Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:14]([N:15]2[CH2:20][CH2:19][S:18][CH2:17][CH2:16]2)=[CH:13][C:5]2[N:6]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[S:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:27](Cl)(Cl)=[S:28]>C(Cl)(Cl)Cl>[C:9]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([N:1]=[C:27]=[S:28])[C:14]([N:15]3[CH2:16][CH2:17][S:18][CH2:19][CH2:20]3)=[CH:13][C:5]=2[N:6]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: S=C(Cl)Cl
Reactant: CC(C)(C)c1nc2cc(N3CCSCC3)c(N)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1nc2cc(N3CCSCC3)c(N=C=S)cc2s1

Procedure:
To a mixture of 2 g of 6-amino-2-tert-butyl-5-[thiomorpholin-4-yl]benzothiazole and 2 g of anhydrous potassium carbonate in 150 ml of chloroform at 0° is added 0.6 ml of thiophosgene in 5 ml chloroform, under stirring. After 4 hours of stirring at ambient temperature the mixture is filtered. The filtrate is evaporated to a solid which is purified by silica gel column chromatography. The column is eluted with hexane/methylenechloride (1:1) to give 2-tert-butyl-6-isothiocyanato-5-[thiomorpholin-4-yl]benzothiazole, melting at 155°-159°.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH2:5])[CH3:4].[C:6](O)(=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[CH3:4][CH:3]1[CH2:2][NH:1][C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N:5]1
Reactant: CCCCCCCCC(=O)O
Reactant: CC(N)CN
Product: CCCCCCCCC1=NC(C)CN1
Temperature: 170 °C

Procedure:
1,2-Diaminopropane 61.5 g (0.7 mole) was delivered to a reaction vessel and pelargonic acid 112 g (0.7 mole) was added slowly. The mixture was slowly heated to 170° C. while removing water of reaction. There was obtained 4-methyl-2-octyl-2-imidazoline. To it was added 42 g of paraformaldehyde with stirring. The mixture was heated to about 100° C. for 3 hours to produce N1 -hydroxymethyl-4-methyl-2-octyl-2-imidazoline.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1([O:26][CH3:27])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Br:28]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:28][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1([O:26][CH3:27])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1
Reactant: COC1(c2ccc(C(F)(F)F)cc2CO)CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC1(c2ccc(C(F)(F)F)cc2CBr)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To a solution of tert-butyl 4-(2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)-4-methoxypiperidine-1-carboxylate (410 mg, 1.05 mmol) in methylene chloride (7 mL) were added N-bromosuccinimide (342 mg; 1.92 mmol) and triphenylphosphine (516 mg; 1.96 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was then purified over 40 g RediSep column (Teledyne Isco Inc. Lincoln Nebr.) (eluted with 5-30% ethyl acetate in heptane) to give 433 mg (90% yield) of a colorless oil. MS (ES+). Calc: 452.3 (81Br), Found: 407.2 (M(81Br)—HCO2−). 1H NMR (400 MHz, CDCl3) δ ppm 7.82 (d, J=1.66 Hz, 1H), 7.52 (dd, J=8.30, 1.66 Hz, 1H), 7.34, (d, J=8.30 Hz, 1H), 5.08 (s, 2H), 4.04 (d, J=12.86 Hz, 2H), 3.21 (t, J=12.86, 13.28 Hz, 2H), 3.02 (s, 3H), 2.26 (d, J=14.11 Hz, 2H), 1.86 (t, J=12.86, 14.11 Hz, 2H), 1.48 (s, 9H).
Reaction SMILES: C([O:3][C:4](=[O:42])[C:5]([CH3:41])([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:24]2[N:25]([CH3:39])[N:26]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)[CH:28]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[CH:10][C:9]=1[CH3:40])[CH3:6])C.[OH-].[Na+]>CCO>[CH3:41][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:24]2[N:25]([CH3:39])[N:26]=[C:27]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:34]=3)[CH:28]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[CH:10][C:9]=1[CH3:40])([CH3:6])[C:4]([OH:42])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN(Cc2ccccc2F)c2cc(-c3ccc(C(F)(F)F)cc3)nn2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(CN(Cc2ccccc2F)c2cc(-c3ccc(C(F)(F)F)cc3)nn2C)ccc1OC(C)(C)C(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
To a solution of example 104 (320 mg, 0.5 mmol) in EtOH (20 mL) was added excess of a 1N NaOH solution and the mixture was stirred at 50° C. for 2 h. The reaction was cooled, evaporated to dryness, the residue taken up with water, neutralized with 1N HCl to pH 7 and then extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and the solvent removed under vacuum to afford the title compound as an oil (150 mg, 50%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:9]1[CH:10]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:9]1[CH2:10][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CN1CCOCC1

