Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([CH3:29])([C:25](=[O:28])[NH:26][CH3:27])[CH3:24])[CH:17]=1)[C:10]([CH3:31])([CH3:30])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:30][C:10]1([CH3:31])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([CH3:29])([C:25](=[O:28])[NH:26][CH3:27])[CH3:24])[CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)NC)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 34.6 %

Procedure:
A mixture of 3,3-dimethyl-2-[3-(1-methyl-1-methylcarbamoyl-ethylamino)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.4 g, 0.95 mmol) in methanol (10 mL) and tetrahydrofuran (20 mL), 30% sodium hydroxide in water (5 mL) was stirred at 50° C. for 16 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-[3-(1-methyl-1-methylcarbamoyl-ethylamino)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (130 mg, 34%) as a white solid: LC/MS m/e calcd for C, 23H; 29N, 3; O, 3; (M+H)+: 396.51, observed: 396.2.
Reaction SMILES: [I:1][C:2]1[C:3]([NH:11]C(=O)C)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[OH-].[Na+]>C(O)C.O>[I:1][C:2]1[C:3]([NH2:11])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: CC(=O)Nc1cc2c(cc1I)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc2c(cc1I)OCO2
Reaction time: 4 h
Yield: 98.5 %

Procedure:
A solution of N-(6-iodobenzo[d][1,3]dioxol-5-yl)acetamide (200 mg, 0.656 mmol) and NaOH (1.31 g, 32.8 mmol) in ethanol (26 mL) and water (6 mL) was heated to reflux with stirring for 4 h. The mixture was cooled and the solvent was removed under vacuum. The residue was partitioned between methylene chloride (100 mL) and water (100 mL). The organic layer was washed with water (2×100 mL), dried (MgSO4) and evaporated under vacuum to give 6-iodobenzo[d][1,3]dioxol-5-amine (170 mg, 98%) as orange solid. LCMS: 264 [M+1]+; 1H NMR (DMSO-d6) δ 4.88 (s, 2H), 5.87 (s, 2H), 6.47 (s, 1H), 7.07 (s, 1H).
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH:8]([NH2:10])[CH3:9])=[CH:3][CH:2]=1.[CH3:28][CH:29]1[CH2:35][C:34](=[O:36])[O:33][C:31](=[O:32])[CH2:30]1>>[C:1]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH:8]([NH:10][C:34]([CH2:35][CH:29]([CH3:28])[CH2:30][C:31]([OH:33])=[O:32])=[O:36])[CH3:9])=[CH:3][CH:2]=1
Reactant: CC1CC(=O)OC(=O)C1
Reactant: CC(N)C(Cc1ccc2ccccc2c1)c1ccc(-c2ccccc2)cc1
Product: CC(CC(=O)O)CC(=O)NC(C)C(Cc1ccc2ccccc2c1)c1ccc(-c2ccccc2)cc1

Procedure:
Compounds of Examples 57 to 65 were prepared in the same manner as in Example 56 except that (1RS,2RS)-2-(4-biphenylyl)-1-methyl-3-(2-naphthyl)propylamine and/or 3-methylglutaric anhydride used as the starting materials in the above reaction were changed to the corresponding amine compounds and/or acid anhydrides.
Reaction SMILES: [O:1]=[C:2]([OH:14])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([C:11]([OH:13])=[O:12])O)O)O)O.O=C(O)[C@@H]([C@H]([C@H]([C@@H](C(O)=O)O)O)O)O>[Re]>[C:11]([OH:13])(=[O:12])[CH2:9][CH2:7][CH2:5][CH2:3][C:2]([OH:14])=[O:1]
Reactant: O=C(O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(=O)O
Agent: [Re]
Agent: O=C(O)[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C(=O)O
Product: O=C(O)CCCCC(=O)O

