Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:11][C@H:10]([CH2:12][OH:13])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>ClCCl>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:11][C@H:10]([CH:12]=[O:13])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](CO)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](C=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.4 %

Procedure:
To a solution of trans-(3-hydroxymethyl-cyclobutyl)-carbamic acid tert-butyl ester (Compound 4a) (0.2 g; 1.0 mmol) in anhydrous dichloromethane (8.0 mL) at 0° C. was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzodioxol-3-(1H)-one (0.84 g; 2.0 mmol). The reaction was allowed to stir at room temperature under nitrogen for 3 h, before partitioning the reaction mixture between dichloromethane and brine. The organic layer was washed with brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash column chromatography, eluting with 30% ethyl acetate in hexanes, to yield Compound 4b as a foam (0.2 g; 88% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4](=[O:17])[C:5]2[CH2:12]S[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[C:6]=2[O:7][CH:8]=1.CC(C1C=CC2SCC3C(=O)C(CO)=C[O:29]C=3C=2C=1)CC.C(C1C=CC2SCC3C(=O)C(CO)=COC=3C=2C=1)CCC.CC1C2C(=O)C(CO)=COC=2C2C=CC=CC=2S1.C(C1C2C(=O)C(CO)=COC=2C2C=CC(C(F)(F)F)=CC=2O1)CC.C(OC1C=CC2C3OC=C(CO)C(=O)C=3CSC=2C=1)CCC.C(C1C2C(=O)C(CO)=COC=2C2C=C(CCCCCC)C=CC=2O1)CCC>>[OH:1][CH2:2][C:3]1[C:4](=[O:17])[C:5]2[CH2:12][O:29][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[C:6]=2[O:7][CH:8]=1
Reactant: CCC(C)c1ccc2c(c1)-c1occ(CO)c(=O)c1CS2
Reactant: O=c1c(CO)coc2c1CSc1ccccc1-2
Agent: CC1Sc2ccccc2-c2occ(CO)c(=O)c21
Agent: CCCC1Oc2cc(C(F)(F)F)ccc2-c2occ(CO)c(=O)c21
Agent: CCCCCCc1ccc2c(c1)-c1occ(CO)c(=O)c1C(CCCC)O2
Product: O=c1c(CO)coc2c1COc1ccccc1-2

Procedure:
In the same manner but replacing 4-oxo-4H,5H-[1]benzopyrano[4,3-b]pyran-3-carboxaldehyde with an equivalent amount of another compound of formula VI described in Example 2, the following compounds of formula VII are obtained respectively: 3-hydroxymethyl-4H,5H-[1]benzothiopyrano[4,3-b]-pyran-4-one, mp 147°-149° C., 9-(1-methylpropyl)-3-hydroxymethyl-4H,5H-[1]benzothiopyrano[4,3-b]pyran-4-one, mp 82°-84° C., 9-butyl-3-hydroxymethyl-4H,5H-[1]benzothiopyrano[4,3-b]pyran-4-one, mp 89°-91° C., 5-methyl-3-hydroxymethyl-4H,5H-[1]benzothiopyrano[4,3-b]pyran-4-one, 6-chloro-3-hydroxymethyl-4H,5H-[1]benzopyrano[4,3-b]pyran-4-one, 5-ethyl-17-methyl-3-hydroxymethyl-4H,5H-[1]-benzopyrao[4,3-b]pyran-4-one, 10-ethoxy-5-methyl-3-hydroxymethyl-4H,5H-[ 1]benzothiopyrano[4,3b]pyran-4-one-1,1-dioxide, 5-propyl-8-trifluoromethyl-3-hydroxymethyl-4H,5H-[1]benzopyrano[4,3-b]pyran-4-one, 7-bromo-5-(1-methylethyl)-3-hydroxymethyl-4H,5H-[]benzothiopyrano[4,3-b]pyran-4-one, 8-butoxy-3-hydroxymethyl-4H,5H-[1]benzothiopyrano[4,3-b]pyran-4-one and 5-butyl-9-hexyl-3-hydroxymethyl-4H,5H-[1]benzopyrano[4,3-b]pyran-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:24]2[C:29](=[O:30])[NH:28][C:27](=[O:31])[C:26]([C:32](NC(=O)OCC)=[O:33])=[N:25]2)[CH:5]=[C:6]([Cl:23])[C:7]=1[C:8]([C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[O:13][N:12]=1)([CH3:10])[CH3:9].C(O)(=[O:42])C>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:24]2[C:29](=[O:30])[NH:28][C:27](=[O:31])[C:26]([C:32]([OH:33])=[O:42])=[N:25]2)[CH:5]=[C:6]([Cl:23])[C:7]=1[C:8]([C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[O:13][N:12]=1)([CH3:9])[CH3:10]
Reactant: CC(=O)O
Reactant: CCOC(=O)NC(=O)c1nn(-c2cc(Cl)c(C(C)(C)c3noc(-c4ccccc4C)n3)c(Cl)c2)c(=O)[nH]c1=O
Agent: Cl
Product: Cc1ccccc1-c1nc(C(C)(C)c2c(Cl)cc(-n3nc(C(=O)O)c(=O)[nH]c3=O)cc2Cl)no1

