3-octadecylcarbamoyloxypropanol V i2, 885 mg (3.38 mM) of triphenylphosphine, and 1.9 ml (3.38 mM) of 1.8 mM benzene solution of hydrazoic acid in 50 ml of tetrahydrofurane at -50° C. is added 0.53 ml (3.38 mM) of diethyl azodicarboxylate dropwise and the mixture is raised to room temperature during 2 hr. Subsequently, 150 mg of 10% palladium carbon is added to the mixture which is stirred under hydrogen gas for 30 minutes. After 10% palladium carbon filtered off, the solvent is evaporated. The residue obtained is purified by column silica gel chromatography using ethyl acetate-chloroform/methanol (9/1) mixture as an eluent and 0.82 g (81% yield) of the title compound is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)[CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][N:32]=[C:31]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=5)[CH:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Fc1cccc(-c2cc(Br)ccn2)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4ccnc(-c5cccc(F)c5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-bromo-2-(3-fluoro-phenyl)-pyridine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]2)=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[N:13][C:12]([C:15]#[N:16])=[CH:11][N:10]=2)=[N:6][CH:7]=1.[BH4-].[Na+].[CH3:34][OH:35]>>[OH:35][CH2:34][C:2]1[CH:3]=[CH:4][N:1]([C:2]2[C:3]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[CH:4][C:5]([NH:8][C:9]3[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=3)=[N:6][CH:7]=2)[CH:7]=1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2N)C1
Agent: [BH4-]
Agent: [Na+]
Product: N#Cc1cnc(Nc2cc(NCC3CCCNC3)c(-n3ccc(CO)c3)cn2)cn1
Temperature: 0 °C
Reaction time: 4 h
Yield: 11 %

Procedure:
tert-Butyl 3-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (37 mg, 0.074 mmol) (Synthesis 107-A) was dissolved in methanol (1.5 mL) and cooled to 0° C. Sodium borohydride (15 mg, 0.396 mmol) was added and the reaction was stirred at 0° C. for 4 h. The solution was evaporated and the residue was partitioned between water and dichloromethane. The two phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were evaporated and the residue was dissolved in methanol (1 mL) and absorbed onto a TsOH solid phase extraction cartridge. After 1.5 h the cartridge was eluted with 7M ammonia in methanol. The basic eluent was evaporated to dryness. The residue was purified by HPLC to give 5-(5-(3-(hydroxymethyl)-1H-pyrrol-1-yl)-4-(piperidin-3-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile (3.18 mg, 11%).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1>C(Cl)Cl.FC(F)(F)C(O)=O>[F:30][C:2]([F:1])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCN(c3ccc(OC(F)(F)F)cc3)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)Oc1ccc(N2CCC(N3CCNCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
Tert-butyl 4-[1-(4-trifluoromethoxyphenyl)-piperidin-4-yl]piperazine-1-carboxylate (1 g, 2.33 mmol) was dissolved in methylene chloride (10 ml), to which trifluoroacetic acid (10 ml) was added while cooling in an ice-bath, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with a 25% sodium hydroxide aqueous solution (40 ml) and brine (10 ml), and dried over sodium sulfate. After filtration, the filtrate was concentrated to afford 1-[1-(4-trifluoromethoxyphenyl)piperidin-4-yl]piperazine (770 mg, quantitative) as a yellow amorphous form.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:28]=[CH:27][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17](Br)=[C:16]([CH3:21])[N:15]([C@@H:22]([CH3:26])[CH2:23][O:24][CH3:25])[CH:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:29][CH:30]([F:40])[C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>>[CH3:1][S:2]([C:5]1[CH:28]=[CH:27][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([CH:30]([F:40])[F:29])[CH:36]=3)=[C:16]([CH3:21])[N:15]([C@@H:22]([CH3:26])[CH2:23][O:24][CH3:25])[CH:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: OB(O)c1cccc(C(F)F)c1
Reactant: COC[C@H](C)n1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)c(Br)c1C
Product: COC[C@H](C)n1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)c(-c2cccc(C(F)F)c2)c1C

Procedure:
Example 42 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 41c and replacing 3-(trifluoromethyl)phenylboronic acid with 3-(difluoromethyl)phenylboronic acid. ESI mass spectrum: [M+H]+=519; Retention time HPLC: 0.97 min (Z018_S04).
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]([C:13]#[N:14])=[CH:6][C:7]([CH3:12])([CH3:11])[CH2:8][CH:9]=[CH2:10])C.[H][H].[ClH:18]>C(O)C.O=[Pt]=O>[ClH:18].[NH2:14][CH2:13][CH:5]([CH2:6][C:7]([CH3:11])([CH3:12])[CH2:8][CH2:9][CH3:10])[C:4]([OH:15])=[O:3]
Reactant: [H][H]
Reactant: C=CCC(C)(C)C=C(C#N)C(=O)OCC
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: CCCC(C)(C)CC(CN)C(=O)O