Procedure:
Further, as described above, the starting material (glucaric acid or galactaric acid), rhenium catalyst, and acid catalyst are added to the reaction solvent, and reacted together at a proper temperature for a proper reaction time, then separated and purified with a conventional method (e.g., purification with silica column) to obtain glucaric acid ester or galactaric acid ester as an intermediate of adipic acid. In one embodiment, the reaction temperature ranges from 100 to 200° C., and the reaction time is 12 to 24 hours.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([C@:15]([C@@H:25]2[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]2)([OH:24])[CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH3:23])=[O:21])[CH:5]=[CH:4][CH:3]=1.Cl>CC#N>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([C@@:15]([OH:24])([CH:25]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]2)[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:21])[O:22][CH3:23])[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)NCCC[C@@](O)(c1cccc(Cl)c1-c1cccc(C)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CC#N
Product: COC(=O)NCCC[C@@](O)(c1cccc(Cl)c1-c1cccc(C)c1)C1CCCNC1
Reaction time: 8 h

Procedure:
To a solution of (R)-tert-butyl 3-((S)-1-(6-chloro-3′-methylbiphenyl-2-yl)-1-hydroxy-4-(methoxycarbonylamino)butyl)piperidine-1-carboxylate (600 mg, 1.13 mg) in CH3CN (18 mL) was added 2N aq HCl (15 mL) and the reaction mixture was vigorously stirred overnight at rt. The solvents were removed in vacuo to give methyl (4S)-4-(6-chloro-3′-methylbiphenyl-2-yl)-4-hydroxy-4-(piperidin-3-yl)butylcarbamate as its hydrochloride salt (500 mg, 95.8%). 1H NMR (400 MHz, CD3OD): 1.00-1.20 (m, 1H), 1.30-1.80 (m, 8H), 1.80-2.00 (m, 2H), 2.40-2.50 (d, 3H), 2.75-2.90 (t, 1H), 2.90-3.05 (m, 3H), 3.05-3.12 (t, 1H), 3.20-3.30 (m, 1H), 3.30-3.40 (m, 1H), 3.60-3.70 (d, 4H), 6.90-6.98 (d, 1H), 7.00-7.12 (m, 1H), 7.25-7.50 (m, 4H), 7.75-7.85 (d, 1H); MS (E/Z): 431 (M+H+)
Reaction SMILES: CC(O[C:6](=[O:20])[NH:7][C@@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]([NH:17][CH3:18])=[O:16])[C:9]1=[O:19])(C)C.C(O)(C(F)(F)F)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[Cl:45][C:46]1[CH:55]=[C:54]2[C:49]([C:50]([N:57]3[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]3)=[CH:51][C:52]([NH2:56])=[N:53]2)=[CH:48][CH:47]=1>>[NH2:56][C:52]1[CH:51]=[C:50]([N:57]2[CH2:58][CH2:59][N:60]([C:6]([NH:7][C@H:8]3[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]([NH:17][CH3:18])=[O:16])[C:9]3=[O:19])=[O:20])[CH2:61][CH2:62]2)[C:49]2[C:54](=[CH:55][C:46]([Cl:45])=[CH:47][CH:48]=2)[N:53]=1
Reactant: CNC(=O)N1CCCC[C@@H](NC(=O)OC(C)(C)C)C1=O
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)N1CCCC[C@H](NC(=O)N2CCN(c3cc(N)nc4cc(Cl)ccc34)CC2)C1=O

Procedure:
As described for example 213, [(3R)-Hexahydro-1-[(methylamino)carbonyl]-2-oxo-1H-azepin-3-yl]carbamic acid-1,1-dimethylethyl ester, TFA, triphosgene, NaHCO3 (sat.), and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a white powder. LC-MS, 473 (M+). 1H NMR (400 MHz, DMSO): 61.38 (m, 1H), 1.57 (m, 1H), 1.9 (m, 2H), 2.03 (br. d, 1H), 2.19 (s, 1H), 2.85 (d, 3H), 3.08 (m, 4H), 3.21 (m, 1H), 3.63 (m, 4H), 4.83 (m, 1H), 4.85 (m, 1H), 4.95 (s, 2H), 5.85 (d, 1H), 6.11 (s, 1H), 7.11 (dd, 1H), 7.56 (d, 1H), 7.67 (d, 1H), 8.91 (q, 1).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27](C(OCC)C)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH:41]([O:44][CH3:45])[O:42][CH3:43])[N:36]=2)[OH:34])=[C:7]([Cl:46])[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl.CO.C([O-])([O-])=O.[Na+].[Na+]>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]([CH:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH:41]([O:42][CH3:43])[O:44][CH3:45])[N:36]=2)[OH:34])=[C:7]([Cl:46])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C(O)c2cccc(C(OC)OC)n2)n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCc1nc(Cl)c(C(O)c2cccc(C(OC)OC)n2)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.3 %

