Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][CH2:4][Mg]Br.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>O1CCCC1.[Cu](Cl)Cl.[Li]>[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:4][CH2:3][CH:2]([CH3:7])[CH3:1]
Reactant: BrCCCCCCCCCCCBr
Reactant: CC(C)CC[Mg]Br
Agent: Cl[Cu]Cl
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)CCCCCCCCCCCCCBr
Temperature: -10 °C
Reaction time: 1 h

Procedure:
By a procedure analogous to that described above, 3-methylbutyl magnesium bromide in tetrahydrofuran is reacted with 34.5 g. (0.11 moles) of 1,11-dibromoundecane and 0.2 g. of lithium copper chloride in 75 ml. of tetrahydrofuran. After 1 hour stirring at -10° C., the solution is evaporated, and the resultant oil is distilled in vacuo to yield the colorless 1-bromo-14-methylpentadecane.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:17][CH2:18][CH2:19][OH:20])=[CH:6][C:7]([F:16])=[C:8]([CH:10]([O:14][CH3:15])[C:11]([OH:13])=O)[CH:9]=1)[CH3:2].[NH2:21][CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>>[C:22]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][C:11](=[O:13])[CH:10]([C:8]2[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[C:5]([O:17][CH2:18][CH2:19][OH:20])=[CH:6][C:7]=2[F:16])[O:14][CH3:15])=[CH:25][CH:24]=1)#[N:21]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CCOc1cc(C(OC)C(=O)O)c(F)cc1OCCO
Product: CCOc1cc(C(OC)C(=O)NCc2ccc(C#N)cc2)c(F)cc1OCCO

Procedure:
(RS)-[5-Ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-2-methoxy-acetamide. Light yellow oil. MS 403.4 ([M+H]+)
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH:7]1[CH2:12][N:11]2[C:13](=[O:23])[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=[C:10]2[N:9]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:25]=2)[CH2:8]1)C.[OH-].[Li+]>O1CCCC1>[O:23]=[C:13]1[N:11]2[CH2:12][CH:7]([CH2:6][CH2:5][C:4]([OH:39])=[O:3])[CH2:8][N:9]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:25]=3)[C:10]2=[N:16][C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:14]1
Reactant: CCOC(=O)CCC1CN(c2ccnc(NCCc3ccccc3)n2)c2nc(-c3ccccc3)cc(=O)n2C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCC1CN(c2ccnc(NCCc3ccccc3)n2)c2nc(-c3ccccc3)cc(=O)n2C1

Procedure:
A solution of 3-[6-oxo-1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,3,4,6-tetrahydro-2H-pyrimido[1,2-a]pyrimidin-3-yl]-propionic acid ethyl ester (240 mg, 0.46 mmol), 10% aqueous lithium hydroxide (0.2 mL), and tetrahydrofuran (5 mL) was heated to 50° C. Reaction partitioned between dichloromethane (50 mL) and 5% sodium dihydrogenphosphate. Organic dried over magnesium sulfate, then concentrated to a white solid under vacuum. M+1=497.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:26])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:25])[C:9]([OH:24])([C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([F:13])([F:12])[F:11].[H-].[Na+].[CH2:29]([O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39]Br)=[CH:35][CH:34]=1)[CH3:30].O>CN(C)C(=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:29]([O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:26][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:25])[C:9]([OH:24])([C:14]3[CH:15]=[N:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]([F:11])([F:13])[F:12])=[C:2]([Cl:1])[CH:3]=2)=[CH:35][CH:34]=1)[CH3:30]
Reactant: CCOC(=O)c1ccc(CBr)cc1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1cnc2ccccc2c1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(COc2ccc(C(C)C(O)(c3cnc4ccccc4c3)C(F)(F)F)c(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.3 %