Procedure:
2-Cyano-4,4-dimethyl-hepta-2,6-dienoic acid ethyl ester (5.88 g, 28 mmol) was dissolved in the mixture of 91 mL of ethanol and 6 mL of HCl and treated with 0.4 g of PtO2. The reaction was carried out under 100 psi of hydrogen pressure at room temperature for 15 hours. The catalyst was filtered and filtrate was concentrated to give 3.8 g of the desired product 2-aminomethyl-4,4-dimethyl-heptanoic acid ethyl ester as an oil. MS (APCI): 216.2 (M+1)+. This oil was refluxed in 75 mL of 6N HCl for 18 hours. While the reaction was cooled, a precipitate formed. The solid was filtered, washed with additional HCl solution and triturated with ether to give the clean title compound. MS (APCI): 188.1 (M+1)+. 186.1 (M−1)+. 1H NMR (400 MHz; CD3OD): 0.91 (9H, m), 1.30 (5H, m), 1.81 (dd, 1H, J=7.2 Hz, 14.4 Hz), 2.72 (1H, m), 3.04 (2H, m); Anal. Calc'd for C10H21NO2.HCl: C: 53.68, H: 9.91, N: 6.26, Cl: 15.85; Found: C: 53.83, H: 10.15, N: 6.22, Cl: 15.40. MP: 229.5–231.0° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23]([NH:26][CH3:27])=[C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH:21]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23]([N:26]([CH3:27])[C:6](=[O:7])[C:5]2[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=2)=[C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH:21]=1
Reactant: CNc1cnc(OC)cc1-c1ccccc1C
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2ccccc2C)c(N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reaction time: 2 h
Yield: 74.7 %

Procedure:
3,5-Bis-trifluoromethylbenzoyl chloride (126 μL, 0.69 mmol, CAS RN 1271-19-8) was added to a solution of 6-methoxy-N-methyl-4-o-tolylpyridin-3-amine (105 mg, 0.46 mmol) and DIPEA (240 μL, 1.38 mmol) in CH2Cl2 and stirred for 2 h. The reaction mixture was then loaded directly onto a silica gel column Elution with 20% EtOAc in n-hexane gave the title product as a colorless foam (161 mg, 76%). MS (ESI): m/z=469.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[CH:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]Br)=[CH:10][CH:9]=1>>[C:11]1([CH2:14][CH2:15][CH2:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH2:5][CH2:15][CH2:14][C:11]2[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=2)[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)CC(C)=O
Reactant: BrCCc1ccccc1
Product: O=C(CCCc1ccccc1)CC(=O)CCCc1ccccc1

Procedure:
Using 2,4-pentandione (93.8 g, 0.94 mol) and β-phenethyl bromide (405 g), the reaction was carried out in the same manner as described in Example 17, (1), and the crude product (350 g) was purified by column chromatography on silica gel (Wako Gel C-200, manufactured by Wako Pure Chemical Industries, Ltd.) with benzene as eluent to give the title compound as a pale yellow oil which was an ca 1:5 mixture of Keto/Enol as seen by the methylene singlet at δ3.43 ppm and the methine singlet at δ5.42 ppm in the 1HNMR spectrum; yield: 66.9 g.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Br:10]Br.O>C(O)(=O)C>[Br:10][CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)=O
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)CBr
Reaction time: 8 h

Procedure:
32.5 g (0.25 mol) of ethyl acetoacetate are dissolved in 64 ml of glacial acetic acid. 40 g (0.25 mol) of bromine are added dropwise to the cooled solution. The mixture is left to stand overnight and then poured into cold water. The oil obtained is washed with water, dried and distilled in a glass filter pump vacuum.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=2)=[CH:2]1.N1C=CC=CC=1.[Cl:20][C:21]([Cl:31])=[CH:22][C@@H:23]1[C@H:25]([C:26](Cl)=[O:27])[C:24]1([CH3:30])[CH3:29]>C(Cl)Cl>[Cl:20][C:21]([Cl:31])=[CH:22][C@@H:23]1[C@H:25]([C:26]([O:13][CH2:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[CH:7]=2)=[O:27])[C:24]1([CH3:29])[CH3:30]
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Reactant: OCc1cccc(-c2ccsc2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)OCc1cccc(-c2ccsc2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 5.2 %