Procedure:
The title compound was prepared from N-(t-butoxycarbonyl)D-prolinal and morpholine according to the general method of Example 200; MS (ES+), m/e 271 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].O[C:18]1[CH:30]=[CH:29][C:28]2[C:27]3[C:22](=[CH:23][C:24]([OH:31])=[CH:25][CH:26]=3)[C:21]([CH3:33])([CH3:32])[C:20]=2[CH:19]=1.B(O)(O)O>C1(C)C(C)=CC=CC=1>[OH:16][C:14]1[CH:13]=[CH:12][C:8]([C:9]([O:31][C:24]2[CH:25]=[CH:26][C:27]3[C:28]4[C:20](=[CH:19][C:18]([O:10][C:9](=[O:11])[C:8]5[CH:12]=[CH:13][C:14]([OH:16])=[CH:15][C:7]=5[F:6])=[CH:30][CH:29]=4)[C:21]([CH3:32])([CH3:33])[C:22]=3[CH:23]=2)=[O:10])=[C:7]([F:6])[CH:15]=1
Reactant: O=C(O)c1ccc(O)cc1F
Reactant: CC1(C)c2cc(O)ccc2-c2ccc(O)cc21
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: Cc1ccccc1C
Product: CC1(C)c2cc(OC(=O)c3ccc(O)cc3F)ccc2-c2ccc(OC(=O)c3ccc(O)cc3F)cc21
Yield: 35 %

Procedure:
In a nitrogen atmosphere, concentrated sulfuric acid (0.2 mL) was added to a mixture of 2-fluoro-4-hydroxybenzoic acid (13.8 g), 2,7-dihydroxy-9,9-dimethylfluorene (10.0 g), boric acid (0.3 g) and xylene (120 mL), and the mixture was heated under reflux for 6 hours while removing water. A deposited matter was filtered and rinsed with toluene. It was recrystallized from a mixed solvent of ethanol (75 mL) and acetone (75 mL) to provide 2,7-bis(4-hydroxy-2-fluorobenzoyloxy)-9,9-dimethylfluorene (compound [H3]) (7.77 g) in the form of pale rose solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]O)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:35]Br.N1C=CN=C1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][Br:35])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cccc(-c2cccc(Br)c2)c1
Reactant: BrBr
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cccc(-c2cccc(Br)c2)c1

Procedure:
A 0.5 M solution of (3′-bromobiphenyl-3-yl)methanol 94 in DCM was added to a 10 min. prestirred suspension of triphenylphosphine resin (1.6 eq.), Br2 (1.6 eq.) and 0.25 M solution of imidazole (1.7 eq.) in DCM. The reaction mixture was gently stirred at RT for 3 h. The resin was then filtered off and washed with DCM, the filtrate was evaporated to dryness to afford the title compound 95 (78% crude yield) as a brown oil. The material was used in the following step without further purification. 1H NMR (400 MHz, DMSO-d6, 300 K) δ 7.90 (s, 1H), 7.86-7.82 (m, 1H), 7.76-7.70 (m, 1H), 7.70-7.65 (m, 1H), 7.65-7.60 (m, 1H), 7.55-7.49 (m, 2H), 7.47 (d, J 7.8, 1H), 4.81 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13][CH:14]([CH3:26])[C:15]([O:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16]>>[CH3:13][CH:14]([CH3:26])[C:15]([O:17][N:18]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[S:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:9])=[O:8])=[O:16]
Reactant: CC(C)C(=O)ONC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: [H-]
Agent: [Na+]
Product: CC(C)C(=O)ON(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)s1