Procedure:
To 50 mg (0.077 mmole) of the compound obtained in step 1 of Example 1 was added 1 ml of 3% hydrogen chloride/methanol solution and the resulting solution was stirred for 10 minutes at room temperature. After being added with a small amount of Na2CO3, the resultant was concentrated under reduced pressure and purified with silica gel column chromatography to obtain 37.7 mg of the title compound (yield 85%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([CH:26]=O)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.Cl.[NH2:29][OH:30]>CO.N1C=CC=CC=1>[OH:30][N:29]=[CH:26][C:20]1([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[CH3:1])=[CH:8][CH:9]=3)[CH:15]=2)[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: Cc1nccn1-c1ccc(Sc2cccc(C3(C=O)CCOCC3)c2)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: Cc1nccn1-c1ccc(Sc2cccc(C3(C=NO)CCOCC3)c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.3 %

Procedure:
4-[3-[4-(2-Methylimidazol-1-yl)phenylthio]phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carbaldehyde (178 mg, 0.47 mmol) and hydroxylamine hydrochloride (210 mg, 3 mmol) were dissolved in a mixture of methanol (4 ml) and pyridine (1 ml) and the reaction mixture was stirred for 5 h at ambient temperature. Volatiles were removed in vacuo and the resultant residue was diluted with 0.1 N aqueous NaOH (20 ml) and extracted with ethyl acetate (30 ml×3). The combined organic layers were washed with water (50 ml) and brine (50 ml), dried (MgSO4) and concentrated in vacuo. The residual solids were recrystallized from ethyl acetate to afford 130 mg (70%) of the titled compound as white solids.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](=[NH:5])[NH2:4].[CH3:8][O:9][C:10](=[O:19])[CH2:11][C:12](=O)[CH2:13][C:14](OC)=[O:15].Cl.CCCCCC>C[O-].[Na+].CO.CC(O)C.CCOC(C)=O>[OH:15][C:14]1[N:4]=[C:3]([C:2]([F:7])([F:6])[F:1])[N:5]=[C:12]([CH2:11][C:10]([O:9][CH3:8])=[O:19])[CH:13]=1
Reactant: N=C(N)C(F)(F)F
Reactant: COC(=O)CC(=O)CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)Cc1cc(O)nc(C(F)(F)F)n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 69.3 %

Procedure:
2,2,2-Trifluoroethanimidamide (6.7 g, 50. mmol, Oakwood) was dissolved in 0.5 M sodium methoxide in methanol (120 mL, 60. mmol) and 3-oxopentanedioic acid dimethyl ester (8.4 mL, 55 mmol, Aldrich Co.) was added. The reaction solution was stirred 50° C. for 18 h. LCMS showed it to be mostly done to give the product, M+H 237. The solvent was rotovapped. 1 N HCl was added (50 mL) (pH5), followed 4M HCl (10 mL). The mixture was then extracted with ethyl acetate. The organic solution was washed with brine, dried over sodium sulfate, filtered and concentrated to 12 g of a yellow semisolid. The product was isolated by automatic silica gel chromatography on a 120 g silica gel column, using solvent A=hexane; solvent B=3% iPrOH/EtOAc; flow 60 mL/min; A, 3 min; gradient to 30% B in 40 min, then 30% B for 20 min; detector set at 256 nm; collected 47 mL fractions. The product eluted at 10-25 min. HPLC showed UVmax at 222 and 254 nm (dropping off to 320 nm). The solvent was removed to give 9 g of product. The product was purified by automatic silica gel chromatography on a 120 g silica gel column, using solvent A=hexane; solvent B=iPrOH; flow 60 mL/min; A, 3 min; gradient to 20% B in 25 min, then 20% B for 10 min; detector set at 264 nm; collected 47 mL fractions. The product eluted at 22-27 min. The solvent was removed by rotary evaporation to give the desired product as light yellow viscous oil, 5.2 g, which slowly began to crystallize. NMR (400 MHz, DMSO-D6) δ 6.95 (s, 1H); 3.87 (s, 2H, ArCH2); 3.63 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[CH3:2].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([F:24])=[C:20]([CH:23]=1)[CH:21]=O>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([F:24])=[C:20]([CH2:21][C:12]2[S:11][C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][CH2:1][CH3:2])=[CH:14][CH:13]=2)[CH:23]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CCOc1ccccc1-c1cccs1
Product: CCOc1ccccc1-c1ccc(Cc2cc(Br)ccc2F)s1