Procedure:
A mixture of intermediate (21) (0.0302 mole) in HCl 36% (10 ml) and acetic acid (200 ml) was stirred and refluxed overnight. The reaction mixture was poured out onto crushed ice and this mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered and the solvent evaporated, yielding 16.3 g of 2-[3,5-dichloro-4-[1-[5-[2-methylphenyl)-1,2,4-oxadiazol-3-yl]-1-methylethyl]phenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carboxylic acid (intermediate 22).
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[O-].[Na+].Br[CH:15]([CH3:26])[C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=O>O1CCCC1>[C:3]1([C:2]2[NH:9][C:15]([CH3:26])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Reactant: N=C(N)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1[nH]c(-c2ccccc2)nc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
A suspension of 47.3 g (0.302 mol) of benzamidine hydrochloride, 16.3 g (0.302 mol) of sodium methylate in 250 ml of tetrahydrofuran was heated under reflux for 1 hour, and cooled to 25° C. A solution of 85.2 g (0.302 mol) of the above-mentioned crude 2-bromo-2′,4′-dichloropropiophenone in 160 ml of tetrahydrofuran was added dropwise in such a manner that the reaction temperature did not exceed 30° C. After the addition was complete, 16.3 g (0.302 mol) of sodium methylate was added, and the resultant was heated under reflux for 1 hour. Subsequently, the reaction solution was cooled to room temperature, and insolubles were then filtered off. The filtrate was evaporated to dryness under reduced pressure, to recover a residual solid. This solid was successively washed with water and toluene and then dried, to give 50.4 g (55.0% crude yield) of crude crystals of the desired product. The crude crystals were recrystallized using a mixture of acetonitrile and DMF, to give colorless purified crystals.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[CH3:16][C:7]1[C:6]2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:22]3[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]=12
Reactant: OB(O)c1ccncc1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccncc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, white solid (29 mg, 38%), MS (ISP) m/z=303.5 [(M+H)+], mp 307° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available pyridin-4-ylboronic acid (39.9 mg, 0.325 mmol).
Reaction SMILES: [C:1]([NH:9][C:10](=[S:28])[NH:11][C:12]1[S:20][C:15]2[CH2:16][O:17][CH2:18][CH2:19][C:14]=2[C:13]=1[C:21]([O:23]C(C)(C)C)=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([NH:9][C:10](=[S:28])[NH:11][C:12]1[S:20][C:15]2[CH2:16][O:17][CH2:18][CH2:19][C:14]=2[C:13]=1[C:21]([OH:23])=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1c(NC(=S)NC(=O)c2ccccc2)sc2c1CCOC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC(=S)Nc1sc2c(c1C(=O)O)CCOC2)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 3.3 %

Procedure:
To a solution of tert-Butyl 2-(3-benzoylthioureido)-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.104 g, 0.25 mmol, 1 equiv.) in DCM (10 mL) was added TFA (2 mL, 26 mmol, 100 equiv.), and the reaction was stirred at rt for 16 h. The solvent was removed and the product was triturated with 1:1 Et2O/hexanes (25 mL) and filtered. The product was purified by mass-directed reverse-phase chromatography and isolated as a white solid (3 mg, 3% yield). 1H NMR (400 MHz, CDCl3) δ 14.92 (br s, 1H), 9.02-9.09 (m, 1H), 7.83-7.91 (m, 1H), 7.55-7.66 (m, 2H), 7.41-7.50 (m, 2H), 7.19-7.23 (m, 1H), 4.69-4.76 (m, 2H), 3.92-3.98 (m, 2H), 2.88-3.03 (m, 2H). LCMS retention time: 2.955 min; LCMS purity at 215 nm=100%. HRMS m/z calculated for C16H15N2O4S2 [M++1]: 363.0468. found 363.0464.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][C:28]([OH:30])=[O:29]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:26][CH2:27][C:28]([OH:30])=[O:29])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCC(=O)O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(=O)O)c2c1