Procedure:
To a stirred solution of 1.0 g (0.005 mol) of 3-(3-thienyl)phenylmethanol and 0.5 g (0.005 mol) of pyridine in 25 mL of methylene chloride was added in one portion 1.2 g (0.005 mol) of cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride in 5 mL of methylene chloride. The reaction mixture was stirred at ambient temperature for 17 hours, then transferred to a separatory funnel, and diluted with 200 mL of methylene chloride. The solution was washed with 200 mL of aqueous 2 N hydrochloric acid, 200 mL of a saturated aqueous solution of sodium chloride, 200 mL of a cold aqueous 2 N solution of sodium hydroxide, and finally, 200 mL of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a residual oil. The oil was subjected to medium pressure liquid chromatography using petroleum ether:ethyl acetate (55:1) as the eluent. The appropriate fractions were combined and subjected to distillation under reduced pressure using a Kugelrohr distilling system to give 0.1 g of 3-(3-thienyl)-phenylmethyl cis-3-(2,2-dichloroetheny)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([Cl:17])=[CH:4][C:3]=1[O:18][CH2:19][CH2:20][O:21][CH2:22][C:23]([F:26])([F:25])[F:24].C[Si](C)(C)[O:29][C@@H:30]1[C@@H:35]([O:36][Si](C)(C)C)[C@H:34]([O:41][Si](C)(C)C)[C@@H:33]([CH2:46][O:47][Si](C)(C)C)[O:32][C:31]1=O.[Li]CCCC>C1COCC1>[Cl:17][C:5]1[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)=[CH:7][C:2]([C@H:31]2[C@H:30]([OH:29])[C@@H:35]([OH:36])[C@H:34]([OH:41])[C@@H:33]([CH2:46][OH:47])[O:32]2)=[C:3]([O:18][CH2:19][CH2:20][O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:4]=1
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Reactant: CCc1ccc(Cc2cc(Br)c(OCCOCC(F)(F)F)cc2Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(OCCOCC(F)(F)F)cc2Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-bromo-4-chloro-5-(4-ethylbenzyl)-2-(2-(2,2,2-trifluoroethoxy)ethoxy)benzene (BR) (96 mg, 0.21 mmol) and (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)-tetrahydropyran-2-one (0.20 g, 0.43 mmol) in anhydrous THF (3 mL), was added n-BuLi (1.6 M, 0.40 mL) in a dropwise fashion at −78° C. over 15 min. The resulting solution was stirred at −78° C. for 30 min. After quenching with methanesulfonic acid (61 μL in 1.0 mL MeOH), the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was filtered through silica and purified by preparative TLC eluting with 7% MeOH in CH2Cl2 to collect the crude product. To a solution of the crude product in a mixture of 1:1 CH3CN:CH2Cl2 (4 mL) was added Et3SiH (200 μL), followed by cooling to −40° C. To the cooled mixture was added BF3.Et2O (40 μL), and it was allowed to warm to 0° C. over 2 h. Triethylamine (100 μL) was then added, the mixture was evaporated, and the residue was purified by preparative HPLC to give compound BS. 1H-NMR (CD3OD, 300 MHz) δ 7.32 (s, 1H), 7.04 (m, 5H), 4.59 (d, J=9.3 Hz, 1H), 416-3.96 (m, 8H), 3.66-3.30 (m, 7H), 2.57 (q, J=7.5, 2H), 1.19 (t, J=7.2 Hz, 3H); MS ESI m/z 532.8 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][NH:7][CH3:8].ClC([O:17][C:18]([Cl:21])(Cl)Cl)=O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][N:7]([CH3:8])[C:18]([Cl:21])=[O:17]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CNCc1ccc(OC)c(OC)c1
Solvent: c1ccncc1
Product: COc1ccc(CN(C)C(=O)Cl)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.00 g (5.52 mmol) of 3,4-dimethoxybenzyl-N-methylamine (obtainable by reductive amination from 3,4-dimethoxybenzaldehyde) are dissolved in 20 ml of anhydrous pyridine. 0.60 g (0.37 mmol, 3.04 mmol) of trichloromethyl chloroformate (“diphosgene”) is added, and the mixture is left to stir at room temperature overnight. The solution is employed without workup directly in the next stage.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[O:17]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18]1>>[O:17]1[CH:21]=[CH:20][C:19]([CH:22]2[C:8]3[NH:9][C:10]4[C:15]([C:7]=3[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:18]1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=Cc1ccoc1
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccoc2)N1

Procedure:
The same method but starting from racemic tryptophan methyl ester and 3-furaldehyde gave the title compound as a yellow solid m.p.: 130° C.