Procedure:
To a suspension of 3-chloro-4-(3,3,3-trifluoro-2-hydroxy-1-methyl-2-quinolin-3-yl-propyl)-phenol (68 mg) in N,N-dimethylacetamide (1 ml) was added NaH (55% dispersion in mineral oil, 8.5 mg) at 0° C. The mixture was stirred at 0° C. for 1 h and at room temperature for 1 h. Ethyl-4-(bromomethyl)benzoate (48 mg) was added and the mixture was stirred overnight. Since the reaction was not finished, tetrabutylammonium iodide (6.5 mg) and NaH (55% dispersion in mineral oil, 8.5 mg) were added and the mixture was stirred overnight at room temperature and for 2 h at 50° C. Ethyl-4-(bromomethyl)benzoate (4 mg) was added and the mixture was stirred for 2 h at 50° C. The reaction mixture was poured into water and extracted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4), filtered and concentrated. The product was purified by chromatography (SiO2, cyclohexane=>cyclohexane/EtOAc 1:1) to give the title compound (40 mg) as an orange solid. MS (m/e)=543.8 [M+H+].
Reaction SMILES: C[O:2][C:3](=[O:27])[C@H:4]([OH:26])[C@H:5]([S:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]=1[NH2:25])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.C(O)C.[OH-].[Na+]>O>[NH2:25][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[S:14][C@H:5]([C:6]1[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[C@@H:4]([OH:26])[C:3]([OH:27])=[O:2]
Reactant: COC(=O)[C@H](O)[C@H](Sc1ccc2ccccc2c1N)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc([C@@H](Sc2ccc3ccccc3c2N)[C@@H](O)C(=O)O)cc1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A mixture of 8.9 g (0.023 mol) of (±)-(S*,R*)-β-[(1-amino-2-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoic acid methyl ester, 50 ml ethanol and 140 ml 1N sodium hydroxide was heated at reflux for 30 minutes. The reaction mixture was cooled to room temperature, diluted with water (50 ml) and extracted with ether (2×75 ml). The aqueous solution was chilled, then neutralized with acetic acid and extracted with ethyl acetate (3×75 ml). The combined extracts were washed with water (75 ml) and dried (MgSO4). Removal of the solvent gave 8.2 g (96%) of (±)-(S*,R*)-β-[(1-amino-2-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoic acid, mp 167°-168°. The analyzed sample was recrystallized from ethyl acetate, mp 167°-168°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25]>>[Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1Cl
Reactant: NCCCCCO
Product: O=C(NCCCCCO)c1ccncc1Nc1ccc(I)cc1Cl

Procedure:
3-(2-Chloro-4-iodo-phenylamino)-N-(5-hydroxy-pentyl)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.30 mmol of 3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid (intermediate 2) and 0.40 mmol of 5-amino-pentan-1-ol. LC/MS [9.33 min; 461 (M+1)]
Reaction SMILES: [Cl:1][C:2]1[C:6]([S:7](Cl)(=[O:9])=[O:8])=[CH:5][N:4]([CH2:11][CH3:12])[N:3]=1.[OH-].[NH4+:14]>O1CCCC1>[Cl:1][C:2]1[C:6]([S:7]([NH2:14])(=[O:9])=[O:8])=[CH:5][N:4]([CH2:11][CH3:12])[N:3]=1
Reactant: CCn1cc(S(=O)(=O)Cl)c(Cl)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCn1cc(S(N)(=O)=O)c(Cl)n1

Procedure:
To a solution of 3-chloro-1-ethyl-1H-pyrazole-4-sulfonyl chloride (0.5 g, 2.2 mmol, the product of Step D) in tetrahydrofuran (20 mL) was added 30% ammonium hydroxide (3.0 mL, 24 mmol) dropwise. The reaction mixture was heated to boiling with a heat gun and then stirred for 30 min Tetrahydrofuran was removed under reduced pressure, water (50 mL) was added, the reaction mixture was extracted into ethyl acetate (2×100 mL). The ethyl acetate was dried over magnesium sulfate and concentrated under reduced pressure to afford a solid. The solid was washed with hexane, and dried to afford 282 mg of the title compound. 1H NMR (CDCl3) δ 7.84 (s, 1H), 4.94 (br s, 1H), 4.15 (q, 2H), 1.51 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(Cl)cc1OCc1ccc(F)cc1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)cc2OCc2ccc(F)cc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-chloro-2-[(4-fluorophenyl)methoxy]phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.07 (2H, s), 5.25 (2H, s), 5.73 (1H, d, J=1.6 Hz), 6.98-7.07 (4H, m), 7.32-7.39 (4H, m), 7.55 (1H, d, J=1.6 Hz), 8.00 (1H, s), 8.67 (1H, d, J=5.2 Hz). [M+H] Calc'd for C23H16ClFN4O2, 435; Found, 435.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[O:19]=[S:20]1(=[O:29])[CH2:25][CH2:24][N:23]([C:26](Cl)=[O:27])[CH2:22][CH2:21]1.C(N(CC)C(C)C)(C)C>O1CCCC1.C(OCC)(=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:26]([N:23]2[CH2:24][CH2:25][S:20](=[O:29])(=[O:19])[CH2:21][CH2:22]2)=[O:27])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)N1CCS(=O)(=O)CC1
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCN2)no1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCN2C(=O)N2CCS(=O)(=O)CC2)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-pyrrolidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (0.092 g; 0.337 mmol) in tetrahydrofuran (2.5 mL) is added 1,1-dioxo-1λ6-thiomorpholine-4-carbonyl chloride (0.067 g; 0.337 mmol) and N,N-diisopropylethylamine (0.123 mL; 0.708 mmol). The mixture is stirred at room temperature for 3 hours before diluting with ethyl acetate and washing with 1N hydrochloric acid and brine. The organics are concentrated in vacuo and purified by preparatory HPLC. The product fractions are pooled and concentrated in vacuo to afford title compound. ESI m/z 399 [M+H]+/397 [M−H]−
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[N:8]=[C:9]3[N:19]([CH:20]=2)[CH2:18][CH2:17][O:16][C:15]2[C:10]3=[CH:11][CH:12]=[C:13]([C:21]3[CH:22]=[N:23][N:24]([CH3:32])[C:25]=3[CH:26]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]3)[CH:14]=2)[N:4]([CH:33]([CH3:35])[CH3:34])[N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[CH2:43]1COCC1>>[CH:33]([N:4]1[C:5]([C:7]2[N:8]=[C:9]3[C:10]4[CH:11]=[CH:12][C:13]([C:21]5[CH:22]=[N:23][N:24]([CH3:32])[C:25]=5[CH:26]5[CH2:31][CH2:30][CH2:29][N:28]([CH3:43])[CH2:27]5)=[CH:14][C:15]=4[O:16][CH2:17][CH2:18][N:19]3[CH:20]=2)=[N:6][C:2]([CH3:1])=[N:3]1)([CH3:35])[CH3:34]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C)c4C4CCCNC4)cc2OCC3)n(C(C)C)n1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C)c4C4CCCN(C)C4)cc2OCC3)n(C(C)C)n1
Yield: 79 %