Procedure:
2-(2-Ethoxyphenyl)thiophene obtained in Reference Example 70-(1) and 5-bromo-2-fluorobenzaldehyde were treated in a manner similar to Reference Example 9 to give the target compound. APCI-Mass m/Z 391/393 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][O:22][CH3:23])=[CH:17][CH:16]=3)[N:12]=[CH:11]2)[C:7]([C:24]([F:27])([F:26])[F:25])=[CH:6][C:5]=1[N+:28]([O-])=[O:29]>O1CCCC1.[Pt]>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][O:22][CH3:23])=[CH:19][CH:20]=3)[N:12]=[CH:11]2)[C:7]([C:24]([F:25])([F:26])[F:27])=[CH:6][C:5]=1[NH:28][OH:29]
Reactant: COCc1ccc(-c2cn(-c3cc(C(=O)OC)c([N+](=O)[O-])cc3C(F)(F)F)cn2)cc1
Agent: [Pt]
Solvent: C1CCOC1
Product: COCc1ccc(-c2cn(-c3cc(C(=O)OC)c(NO)cc3C(F)(F)F)cn2)cc1
Yield: 68.3 %

Procedure:
1.00 g of 5-[4-(4-methoxymethyl-phenyl)-imidazol-1-yl]-2-nitro-4-trifluoromethyl-benzoic acid methyl ester in 20 ml of tetrahydrofuran is hydrogenated in presence of 200 mg of platinum on carbon. After filtration of the catalyst the solution is evaporated to dryness yielding 0.661 g of 2-hydroxyamino-5-[4-(4-methoxymethyl-phenyl)-imidazol-1-yl]-4-trifluoromethyl-benzoic acid methyl ester as a yellow solid. 1H-NMR (DMSO-d6, 400 MHz): 3.30 s, 3H; 3.82 s, 3H; 4.40 s, 2H; 7.35 d, J=10.4 Hz, 2H; 7.62 s, 1H; 7.80 d, J=10.4 Hz, 2H; 7.85-7.90 m, 3H.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][C:14]1[C:23]2[CH:24]=[CH:25][NH:26][C:27](=[O:28])[C:22]=2[C:21]2[C:16](=[CH:17][CH:18]=[N:19][CH:20]=2)[N:15]=1.C1C(=O)N([Br:36])C(=O)C1>CN(C=O)C>[Br:36][C:24]1[C:23]2[C:14]([NH:13][C:3]3[C:2]([Cl:1])=[CH:7][C:6]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:5][C:4]=3[Cl:12])=[N:15][C:16]3[C:21]([C:22]=2[C:27](=[O:28])[NH:26][CH:25]=1)=[CH:20][N:19]=[CH:18][CH:17]=3
Reactant: CC(C)(O)c1cc(Cl)c(Nc2nc3ccncc3c3c(=O)[nH]ccc23)c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(C)(O)c1cc(Cl)c(Nc2nc3ccncc3c3c(=O)[nH]cc(Br)c23)c(Cl)c1
Reaction time: 1.5 h

Procedure:
To a solution of 6-{[2,6-dichloro-4-(1-hydroxy-1-methylethyl)phenyl]amino}pyrido[4,3-c]-1,6-naphthyridin-10(9H)-one (Example 146, Step 1) (86, 0.21 mmol) in DMF (4 mL) at 0° C. was added NBS (44 mg, 0.25 mmol) and the reaction mixture was stirred for 1.5 hr. The solution was quenched with 10% sodium thiosulfate and saturated NaHCO3 and stirred for 30 min. The reaction mixture was diluted with CH2Cl2 and the layers were separated. The organic layers were dried with MgSO4, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (100% CH2Cl2 to 65% CH2Cl2/35% MeOH) afforded the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:14]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15]([CH:20]=O)=[CH:16][CH:17]=[CH:18][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:14]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1
Reactant: O=Cc1ccccc1-c1ccccc1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Fc1ccc(N2CCN(Cc3ccccc3-c3ccccc3)CC2)cc1