Procedure:
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and glycine. MS obsd. (ESI+) [(M+H)+] 412, 1H NMR (400 MHz, CD3OD) δ ppm 8.01 (d, J=1.8 Hz, 1 H), 7.89 (d, J=1.9 Hz, 1 H), 7.68 (t, J=2.9 Hz, 2 H), 7.54 (d, J=2.1 Hz, 1 H), 7.48 (t, J=2.2 Hz, 1 H), 7.40 (d, J=0.9 Hz, 1 H), 5.73 (s, 1 H), 5.09 (s, 2 H), 4.36 (brs, 2 H), 3.3 (s, 2 H), 3.58 (s, 2 H), 2.41 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[CH:12]=[O:13].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][C:16]=1O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]1[O:13][C:16]2[CH:17]=[C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:20][C:15]=2[N:14]=1
Reactant: COC(=O)Cc1ccc(N)c(O)c1
Reactant: Cn1cc(C=O)c2cc(Cl)ccc21
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)Cc1ccc2nc(-c3cn(C)c4ccc(Cl)cc34)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
In EtOH (9.0 ml), 5-chloro-1-methylindole-3-carbaldehyde (534 mg, 2.76 mmol) and methyl 4-amino-3-hydroxyphenylacetate (500 mg, 2.76 mmol) were stirred for hours. After iodobenzene diacetate (2.03 g, 6.31 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for 1 hour, the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby from n-hexane-ethyl acetate (1:1, v/v) eluate fractions, a mixture (594 mg) of methyl (2-(5-chloro-1-methyl-3-indolyl)-6-benzoxazolyl)acetate and 5-chloro-1-methylindole-3-carboxaldehyde was obtained. To the resulting mixture were added THF (17 ml) and 0.25N NaOH (10.0 ml, 2.50 mmol) and the mixture was stirred at room temperature for 23 hours. The reaction mixture was distilled under reduced pressure to remove the solvent. To the residue was added 1N HCl (10 ml), followed by extraction with chloroform-methanol (4:1, v/v). The extract was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent to give (2-(5-chloro-1-methyl-3-indolyl)-6-benzoxazolyl)acetic acid (88 mg, 9%) as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][N:7]=1.[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22](Br)=[N:21][C:20]=1[CH3:25])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22]([N:4]2[CH:5]=[CH:6][N:7]=[C:2]([CH3:1])[C:3]2=[O:8])=[N:21][C:20]=1[CH3:25])=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Reactant: Cc1ncc[nH]c1=O
Product: Cc1nc(-n2ccnc(C)c2=O)sc1C(=O)NCc1ccccc1
Yield: 5 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 3-methylpyrazin-2(1H)-one in place of 4-aminopyridin-2(1H)-one to react with N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 5% yield: mp 186-187° C.; 1H NMR (300 MHz, CDCl3) δ 8.44 (s, 1H), 7.45-7.25 (m, 6H), 6.12 (s, 1H), 4.59 (d, J=5.7 Hz, 2H), 2.69 (s, 3H), 2.55 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.6, 159.2, 153.4, 152.4, 152.0, 137.5, 128.8, 127.9, 127.8, 124.5, 123.5, 119.3, 44.2, 20.8, 17.3; MS (ES+) m/z 341.2 (M+1).
Reaction SMILES: [CH2:1]([OH:8])[C:2]([NH2:7])([CH2:5][OH:6])[CH2:3][OH:4].[OH-].[K+].[C:11](#[N:14])[CH:12]=[CH2:13].Cl>O1CCOCC1>[NH2:7][C:2]([CH2:5][O:6][CH2:13][CH2:12][C:11]#[N:14])([CH2:3][O:4][CH2:13][CH2:12][C:11]#[N:14])[CH2:1][O:8][CH2:13][CH2:12][C:11]#[N:14]
Reactant: C=CC#N
Reactant: NC(CO)(CO)CO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: N#CCCOCC(N)(COCCC#N)COCCC#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
Tris(hydroxymethyl)aminomethane (24.2 g, 0.2 mol) was added to a mixture of dioxane (25 ml) and aqueous potassium hydroxide (1.2 g KOH in 3 ml water). Acrylonitrile (40 ml, 0.61 mol) was added dropwise. After 2 h the solution was stood in a cold water bath to moderate any exothermic reaction and stirred for 16 h at RT. The solution was neutralized with dil. HCl and filtered. The oil was dissolved in DCE, dried (MgSO4), filtered and concentrated. The brown oil was purified by chromatography (SiO2, CH2Cl2/MeOH 1% to 4%) to give the title product (26.9 g, 0.096 mol, 48%) as a colourless oil. δH (400 MHz, CDCl3) 3.71 (6H, t, J 6.0), 3.47 (6H, s), 2.63 (6H, t, J 6.0); TLC (CH2Cl2/MeOH 10%) 0.55.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:10](Cl)[CH:11]=[C:12]([CH3:14])[CH3:13]>>[CH2:10]([C:3]1[C:4]([OH:5])=[CH:6][C:7]([OH:8])=[CH:9][C:1]=1[OH:2])[CH:11]=[C:12]([CH3:14])[CH3:13]
Reactant: Oc1cc(O)cc(O)c1
Reactant: CC(C)=CCCl
Product: CC(C)=CCc1c(O)cc(O)cc1O