Procedure:
N-[(tert-Butoxy)carbonyl]5-chlorothiophene-2-sulfonamido 2-methylpropanoate (108) is synthesised from 5-chlorothiophene sulfonyl chloride, sodium hydride and [(tert-butoxy)carbonyl]amino 2-methylpropanoate according to Scheme 2. δH (500 MHz, CHLOROFORM-d) 7.65 (1H, d, 4.1 Hz), 6.99 (1H, d, 4.1 Hz), 2.81 (1H, sept, 7.0 Hz), 1.49 (9H, s), 1.31 (6H, d, 7.0 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][NH2:19].C[Si]([C:24]#[N:25])(C)C>C(#N)C>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][NH:19][CH:6]([C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:24]#[N:25]
Reactant: Cc1ccc(C=O)cc1
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccccc1CN
Solvent: CC#N
Product: COc1ccccc1CNC(C#N)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-methylbenzaldehyde (4.38 g, 36 mmol) in 130 mL of acetonitrile at room temperature, 1-(2-methoxyphenyl)methanamine (5 g, 36 mmol) and trimethylsilyl cyanide (5.2 mL, 50 mmol) were added. The mixture was stirred for 16 h at room temperature until the starting materials had been completely consumed as judged by TLC (petroleum ether/ethyl acetate 90:10) and GC analysis. The mixture was quenched with 40 mL of saturated ammonium chloride, stirred for 15 min, added with 100 mL of water and then extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate 90:10) to afford [(2-methoxybenzyl)amino](4-methylphenyl)acetonitrile as a red oil (6.1 g, y=64%). 1H NMR (CDCl3) δ (ppm): 7.45 (d, 2H, J=7.3 Hz), 7.33-7.25 (m, 2H), 7.21 (d, 2H, J=7.2 Hz), 6.91-6.85 (m, 2H), 4.79 (s, 1H), 4.03 (d, 1H, J=13.2 Hz), 3.95 (d, 1H, J=13.2 Hz), 3.86 (s, 3H), 2.38 (s, 3H). MS (ES1+) m/z: 266.85 (M+1), 240.04 (M-HCN+1).
Reaction SMILES: [C:1]1([N:7]2[C:12](=O)[CH2:11][C:10](=[O:14])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]2=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:24])=O>O>[Cl:24][C:12]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8](=[O:21])[N:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10](=[O:14])[CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CC(=O)N(c2ccccc2)C(=O)N1c1ccccc1
Solvent: O
Product: O=c1cc(Cl)n(-c2ccccc2)c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 74 %

Procedure:
To 1,3-diphenyl-pyrimidine-2,4,6-trione 19 (78.0 g) obtained in Step 1 was added water (16 ml). Phosphorus oxychloride (422 ml) was added dropwise under stirring at room temperature over 50 min. After the completion of the dropwise addition, the mixture was stirred under heating at 110° C. for 3 hrs. After allowing to cool to room temperature, the reaction mixture was added to ice water by small portions and the mixture was stirred at room temperature and extracted with ethyl acetate. The organic layer was washed with brine and saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=2:1→3:2) to give 6-chloro-1,3-diphenyl-1H-pyrimidine-2,4-dione 20 (61.5 g, yield 74%) as pale-yellow crystals.
Reaction SMILES: [CH2:1]([O-:3])[CH3:2].Cl.Cl.[NH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1.C(Cl)(=O)C>>[C:1]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)(=[O:3])[CH3:2]
Reactant: CC[O-]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Agent: Cl
Solvent: CC(=O)Cl
Product: CC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 78.3 %