Procedure:
96 mg of the target compound (0.28 mmol, 34.0%) was obtained using 1-(4-fluorophenyl)piperazine (296 mg, 1.64 mmol), biphenyl-2-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=1)=[O:4].[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>>[CH2:15]([O:14][C:12]([C:8]1[CH:7]=[C:6]([N:5]([CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C:3](=[O:4])[CH2:2][NH:1][C:33]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[CH:27]=2)=[O:34])[CH:11]=[CH:10][CH:9]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1cccc(N(CC(=O)OC(C)(C)C)C(=O)CN)c1
Reactant: Cc1cccc(N=C=O)c1
Product: CCOC(=O)c1cccc(N(CC(=O)OC(C)(C)C)C(=O)CNC(=O)Nc2cccc(C)c2)c1
Yield: 18.5 %

Procedure:
Using a procedure similar to that described in Example 1, but starting with tert-butyl 2-[2-amino-N-(3-ethoxycarbonylphenyl)acetamido]acetate (3.3 g) and 3-methylphenyl isocyanate (1.3 g), and after recrystallisation in diisopropyl ether, tert-butyl 2-{N-(3-ethoxycarbonylphenyl)-2-[3-(3-methylphenyl)ureido]acetamido}acetate (0.85 g), m.p. 71° C., is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C@H:3]1[C:8]1[CH:9]=[CH:10][CH:11]=[N:12][CH:13]=1.[OH:14]N1C(=O)CCC1=O.C(N=C=NCCCN(C)C)C>>[CH3:1][N:2]1[C:6](=[O:7])[CH:5]([OH:14])[CH2:4][CH:3]1[C:8]1[CH:9]=[CH:10][CH:11]=[N:12][CH:13]=1
Reactant: O=C1CCC(=O)N1O
Reactant: CN1C(=O)CC[C@H]1c1cccnc1
Agent: CCN=C=NCCCN(C)C
Product: CN1C(=O)C(O)CC1c1cccnc1

Procedure:
Hydroxycotinine hemisuccinate succinic ester was prepared by adding to 1 ml of cotinine hemisuccinate 14 mg of N-hydroxysuccinimide (Sigma) and 23 mg of 1-ethyl-3-(dimethylaminopropyl) carbodiimide (Sigma) and incubating at room temperature for 3 ]]ours.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:12][CH2:13]/[CH:14]=[C:15](/[CH3:22])\[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:3]/[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.O.BrN1C(=[O:30])CCC1=O>C(COC)OC>[CH3:20][C:19]([CH:18]([OH:30])[CH2:17][CH2:16]/[C:15](/[CH3:22])=[CH:14]\[CH2:13][CH2:12]/[C:2](/[CH3:1])=[CH:3]\[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)=[CH2:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)=CCC/C(C)=C\CC/C(C)=C\COC1CCCCO1
Solvent: O
Solvent: COCCOC
Product: C=C(C)C(O)CC/C(C)=C\CC/C(C)=C\COC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2 g (0.0065 mol) of tetrahydro-2-[[(2Z,6Z)-3,7,11-trimethyl-2,6,10-dodecatrienyl]oxy]-2H-pyran dissolved in 13 ml of monoglyme and 2.6 ml of water is treated portionwise at -10° with 1.3 g of N-bromosuccinimide. The mixture is subsequently stirred at 0° for 1/4 hour and at room temperature for 2 hours. The reaction solution is poured into 100 ml of water and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution. After drying and removing the solvent the residue, containing tetrahydro-2-[[(2Z,6Z)-10-bromo-11-hydroxy-3,7,11-trimethyl-2,6,10-dodecatrienyl]oxy]-2H-pyran, is dissolved in 18 ml of methanol and treated with 600 mg of potassium carbonate. The suspension is stirred at room temperature for 1.5 hours under argon. After removing the methanol on a rotary evaporator the residue is treated with 500 ml of ether and 200 ml of water. The organic phase is washed with saturated sodium chloride solution. After drying and removing the solvent the residue, containing (6Z,10Z)-2,3-epoxy-2,6,10-trimethyl-12-[(tetrahydro-2H-pyran-2-yl)oxy]-6,10-dodecadiene, is dissolved in 30 ml of toluene and treated with 1.35 g of aluminum isopropylate. The reaction mixture is boiled at reflux for 17 hours. After cooling to room temperature the reaction mixture is poured into 200 ml of an ice-water mixture. After acidification with 1N hydrochloric acid the mixture is extracted with 3×150 ml of hexane. The organic phase is washed with 500 ml of saturated sodium chloride solution. After drying and removing the solvent the residue is chromatographed on silica gel with a 1:2 ether-hexane mixture which additionally contains 0.1% triethylamine. There is obtained (6Z,10Z)-2,6,10-trimethyl-12 -[(tetrahydro-2H-pyran-2-yl)oxy]-1,6,10-dodecatrien-3-ol which has the following bands in the IR spectrum: 3449 cm-1, 1647 cm-1, 1449 cm-1, 1377 cm-1, 901 cm-1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH:8]=[O:9].[BH4-].[Na+]>C(O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9]
Reactant: O=CCC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCCC1CCCCO1
Temperature: 50 °C
Yield: 86.7 %