Procedure:
To a solution of 4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-12-[1-methyl-5-(piperidin-3-yl)-1H-pyrazol-4-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1 (14),2,4,10,12-pentaene, also named as 2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-(1-methyl-5-(piperidin-3-yl)-1H-pyrazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (220 mg, 0.39 mmol) in dry THF (5.0 mL), was added LiAlH4 (59.3 mg, 1.56 mmol) in small portions at room temperature. The resultant mixture was heated to reflux for 1 h. Water (2.0 mL) was added to quench the reaction. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give racemic 246 (150 mg, 79% yield), which was separated by chiral SFC (Cellulose-2 column, 0.1% DEA in MeOH isocratic) to give: 5.5 mg of one enantiomer and 70 mg of the other (39% total yield). LCMS (ESI): RT=4.96 min, m/z: 487.4 [M+H+]. 1H NMR (500 MHz, DMSO-d6) δ 8.42 (d, J=2.0 Hz, 1H), 7.91 (s, 1H), 7.43 (s, 1H), 7.09-7.06 (m, 1H), 6.93 (d, J=1.5 Hz, 1H), 5.87-5.84 (m, 1H), 4.54 (d, J=6.0 Hz, 4H), 3.90 (s, 3H), 3.17 (s, 1H), 2.78-2.74 (m, 2H), 2.26 (s, 3H), 2.18-2.13 (m, 3H), 1.64-1.48 (m, 5H), 1.45 (d, J=7.0 Hz, 6H)
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[O:12]CCCOC)[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[OH:12])[CH3:2]
Reactant: CCc1ccc(C(=O)O)cc1OCCCOC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1ccc(C(=O)O)cc1O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 4-ethyl-3-(3-methoxy-propoxy)-benzoic acid (6.44 g, 27.03 mmol) in CH2Cl2 (150 mL) at −78° C. is slowly added BBr3 (9 mL, 93.41 mmol). The reaction mixture is allowed to reach RT and stirred for 3 hours, then poured into ice/water and filtrated to afford the title product as a white solid. TLC, Rf (CH2Cl2/MeOH 95:5)=0.2.
Reaction SMILES: C([S:4][CH:5]([CH3:14])[CH:6]([CH3:13])[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])(=O)C>C(O)(C)C>[SH:4][CH:5]([CH3:14])[CH:6]([CH3:13])[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8]
Reactant: CC(=O)SC(C)C(C)C(=O)OC(C)C
Solvent: CC(C)O
Product: CC(C)OC(=O)C(C)C(C)S
Yield: 37 %