Procedure:
Beginning with 2.00 gm (5.74 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole dihydrochloride ethanolate and 1.13 gm (25.8 mMol) acetyl chloride, 1.22 gm (78.3%) of the title compound were recovered as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[CH:16]=1)[C:11](O)=[O:12])#[N:2].[C:29]([O:33][C:34](=[O:44])[NH:35][CH2:36][CH2:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34](=[O:44])[NH:35][CH2:36][CH2:37][CH:38]1[CH2:39][CH2:40][N:41]([C:11](=[O:12])[C:10]2[CH:14]=[C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)[CH:16]=[C:8]([O:7][CH2:6][C:5]3[CH:26]=[CH:27][CH:28]=[C:3]([C:1]#[N:2])[CH:4]=3)[CH:9]=2)[CH2:42][CH2:43]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: N#Cc1ccc(Oc2cc(OCc3cccc(C#N)c3)cc(C(=O)O)c2)cc1
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2cc(OCc3cccc(C#N)c3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 59.7 %

Procedure:
Following the procedure of Example 5(c) 3-(3-cyano-benzyloxy)-5-(4-cyano-phenoxy)-benzoic acid 0.75 g (2.02 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.46 g, 2.02 mmol) were used to afford 0.7 g of the required product. Percentage purity (LCMS): 62.3%, (M+1)=480.2+1 (de-Boc mass, −100).
Reaction SMILES: [C-:1]#[N:2].[Na+].[F:4][C:5]([F:11])([F:10])[CH2:6][CH2:7][CH2:8]Br>CS(C)=O>[F:4][C:5]([F:11])([F:10])[CH2:6][CH2:7][CH2:8][C:1]#[N:2]
Reactant: FC(F)(F)CCCBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCCC(F)(F)F
Temperature: 80 °C
Yield: 96.8 %

Procedure:
A mixture of 882 mg (18 mmole) of sodium cyanide and 9 mL of DMSO was heated in an oil bath at 80° C. for 10 minutes until most of the solid had dissolved. The mixture was then removed from the oil bath and treated with 2.87 g (15 mmole) of 4,4,4-trifluorobutyl bromide. The mixture was heated to 110° C. for about 30 minutes and then cooled to room temperature. The mixture was partitioned between H2O and ether, and the aqueous layer was extracted with an additonal 2 portions of ether. The combined organic fractions were washed successively with 2N HCl (twice), H2O (twice), and brine. The ether phase was dried over anhydrous Na2SO4, filtered, and concentrated to yield 1.99 g (97%) of the title compound as a colorless liquid, suitable for use without further purification; IR (neat) νCO 2260 cm-1.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([NH:15][C:16](=[O:20])[O:17][CH2:18][CH3:19])=[CH:13][S:12][C:11]=2[CH:21]=1.[OH-].[NH4+]>ClCCl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([NH:15][C:16](=[O:20])[O:17][CH2:18][CH3:19])=[CH:13][S:12][C:11]=2[CH:21]=1
Reactant: CCOC(=O)Nc1csc2cc(OC)ccc12
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)Nc1csc2cc(O)ccc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
46 ml of a 1M solution of boron tribromide (0.046 mol) in dichloromethane are added to a solution of 7.7 g (0.031 mol) of ethyl (6-methoxybenzo[b]thien-3-yl)carbamate in 80 ml of dichloromethane, while maintaining the temperature at 0° C. The mixture is allowed to return to room temperature and 15 ml of a 1M solution of boron tribromide (0.015 mol) in dichloromethane are added. The mixture is stirred for 180 min, neutralization is then carried out with a dilute ammonium hydroxide solution and the precipitate obtained is filtered off. The latter is washed with water and dried. Purification is carried out by chromatography on a column of silica gel with dichloromethane. 6 g of product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]([CH2:29][CH2:30][O:31][CH3:32])[C:24]([O:26]CC)=[O:25])[CH:5]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.CO.O.O[Li].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]([CH2:29][CH2:30][O:31][CH3:32])[C:24]([OH:26])=[O:25])[CH:5]=[C:6]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)[C:7]=1[O:8][CH2:9][CH:10]1[CH2:11][CH2:12]1
Reactant: CCOC(=O)C(CCOC)c1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COCCC(C(=O)O)c1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.4 %

