Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([Cl:30])[N:18]=[C:17](Cl)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:32]1([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([Cl:30])[N:18]=[C:17]([N:41]3[CH2:42][CH2:43][N:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:39][CH2:40]3)[N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1ccccc1Oc1c(Cl)nc(Cl)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Product: COc1ccccc1Oc1c(Cl)nc(N2CCN(c3ccccc3)CC2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The procedure described in Synthesis Example 2 was repeated by use of 4-t-butyl-N-[2,6-dichloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide (5) and 1-phenylpiperazine, to thereby obtain the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:26])[C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=[O:21])=[CH:12][CH:11]=2)=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2].C(C1C=CC(OCC2C=CC(C(C3C=C(C=CC=3)C#N)=O)=CC=2)=C(CCC)C=1O)(=O)C>>[C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=[O:21])=[O:26])=[CH:14][CH:15]=2)=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2ccc(C(O)c3cccc(C(=O)O)c3)cc2)ccc(C(C)=O)c1O
Agent: CCCc1c(OCc2ccc(C(=O)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Product: CCCc1c(OCc2ccc(C(=O)c3cccc(C(=O)O)c3)cc2)ccc(C(C)=O)c1O
Yield: 100 %

Procedure:
The title compound is prepared essentially as described for 3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzoic acid employing 3-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-benzoyl]-benzonitrile, to give the title compound (52 mg, 100%), as a white powder. 1H NMR (DMSO-d6) δ 13.34 (bs, 1H), 12.89 (s, 1H), 8.22-8.26 (m, 2H), 8.01 (d, 1H), 7.82-7.87 (m, 3H), 7.75 (t, 1H), 7.65-7.68 (m, 2H), 6.75 (d, 1H), 5.42 (s, 2H), 2.60-2.68 (m, 5H), 1.50-1.55 (m, 2H), 0.91 (t, 3H). LCMS M−1 431.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:19][C:20]1[S:21][CH:22]=[CH:23][C:24]=1[CH3:25]>O1CCOCC1.ClCCl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][C:20]1[S:21][CH:22]=[CH:23][C:24]=1[CH3:25])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccsc1N
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1sccc1C
Yield: 36.4 %

Procedure:
3-Butyryl-4-chloro-8-methoxyquinoline (3.6 g, 0.0137 mol) and 2-amino-3-methylthiophene (3.4 g, 0.03 mol) in 1,4 dioxan (30 ml) under a nitrogen atmosphere were stirred at room temperature for 20 hours. The solvent was evaporated under reduced pressure to give an oil. The oil was taken up in dichloromethane and extracted with 2N hydrochloric acid (3×100 ml). The dichloromethane extracts were then washed with sodium carbonate solution (100 ml), dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a solid. The solid was purified by flash chromatography using a gradient elution of dichloromethane/methanol (0-5%, 500 ml). The fractions containing the product were combined and evaporated under reduced pressure to give a solid, (1.94 g), m.p. 130°-132°. Recrystallization from ethyl acetate gave the title compound, (1.7 g), m.p. 132°-133°.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[CH2:34]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=O)=[CH:38][CH:37]=1)[CH3:35]>>[CH2:34]([C:36]1[CH:44]=[CH:43][C:39]([CH2:40][C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[CH3:1])[N:6]([C@@H:11]3[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]3[OH:13])[CH:5]=2)=[CH:38][CH:37]=1)[CH3:35]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCc1ccc(C(=O)Cl)cc1
Product: CCc1ccc(Cc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3cccc(C)c23)cc1