Procedure:
Conditions are the same as for Example 2, but with the product of Example 5 as the starting component and isopropyl alcohol as solvent; 37% yield. Odor: at 1 ppm in DPG—exotic fruit, sweet, sulfury, fatty, floral, slightly rosy. GC/MS (EI): m/z (%) 176(48), 143(14), 134(72), 117(51), 89(91), 61(93), 56(100). 1H NMR (CDCl3): δ 4.98-5.05 (m, 1H), 3.14-3.30 (m, 1H), 2.42-2.53 (m, 1H), 1.67 & 1.49 (2d, J=7.33 Hz, 1H mix of diastereomers), 1.31-1.35 (m, 3H), 1.17-1.25 (m, 9H). 13C NMR (CDCl3) for mix of diastereomers: δ 174.2, 68.3, 67.6, 48.8, 47.9, 37.8, 23.6, 21.8, 14.2, 13.5.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([OH:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20]>O>[C:4]([O:6][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])(=[O:5])[C:3]1[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:1]([O:22][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([CH3:20])[CH3:21])=[O:11]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)CCCCCCCO
Solvent: O
Product: CC(C)CCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCC(C)C
Temperature: 210 °C

Procedure:
A standard 1-liter esterification system was charged with 111 g of phthalic anhydride, 284 g of isodecyl alcohol and 0.5 g of catalyst ATC-II. The system was heated to reflux and the temperature was maintained at 210° C. at reduced pressure. At the end of 1.25 hours the water of reaction was collected and the acid number of the residue was measured to be 0.03 mg KOH/g. Heating was discontinued and excess alcohol removed as the pressure was reduced to 100 torr. Adjusting the temperature to 150° C., hydrolysis of the catalyst and removal of remaining alcohol was accomplished by steam distillation using 40 ml water during 35 minutes at 150° C. and 100 torr. After drying for 15 minutes at these conditions the cloudy crude product was cooled to 90° C. and filtered through a No. 1 Whatman paper to yield a clear residue product diisodecyl phthalate (DIDP) (nD25 =1.4850) having an acid number of 0.04 mg KOH/g and a color of 15 APHA.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][OH:6]
Reactant: COc1c(C=O)cccc1Oc1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1c(CO)cccc1Oc1ccccc1Cl
Yield: 55.6 %

Procedure:
A solution of 2-methoxy-3-(2-chlorophenoxy)benzaldehyde (5.0 g) in methanol (50 ml) and sodium borohydride (720 mg) were treated in a similar manner to that of Example 3-(5). The resultant residue was subjected to column chromatography on silica gel (100 g) and eluted with a mixture of benzene and ethyl acetate (10:1) to give crystalline 2-methoxy-3-(2-chlorophenoxy)benzyl alcohol (2.8 g).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:6][CH:7]=1.[C-:14]#[N:15].[K+].C(OCC)(=O)C>C(#N)C.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>[C:14]([CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:6][CH:7]=1)#[N:15]
Reactant: [C-]#N
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: [K+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#CCc1csc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 73.8 %

Procedure:
1.39 g of 4-chloromethyl-2-phenylthiazole was dissolved in 10 ml of acetonitrile, and 0.65 g of potassium cyanide and 0.05 g of dibenzo-18-crown-6-ether were added thereto at room temperature, and then heated under reflux for 10 hours. After the temperature was returned to room temperature, ethyl acetate was added the resulting mixture, and the insoluble solid was removed through filtration. The resulting ethyl acetate solution was washed with saturated saline and water, and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was purified through silica gel column chromatography to obtain 0.98 g of 4-cyanomethyl-2-phenylthiazole from the fraction eluted with chloroform.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][C@H:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)=[CH:20][CH:19]=1)[CH2:9][C@:10]([CH2:15][OH:16])([CH3:14])[C:11]([OH:13])=[O:12]>C(Cl)Cl.CCN(CC)CC>[Cl:30][C:26]1[CH:25]=[C:24]([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][C@@H:8]([NH:7][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH2:9][C@:10]([CH2:15][OH:16])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:23][CH:22]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@](C)(CO)C(=O)O
Reaction time: 0.17 h
Yield: 16.7 %

Procedure:
Methoxy-acetyl chloride (7 mg, 30 μmol) was combined with a 0.4 mL solution of 0.075 M of (2S,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxymethyl-2-methyl-pentanoic acid (136 mg, 30 μmol) in DCM and Et3N (110 μL). The resulting mixture was stirred for 10 minutes. The solvent was evaporated and the residue was dissolved in AcOH and purified by preparative HPLC to yield the title compound (2.1 mg). MS m/z [M+H]+ calc'd for C22H26ClNO5, 420.15. found 420.2.
Reaction SMILES: [F:1][C:2]([F:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][O:4][CH2:5][CH:6]=[CH2:7].C1(CCCC[O:25]CCCO)C=CC=CC=1>>[F:1][C:2]([F:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][O:4][CH2:5][CH2:6][CH2:7][OH:25]
Reactant: C=CCOCC(F)(F)c1ccccc1
Reactant: OCCCOCCCCc1ccccc1
Product: OCCCOCC(F)(F)c1ccccc1
Yield: 96 %