Procedure:
To a stirred solution of ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methoxybutanoate (0.3 g, 0.638 mmol) in a mixture of THF (10 mL), methanol (10 mL) and water (5 mL) was added LiOH.H2O (53 mg, 12.030 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL); combined organic extracts were washed with water (20 mL), brine (30 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography to afford 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methoxybutanoic acid (100 mg) as an off white solid. 1HNMR (500 MHz) (CDCl3): δ ppm 7.68 (m, 4H), 7.40 (s, 1H), 7.20 (s, 1H), 3.80 (t, 1H), 3.41 (d, 2H), 3.25 (m, 5H), 2.39 (m, 1H), 1.99 (m, 1H), 0.95 (m, 1H), 0.4 (d, 2H), 0.0 (m, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[C:13]([NH2:14])=[CH:12][N:11]=[CH:10][N:9]=1.[N:15]([CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]1)=[C:16]=[S:17]>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[C:13]([NH:14][C:16]([NH:15][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]2)=[S:17])=[CH:12][N:11]=[CH:10][N:9]=1
Reactant: CCOC(=O)N1CCC(N=C=S)CC1
Reactant: Nc1cncnc1NCc1ccco1
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(NC(=S)Nc2cncnc2NCc2ccco2)CC1
Reaction time: 48 h
Yield: 96.2 %

Procedure:
A mixture of 42.5 parts of N4 -(2-furanylmethyl)-4,5-pyrimidinediamine, 50.5 parts of ethyl 4-isothiocyanato-1-piperidinecarboxylate and 630 parts of tetrahydrofuran was stirred for 48 hours at reflux temperature. After cooling, the product was filtered off, washed with tetrahydrofuran and 1,1'-oxybisethane and dried, yielding 86.4 parts (96.2%) of ethyl 4-[[[[4-[(2-furanylmethyl)amino]-5-pyrimidinyl]amino]thioxomethyl]-amino]-1-piperidinecarboxylate (interm. 31).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.C(Cl)(=O)O[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:29](=O)([O-])[OH:30].[Na+]>ClCCl>[CH2:20]([O:19][C:29]([N:1]1[CH2:9][CH2:8][CH:4]([C:5](=[O:6])[NH2:7])[CH2:3][CH2:2]1)=[O:30])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C([O-])O
Reactant: NC(=O)C1CCNCC1
Reactant: O=C(Cl)OOCc1ccccc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Isonipecotamide (19.4 g) and triethylamine (42 mL) were dissolved in dichloromethane (500 mL), and benzyloxy chlorocarbonate (24 mL) was added thereto under ice-cooling. The mixture was stirred at room temperature for 18 hr. The reaction mixture was added to saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with chloroform. The extract was dried and concentrated under reduced pressure to give 1-benzyloxycarbonyl-4-carbamoylpiperidine (33.3 g) as a white solid.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]([N:28]2[CH2:33][CH2:32][CH2:31][C@@H:30]([NH:34]C(=O)OC(C)(C)C)[C@H:29]2[CH3:42])=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O.C(Cl)[Cl:51]>>[NH2:34][C@@H:30]1[CH2:31][CH2:32][CH2:33][N:28]([C:7]2[N:8]=[C:9]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([CH:17]4[CH2:22][CH2:21][N:20]([CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[CH2:19][CH2:18]4)=[CH:15][CH:16]=3)[C:4]([C:1]([NH2:2])=[O:3])=[N:5][CH:6]=2)[C@@H:29]1[CH3:42].[ClH:51]
Reactant: C[C@@H]1[C@H](NC(=O)OC(C)(C)C)CCCN1c1cnc(C(N)=O)c(Nc2ccc(C3CCN(C4CCCC4)CC3)cc2)n1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1[C@H](N)CCCN1c1cnc(C(N)=O)c(Nc2ccc(C3CCN(C4CCCC4)CC3)cc2)n1
Product: Cl