Procedure:
The above 4-methyl-1-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyl)indole and 4-ethylbenzoyl chloride were treated in a manner similar to Example 3 to give the titled compound, 3-(4-ethylphenylmethyl)-4-methyl-1-(β-D-glucopyranosyl)-indole as a colorless powder. APCI-Mass m/Z 412 (M+H). 1H-NMR (DMSO-d6) δ 1.15 (t, J=−1.6 Hz, 3H), 2.41 (s, 3H), 2.56 (q, J=7.5 Hz, 2H), 3.23 (td, J=8.9, 5.2 Hz, 1H), 3.37-3.47 (m, 3H), 3.64-3.69 (m, 2H), 4.16 (s, 2H), 4.51 (t, J=5.3 Hz, 1H), 5.06 (d, J=5.1 Hz, 1H), 5.13-5.15 (m, 2H), 5.34 (d, J=9.0 Hz, 1H), 6.70 (d, J=7.1 Hz, 1H), 6.97 (t, J=7.7 Hz, 1H), 7.07-7.12 (m, 5H), 7.34 (d, J=8.3 Hz, 1H).
Reaction SMILES: [O:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[OH2:6].[CH3:7]O>>[C:2]([O:6][CH3:7])(=[O:1])[C:3]([CH3:4])=[CH2:5].[O:1]=[CH:2][C:3](=[CH2:4])[CH3:5]
Reactant: CO
Reactant: O
Agent: C=C(C)C=O
Product: C=C(C)C(=O)OC

Procedure:
Liquid mixture (IV): a liquid mixture containing liquid methacrolein and liquid methanol, which, in the method of the present invention, is obtained by separation from a reaction mixture (containing methyl methacrylate, water, methacrolein and methanol) produced by the above-mentioned oxidative esterification reaction (the direct ML-to-MMA synthesis reaction). This liquid mixture (IV) can be recycled and introduced into the dehydration tower at an upper portion thereof as the above-mentioned liquid mixture (I) and/or into the absorption tower at an upper portion thereof as the above-mentioned liquid mixture (II).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([OH:28])=[O:27])[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:14]=2)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].C1(C)C=CC=CC=1.[C:45](Cl)(=[O:50])[CH2:46][CH:47]([CH3:49])[CH3:48]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:45](=[O:50])[CH2:46][CH:47]([CH3:49])[CH3:48])[C:9]2[CH:10]=[C:11]([CH:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([OH:28])=[O:27])[CH:12]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=3)[CH:14]=2)=[CH:6][CH:7]=1
Reactant: CC(C)CC(C(=O)O)c1cc(Nc2ccc(Cl)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CC(C)CC(=O)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)CC(=O)N(c1ccc(Cl)cc1)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C(CC(C)C)C(=O)O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 27.1 %

Procedure:
To a solution of 2-[5-(4-chloro-phenylamino)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid (51.1 mg, 0.11 mmol), sodium acetate 40 mg, 1.1 mmol) and toluene (0.5 mL) was added isovaleryl chloride (60 μL, 0.55 mmol) and the resulting mixture was stirred at RT for 48 hr. The mixture was treated with water (10 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were dried with MgSO4, filtered and the solvent was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (gradient 0% to 30% EtOAc/heptane) to afford 16.3 mg (27%) of the title compound as a solid. 1H-NMR (CDCl3; 300 MHz): δ 7.6-7.7 (m, 4H), 6.98-7.45 (m, 7H), 3.7 (m, 1H), 2.2 (m, 2H), 2.0 (m, 1H), 1.7 (m, 1H), 1.5 (m, 1H), 1.25 (bs, 1H), 0.85-1.0 (m, 12H). Mass spectrum (ESI, m/z): Calcd. for C30H31ClF3NO3, 546.03 (M+H), found 548.26, 546.29.
Reaction SMILES: [N:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]([C:10]([OH:12])=O)=[N:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:17][N:18]([CH3:21])C=O.[C:22]1(C)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:17]([N:18]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:10]([C:4]1[CH:5]=[C:6]([C:7]([OH:9])=[O:8])[N:1]=[CH:2][N:3]=1)=[O:12])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN(C)C=O
Reactant: Cc1ccccc1
Reactant: O=C(O)c1cc(C(=O)O)ncn1
Solvent: O=S(Cl)Cl
Product: O=C(O)c1cc(C(=O)N(Cc2ccccc2)Cc2ccccc2)ncn1
Temperature: 10 °C
Reaction time: 12 h