Procedure:
To a stirred solution of tetrahydro-2H-pyran-2-ylacetaldehyde (528 mg) in ethanol (5 mL) was added sodium borohydride granules (156 mg). The mixture was heated at 50° C. for 2 h under nitrogen. After cooling, the solvent was evaporated and the residue treated with brine. The mixture was acidified by careful addition of 2N HCl and this mixture was extracted with DCM (×3). The combined organics were washed with brine, dried using a hydrophobic frit and evaporated to give the title compound as a clear oil (465 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][N:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][N:10]=1)[C:5]([Cl:17])=[O:6]
Reactant: O=C(O)c1cc(Cl)ncc1C(F)(F)F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(Cl)ncc1C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of 0.66 g of 2-chloro-5-trifluoromethyl isonicotinic acid and 4 ml of thionyl chloride was heated to reflux for 2.5 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure to give 2-chloro-5-trifluoromethyl isonicotinic acid chloride. A mixture of the resultant 2-chloro-5-trifluoromethyl isonicotinic acid chloride and 4 ml of DMF was added dropwise to a mixture of 0.48 g of 2-amino-4-tert-butylphenol, 0.59 g of triethylamine and 4 ml of DMF while ice-cooling. The reaction mixture was stirred at room temperature for one hour, and stirred while heating at 50° C. for one hour. The mixture was cooled to room temperature, and water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.75 g of N-(5-tert-butyl-2-hydroxyphenyl)-2-chloro-5-trifluoromethylisonicotinamide.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8](=O)[CH3:9])[CH:4]=[N:3]1.[C:11]1([C@H:17]([NH2:19])[CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)C.[BH4-].[Na+]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].C1COCC1>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C@H:8]([NH:19][C@@H:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:18])[CH3:9])[CH:4]=[N:3]1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC(=O)c1cnn(C)c1C
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c([C@@H](C)N[C@H](C)c2ccccc2)cnn1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.5 %

Procedure:
1-(1,5-Dimethyl-1H-pyrazol-4-yl)ethanone (J. Heterocyclic Chem. 1986, 23, 275-279, 4.82 g, 34.9 mmol) and (R)-1-Phenylethylamine (5.07 g, 41.9 mmol) in Titanium tetraisopropoxide (22.1 g, 77.7 mmol) were stirred at room temperature for 16 hours. Ethanol (30 ml) and THF (30 ml) were added at −20° C., then Sodium borohydride (3.96 g, 105 mmol) was added at −20° C. then the whole mixture was stirred for 3 h whilst warming to room temperature. The reaction was quenched with water (20 ml) and diluted with ethyl acetate-THF. Then the mixture was filtered through celite and washed with ethyl acetate. The filtrate was dried over Na2SO4, concentrated and purified by silica gel column chromatography eluted with ethyl acetate/n-Hexane=2/1 to 100/0 to furnish the title compound (3.44 g, 41% yield) as colorless oil. 1H NMR (270 MHz, CDCl3) δ 1.26 (3H, d, J=6.6 Hz), 1.27 (3H, d, J=6.6 Hz), 1.96 (3H, s), 3.44 (1H, q, J=6.6 Hz), 3.60 (1H, q, J=6.6 Hz), 3.76 (3H, s), 7.20-7.38 (6H, m).