Procedure:
Phloroglucinol was treated with prenylchloride using the same procedure as described in Example 2 to yield prenylphloroglucinol. Prenylphloroglucinol was treated with butyrylchloride, according to the same procedure as described for the preparation of 2,4-dibutyrylphloroglucinol in Example 34 (Method 2) to yield 5,7-dihydroxy-6,8-dibutyryl-2,2-dimethylchroman (36) after chromatography with silica gel (petroleum ether, ethyl acetate, 4:1).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4](O)=[O:5].[CH3:10][NH:11][C:12]([NH:14][CH3:15])=[O:13].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[CH3:10][N:11]1[CH2:7][CH:3]([C:2]([F:9])([F:8])[F:1])[C:4](=[O:5])[N:14]([CH3:15])[C:12]1=[O:13]
Reactant: C=C(C(=O)O)C(F)(F)F
Reactant: CNC(=O)NC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CN1CC(C(F)(F)F)C(=O)N(C)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
A mixture of α-trifluoromethylacrylic acid (700 mg; 5.0 mmoles) and 1,3-dimethylurea (419 mg; 4.8 mmoles) in DMF (5 ml) was cooled to 0° C., and then a solution of DCC (1.21 g; 5.9 mmoles) in DMF (3 ml) was added dropwise. The mixture was stirred at 0° C. for 1 hour. The precipitated solid was filtered off, and washed with ethyl acetate. The solvents were evaporated under reduced pressure from the combined filtrates. The residue was purified by a column chromatography on silica gel to give 566 mg (yield 57%) of 1,3-dimethyl-5-trifluoromethyl-5,6-dihydrouracil (OF-1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[CH:14]1([NH2:17])[CH2:16][CH2:15]1.O1CCCC1>O>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([NH:17][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: NC1CC1
Solvent: O
Solvent: C1CCOC1
Product: Nc1cccc(S(=O)(=O)NC2CC2)c1
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
A mixture of 2.0 g 3-nitrobenzene sulfonyl chloride, 1.8 g cyclopropyl amine and 50 mL tetrahydrofuran was stirred for 30 minutes under ice-cooling. Water was added to the mixture which was then extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, then the residue was dissolved in 100 mL solvent mixture of tetrahydrofuran and methanol, 50 mg of 10% palladium-carbon was added thereto, and the mixture was hydrogenated at ordinary pressure for 12 hours. The reaction mixture was filtered through Celite, and the solvent was evaporated, whereby 1.5 g of the title compound was obtained as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.Cl[O-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:11])([F:12])[F:10])=[CH:4][N:3]=1
Reactant: OC(c1ccc(Cl)nc1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Cl)nc1)C(F)(F)F

Procedure:
21.13 g (0.1 mol) of 2-chloro-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine and 1.8 g (0.005 mol) of tetrabutylammonium hydrogen sulfate are dissolved in 200 ml of ethyl acetate at room temperature. 61 ml (0.12 mol) of an approximately 12% strength sodium hypochlorite solution are metered in within 15 minutes with vigorous stirring and the mixture is stirred for a further 2 hours during which the reaction temperature rises to 40° C. The phases are separated, the aqueous phase is extracted several times with ethyl acetate and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying the organic phase with sodium sulfate, the volatiles are distilled off. Following distillation of the crude product at 0.3 mbar, 15.6 g (74.4% of theory) of 2-chloro-5-trifluoroacetylpyridine with a boiling point of 50°-51° C. are obtained, which, according to GC, is 99.8% pure. nD20 : 1.4887.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[N+](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[CH2:7][CH:12]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC1c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 9.6 %