Procedure:
1.7 g of pyrimidine-4,6-dicarboxylic acid are suspended in 20 ml of toluene and 2.4 g of thionyl chloride and 0.2 ml of dimethylformamide are added. The mixture is heated to reflux until it is no longer possible to observe any gas evolution (about 3 hours (h)). About 5 ml of solvent are distilled off and the mixture is then cooled down to from 0 C to 10° C. and 2.7 g of benzylamine, dissolved in 10 ml of toluene, are added. The solution is slowly heated to room temperature, then stirred at room temperature for 12 hours and evaporated down to dryness. The residue is taken up in 50 ml of methylene chloride and the solution is extracted 3 times by shaking with saturated sodium hydrogen carbonate solution; the organic phase is washed with water, dried with magnesium sulfate and evaporated.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[N:9][NH:10][CH:11]=1.[CH2:13]([NH2:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]CCCCCCC.C(C=O)=O.[C:36]([OH:55])(=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]/[CH:44]=[CH:45]\[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]>C1(C)C=CC=CC=1.C(O)C>[C:48]1([CH3:47])[CH:49]=[CH:50][CH:51]=[CH:52][C:53]=1[NH:31][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:12][CH2:1][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:7]1[N:8]=[N:9][NH:10][CH:11]=1.[C:36]([OH:55])(=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]/[CH:44]=[CH:45]\[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: Cc1ccccc1-c1c[nH]nn1
Reactant: CCCCCCCC/C=C\CCCCCCCCN
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: O=CC=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccccc1NCCCCCCCC/C=C\CCCCCCCCc1c[nH]nn1
Yield: 343.6 %

Procedure:
Approximately 53 grams (0.4 mole) tolyltriazole, 111 grams (0.4 mole) oleyl amine, 100 ml ethanol, and 100 ml toluene were charged to a 1 liter flask equipped with an agitator, Dean-Stark apparatus, and dropping funnel. This mixture was stirred to a homogeneous mixture. Glyoxal (29 grams, 0.2 mole, 40% in water) was added dropwise and then stirred at room temperature for 12 hours. Water was then azeotropically removed by heating to reflux temperatures of approximately 100°-120° C. While maintaining a temperature of less than or equal to 60° C., 56 grams (0.2 mole) oleic acid was added slowly. The reaction mixture was stirred at 60° C. for 1 hour. The orange product (243 grams) was isolated by filtration and removal of solvent under reduced pressure.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC2OC3C=CC=CC=3C=2C=1)(=O)C.[N:33]1[CH2:37][CH2:36][CH2:35][CH:34]=1.N1CCCCC=1>>[NH:33]1[CH2:37][CH2:36][CH2:35][CH:34]1[CH2:2][C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc2c(c1)Cc1ccccc1-2
Reactant: C1=NCCC1
Agent: C1=NCCCC1
Agent: CC(=O)c1ccc2oc3ccccc3c2c1
Product: O=C(CC1CCCN1)c1ccc2c(c1)Cc1ccccc1-2

Procedure:
Following essentially the same procedure as in Example XI above, but substituting 2-acetylfluorene for the 2-acetyldibenzofuran above and substituting 1-pyrroline as the trimer for the 2,3,4,5-tetrahydropyridine (as α-tripiperidein) above results in the formation of 2-fluorenyl 2-pyrrolidinylmethyl ketone as the hydrochloride salt, and which when recrystallized from isopropyl alcohol has a M.P. of 234-44°C. (dec.)
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15]O)[N:10]=[CH:9]2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:48][C:49]1[CH:54]=[CH:53][C:52]([CH2:55][CH2:56][C:57](=[O:59])[CH3:58])=[CH:51][CH:50]=1.N(C(OCC)=O)=NC(OCC)=O.Cl>C1COCC1.C(OCC)(=O)C>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:48][C:49]2[CH:50]=[CH:51][C:52]([CH2:55][CH2:56][C:57](=[O:59])[CH3:58])=[CH:53][CH:54]=2)[N:10]=[CH:9]1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(=O)CCc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)CCc1ccc(OCCCc2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol, 6 mmol of triphenylphosphine and 5 mmol of 4-(4-hydroxyphenyl)-2-butanone are dissolved under nitrogen in the cold. 6 mmol of diethyl azodicarboxylate, dissolved in 4 ml of THF, are added and the reaction mixture is stirred at room temperature for 48 hours. After evacuation of the solvent under reduced pressure and column chromatography (eluent: ethyl acetate), the residue is dissolved in 10 ml THF and 30 ml of 2N HCl and heated to 70° C. for 2 hours. The solvent is evaporated off under reduced pressure and triphenylmethanol is extracted using diethyl ether. The aqueous phase is neutralized with potassium carbonate and the product extracted with diethyl ether. The ethereal solution is dried and evaporated to obtain an oil, which is crystallized as hydrogen maleate from diethyl ether and ethanol.
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]1=O.[CH3:15][CH:16](C)[C:17](=O)C.N>CO>[CH:16]([C:7]1[CH:6]=[CH:5][C:4]([N+:11]([O-:13])=[O:12])=[CH:3][N:2]=1)([CH3:17])[CH3:15]
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Reactant: CC(=O)C(C)C
Agent: N
Solvent: CO
Product: CC(C)c1ccc([N+](=O)[O-])cn1
Temperature: 70 °C
Yield: 28.3 %