Procedure:
tert-Butyl (2R,3R)-1-(5-carbamoyl-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-ylcarbamate (313) (430 mg, 0.74 mmol) was treated in DCM (20 mL) and TFA (7 mL) at room temperature for 2 hours. The mixture was concentrated in vacuo, dissolved in MeOH/water, and subjected to reverse phase prep HPLC using 5 mM HCl in water and neat MeCN as mobile phases to isolate 5-((2R,3R)-3-amino-2-methylpiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (314) as HCl salt. LC-MS (ESI): m/z (M+1) 478.5. UV: λ=264, 274, 304, 335, 372 nm. Proton NMR (CD3OD): δ 7.66 (1H, s), 7.58 (2H, d, J=8.5 Hz), 7.27 (2H, d, J=8.5 Hz), 5.03 (1H, m), 4.32 (1H, d, J=11.0 Hz), 3.72 (2H, d, J=10.0 Hz), 3.56 (1H, m), 3.45 (1H, m), 3.14 (2H, m), 3.11 (1H, m), 2.88 (1H, m), 2.22-1.70 (16H, m), 1.32 (3H, d, J=7.0 Hz) ppm.
Reaction SMILES: [C:1]1(C)C=CC=CC=1.[O:8]1[C:14]2(C)[CH:9]1[CH:10]1[C:16]([CH3:18])([CH3:17])[CH:11]1[CH2:12][CH2:13]2>CCOCC.[Zn+2].[Br-].[Br-]>[CH3:1][CH:9]1[CH:10]=[C:11]([CH:16]([CH3:17])[CH3:18])[CH2:12][CH2:13][C:14]1=[O:8]
Reactant: CC12CCC3C(C1O2)C3(C)C
Reactant: Cc1ccccc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCOCC
Product: CC(C)C1=CC(C)C(=O)CC1

Procedure:
Approximately 20 mg of ZnBr2 (Fisher Certified-not fused) was added to 3 mL of toluene which had been distilled and stored over molecular sieves. The mixture was brought to reflux with vigorous stirring (to disperse the solid zinc bromide) in an apparatus which had been well flushed with nitrogen and equipped with a drying tube. Three quarters of a mixture of 2,3-epoxycarane (150 mg, 0.98 mmol) and 3 mL of toluene was added immediately. After 10 min the remaining one quarter was added over a 10 min period. Forty minutes after initial oxide addition the reaction mixture was cooled, taken up in 30 mL of ether, washed successively with water (2 × 10 mL), saturated NaHCO3 (1 × 10 mL), saturated NaCl (1 × 10 mL) and dried over anhydrous Na2SO4. Partial removal of solvent under reduced pressure afforded an oily residue from which 2-methyl-4-isopropylcyclohex-3-en-1-one (MICO) was isolated by preparative VPC. IR (CCl4) 2975, 1720, 1360, 1200, 1180(d), 970 and 930 reciprocal centimeters; UV (95% EtOH) lambda (max) 290 nm (extinction coefficient = 90.9); NMR (DCCl3) PPM 1.04 (d, 6H, J = 7 Hz, CH3 --C--CH3), 1.14 (d, 3H, J = 7 Hz, CH3 --C--), 2.3 (quintet, 1H, J = 7 Hz), 2.46 (n, M, 4H), 2.88 (br, Q with additional splitting H--C--C=O), 5.37 (n, M, 1H, H--C=C); MS m/e (rel. intensity) 153(4), 152(42), 135(5), 100(65), 109(10), 96(11), 95(100), 81(30), 68(10), 67(25), 55(11). Anal. calcd. for C10H16O: C, 78.89; H, 10.59. Found: C, 79.08; H, 10.41. An IR of the major product of the reaction showed a peak at 1720 reciprocal centimeters, attributed to the presence of a nonconjugated carbonyl. The product MICO exhibited a cool, refreshing menthol fragrance with a slight raspberry note which finds utility for the compound in odorant compositions.