Procedure:
To a mixture of 4-chlorostyrene (1.20 ml, 10.0 mmol), Rh2(OAc)4 (0.221 g, 0.500 mmol), and toluene (20 ml) was added ethyl diazoacetate (1.09 ml, 10.50 mmol). Gas evolution was observed. The mixture was heated to 80° C. for 1 hour. The mixture was purified on silica gel (EtOAc in hexanes gradient) to provide 0.216 g of the title compound as an oil (9%).
Reaction SMILES: [C-:1]#[N:2].[K+].[C:4]1(=[C:8]2[C:13](=[O:14])[O:12][C:11]([CH3:16])([CH3:15])[O:10][C:9]2=[O:17])[CH2:7][CH2:6][CH2:5]1.Cl>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C(O)C>[CH3:16][C:11]1([CH3:15])[O:12][C:13](=[O:14])[CH:8]([C:4]2([C:1]#[N:2])[CH2:5][CH2:6][CH2:7]2)[C:9](=[O:17])[O:10]1
Reactant: CC1(C)OC(=O)C(=C2CCC2)C(=O)O1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: CCO
Product: CC1(C)OC(=O)C(C2(C#N)CCC2)C(=O)O1
Temperature: 80 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
Potassium cyanide (0.12 g, 1.8 mmol) was added to a mixture of 5-cyclobutylidene-2,2-dimethyl-1,3-dioxane-4,6-dione (0.30 g, 1.5 mmol) and tetra-N-butylammonium bromide (0.049 g, 0.15 mmol) (Sigma-Aldrich, Cat. #193119) in ethanol (5.0 mL). The reaction mixture was stirred at 80° C. for 2 h. After cooled to r.t., the mixture was adjusted to pH=2 with aqueous HCl. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in dichloromethane (0-80%) to afford the desired product (0.32 g, 94%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[C:8]([OH:15])[C:7]=1[CH2:16][CH2:17][CH3:18].[CH2:20]([CH:22]1[O:24][CH2:23]1)Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[C:8]([O:15][CH2:20][CH:22]2[CH2:23][O:24]2)[C:7]=1[CH2:16][CH2:17][CH3:18]
Reactant: CCCc1c(OCC(=O)OC)ccc(C(C)=O)c1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCC(=O)OC)ccc(C(C)=O)c1OCC1CO1

Procedure:
A mixture of 7.75 g of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid methyl ester, 7.5 ml of epibromohydrin, 4.8 g of potassium iodide and 6.0 g of anhydrous potassium carbonate in 80 ml of anhydrous acetone and 40 ml of anhydrous dimethylformamide was stirred at reflux for 50 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil which was purified by high pressure liquid chromatography (HPLC) using 10% ethyl acetate-hexane to yield 6.16 g of [4-acetyl-3-(oxiranylmethoxy)-2-propylphenoxy]acetic acid methyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1O.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1.CN(C)C1C=CN=CC=1.CC(O)=O>[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[O:15][C:14](=[O:16])[C@@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: C[C@@H]1CCCC[C@H]1O
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@@H]1CCCC[C@H]1OC(=O)[C@@H](C)NC(=O)OCc1ccccc1

Procedure:
N-Benzyloxycarbonyl-D-alanine (2.5 mmol. 0.556 g) and trans-2-methylcyclohexanol (3 equivalents, 1 mL) were dissolved in 7 mL THF at room temperature, followed by the addition of 70 mg 4-dimethylaminopyridine. DCC (2.5 mmol, 0.515 g) was then introduced with stirring. The solution turned cloudy immediately and was stirred at room temperature overnight. The reaction mixture was stirred for another 15 min after several drops of HOAc were added to it. Dicyclohexylurea (DCU) was filtered off and the filtrate evaporated to dryness. The residue was dissolved in ethyl acetate. The EtOAc solution was filtered, washed with 0.5N HCl (2×), brine (2×), 5% NaHCO3 (2×) and finally brine (2×). The organic phase, after being dried over anhydrous Na2SO4, showed one UV-positive tlc spot. A second spot, which could only be detected by phosphomolybdic acid (PMA)--Ce(SO4)2 spray, was identified as the unreacted alcohol by tlc comparison with authentic material. The ethyl acetate solution was evaporated to dryness and dried under high vacuum, giving a clear oil weighing 0.965 g. The crude material was chromatographed on a Merck Si--60 size C prepacked column by gradient elution with toluene to toluene:ethyl acetate (9:1). After evaporation, 0.629 g (72.0%) of clear, colorless oil was recovered: nmr (CDCl3, ppm), 0.85-2.05 (13H, m, aliphatic H of cyclohexanol), 0.9 (3H, d, J=6 Hz, CH3) 1.3 (3H, d, J=7 Hz, obscured by other aliphatic protons, β--CH3 of Ala), 4.3 (2H, m, CH--O-- and α--H), 5 (2H, s, ArCH2 --), 5.25 (1H, broad s, amide H), 7.15 (5H, s, ArH5).