Procedure:
To a solution of 1-methyl-3,5-dinitro-2-pyridone (8.0 g, 40 mmol) in methyl alcohol (20 mL) was added dropwise 3-methyl-2-butanone (5.1 mL, 48 mmol), followed by ammonia solution in methyl alcohol (10.0 g, 17%, 100 mmol). The reaction mixture was heated at 70° C. for 2.5 h under atmospheric pressure. The solvent was removed under vacuum and the residual oil was dissolved in CH2Cl2, and then filtered. The filtrate was dried over Na2SO4 and concentrated to afford 2-isopropyl-5-nitro-pyridine (1.88 g, 28%).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[CH3:16][O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=1[O:17][CH3:16]
Reactant: CN(C)CCNc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccccc1C(=O)Cl
Product: COc1ccccc1C(=O)N(CCN(C)C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-(2-dimethylamino-ethylamino)-nitrobenzene and 2-methoxy-benzoyl chloride
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[NH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:42])=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)[CH:23]=2)[CH:21]=1.CCN(CC)CC>C(Cl)Cl>[CH3:41][C:38]([O:37][C:35]([N:32]1[CH2:33][CH2:34][N:29]([CH2:28][C:24]2[CH:23]=[C:22]([C:20]3[C:19]([F:42])=[CH:18][CH:17]=[C:16]([CH2:15][NH:14][S:2]([C:5]4[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=4)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[CH:21]=3)[CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31]1)=[O:36])([CH3:39])[CH3:40]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cc(CN)ccc3F)c2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cc(CNS(=O)(=O)c4cccc(C(=O)O)c4)ccc3F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
To a solution of 3-(chlorosulfonyl)benzoic acid (0.0331 g, 0.15 mmol) in DCM (1.5 mL) was added 1,1-dimethylethyl 4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-1-piperazinecarboxylate (0.060 g, 0.15 mmol), and Et3N (0.0211 mL, 0.15 mmol). The resulting mixture was stirred at room temperature for 1 h before it was concentrated and purified using a Gilson HPLC to afford the title compound 0.0374 g (43%). LC-MS m/z 584 (M+H)+.
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH:13]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:8][C:7]1=[O:21])(=O)[CH2:2][CH2:3][CH3:4].[CH2:22]([O:24][NH2:25])[CH3:23]>C(O)C>[CH2:22]([O:24][NH:25][C:1](=[C:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH:13]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:8][C:7]1=[O:21])[CH2:2][CH2:3][CH3:4])[CH3:23]
Reactant: CCON
Reactant: CCCC(=O)C1C(=O)CC(C2CCCCCCC2)CC1=O
Solvent: CCO
Product: CCCC(NOCC)=C1C(=O)CC(C2CCCCCCC2)CC1=O
Yield: 94 %