Procedure:
Obtained from Intermediate 80 (10.6 g, 53 mmol) by the procedure described in Intermediate 12. Purification by column chromatography with silica gel eluting with ethyl acetate/n-hexane (from 1:4 to pute ethyl acetate) gave the title compound (10.7 g, 96%) as oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][C:24]=1[CH3:25])[NH:21][N:20]=[C:19]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>N1C=CC=CC=1.O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][C:24]=1[CH3:25])[NH:21][N:20]=[C:19]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:13])=[O:12])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: Cc1cc2[nH]nc(-c3ccccc3)c2cc1N
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc2[nH]nc(-c3ccccc3)c2cc1NS(=O)(=O)c1ccccc1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34.6 %

Procedure:
2-Methylsulfonyl-N-(6-methyl-3-phenyl-1H-indazol-5-yl)benzenesulfonamide can be obtained in the following way: 0.45 g of 2-methylsulfonylbenzenesulfonyl chloride is added to a solution, at a temperature in the region of 0° C. and under argon, of 0.4 g of 5-amino-6-methyl-3-phenyl-1H-indazole in 35 ml of pyridine. The reaction mixture is then stirred for 10 minutes at a temperature in the region of 0° C. then 16 hours at a temperature in the region of 20° C., and is then diluted with 50 ml of water. After settling out, the aqueous phase is extracted with 50 ml and then 25 ml of ethyl acetate. The organic extracts are pooled, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue thus obtained is purified by chromatography on a silica column (particle size 63-200 μm), eluting with a dichloromethane/methanol (99/1 by volume) mixture. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up and recrystallized from 20 ml of diethyl ether. The crystals are filtered off through sintered glass, washed with 2 times 10 ml of diisopropyl ether, partially dried and then dried under reduced pressure (3 kPa) at a temperature in the region of 50° C. 0.27 g of 2-methylsulfonyl-N-(6-methyl-3-phenyl-1H-indazol-5-yl)benzenesulfonamide are obtained in the form of a beige powder melting at 239° C. (analysis C21H19N3O4S2 % calculated C, 57.13; H, 4.34; N, 9.52; O, 14.49; S, 14.52. % found C, 56.66; H, 4.52; N, 9.41; S, 14.15).
Reaction SMILES: C([C:3]1([C:17]2([OH:28])[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]2)[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[N:4]1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)#N.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[OH:28][C:17]1([CH:3]2[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[N:4]2[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:18]1
Reactant: CC1CCCC(C#N)(C2(O)CN(C(=O)OC(C)(C)C)C2)N1Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC1CCCC(C2(O)CN(C(=O)OC(C)(C)C)C2)N1Cc1ccccc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
To a stirred solution of 1,1-dimethylethyl 3-[2-cyano-6-methyl-1-(phenylmethyl)piperidin-2-yl]-3-hydroxyazetidine-1-carboxylate (180 mg, 0.47 mmol) in ethanol (1 mL) was added acetic acid (53.5 μL, 0.94 mmol) followed by sodium cyanoborohydride (58.7 mg, 0.94 mmol) and the reaction mixture stirred at 70° C. overnight. After cooling to room temperature the suspension was filtered through celite and the solid washed with additional ethanol. The filtrate was concentrated in vacuo and taken up in ethyl acetate (30 mL). The organic layer was washed with 2 M sodium hydroxide solution. The sodium hydroxide layer was separated and washed with ethyl acetate (10 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give crude 1,1-dimethylethyl 3-hydroxy-3-[6-methyl-1-(phenylmethyl)piperidin-2-yl]azetidine-1-carboxylate as yellow oil (60 mg, 36% yield). Crude product was used further without purification. 1H NMR (400 MHz, CDCl3): 7.22-7.35 (m, 5H), 4.08 (d, 1H), 3.85-3.96 (m, 3H), 3.57 (d, 1H), 3.33-3.36 (m, 1H), 2.91-3.06 (m, 2H), 1.63-1.70 (m, 4H), 1.44 (s, 9H), 1.23 (d, 3H), 1.05 (d, 2H); MS (EI) for C21H32N2O3: 361 (MH+).