Procedure:
4.9 parts by weight of 2-butyryl-5-cyclooctylcyclohexane-1,3-dione, 1.1 parts by weight of ethoxyamine and 80 parts by volume of ethanol were stirred at room temperature for 12 hours, the solvent was distilled off under reduced pressure, the residue was taken up in 150 parts of dichloromethane, the solution was washed twice with water and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. 2-(1-ethoxyamino-butylidene)-5-cyclooctylcyclohexane-1,3-dione was obtained in 94% yield as an oil (compound no. 1); nD33 : 1.5234.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:6]=[CH:7][CH:8]=1.CC(C)([O-])C.[K+].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][CH:33]([CH2:37]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>CC(N(C)C)=O>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][CH:33]([CH2:37][O:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: COc1cccc(CCc2ccccc2O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCN(C(=O)OC(C)(C)C)C2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cccc(CCc2ccccc2OCC2CCCN(C(=O)OC(C)(C)C)C2)c1
Yield: 74 %

Procedure:
Following a procedure similar to that described in Example 40, 0.790 g of 2-[2-(3-methoxyphenyl)ethyl]phenol (prepared as described in Preparation 20), 0.388 g of potassium t-butoxide and 1.28 g of 1-t-butoxycarbonyl-3-(p-toluenesulfonyloxymethyl)piperidine were reacted in 15 ml of dimethylacetamide. The mixture was then worked up as described in Example 40, and the crude product thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.09 g (yield 74%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:41])[CH2:13][CH2:12][N:11]([C:14](=[O:38])[C@H:15]([NH:19][C:20]([C@@H:22]3[CH2:26][CH2:25][C:24]([NH:30]C(=O)OC(C)(C)C)([CH2:27][CH2:28][OH:29])[CH2:23]3)=[O:21])[CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2([CH3:40])[CH3:39])=[CH:4][CH:3]=1.Cl>>[Cl-:1].[NH2:30][C:24]1([CH2:27][CH2:28][OH:29])[CH2:25][CH2:26][C@@H:22]([C:20]([NH:19][C@H:15]([CH:16]([CH3:18])[CH3:17])[C:14]([N:11]2[CH2:12][CH2:13][C@@:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([OH:41])[C:9]([CH3:40])([CH3:39])[CH2:10]2)=[O:38])=[O:21])[CH2:23]1
Reactant: CC(C)[C@@H](NC(=O)[C@@H]1CCC(CCO)(NC(=O)OC(C)(C)C)C1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: Cl
Product: CC(C)[C@@H](NC(=O)[C@@H]1CCC(N)(CCO)C1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 191.8 %

Procedure:
To t-butyl(3R)-3-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamoyl)-1-(2-hydroxyethyl)cyclopentylcarbamate (58 mg, 0.098 mmol) was added hydrogen chloride (4M in dioxane, 0.5 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to yield (1R)-3-amino-N—((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-3-(2-hydroxyethyl)cyclopentanecarboxamide, hydrogen chloride salt (50 mg, 0.094 mmol, 97% yield) as an oil. It was used as such for the next step without further purification. MS (ESI+) m/z 494 M+
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([OH:13])=O)=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:14]([C:18]1[CH:33]=[CH:32][C:21]([CH2:22][NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C(Cl)Cl.CCN=C=NCCCN(C)C.Cl>>[C:14]([C:18]1[CH:33]=[CH:32][C:21]([CH2:22][N:23]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:11]([C:10]2[C:2]([F:1])=[CH:3][CH:4]=[C:5]3[C:9]=2[NH:8][CH:7]=[CH:6]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(CNCCc2ccccc2)cc1
Reactant: O=C(O)c1c(F)ccc2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccccc2)C(=O)c2c(F)ccc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
To a solution of 89 mg (0.5 mmol) of 6-fluoro-1H-indole-7-carboxylic acid and 134 mg (0.3 mmol) of (4-tert-butyl-benzyl)-phenethyl-amine in 5 ml DCM 105 mg (0.55 mmol) of EDC.HCl were added and the reaction mixture was stirred over night at rt. The solvent was evaporated and the residue was partitioned between diethyl ether/EtOAc and 1N aqueous HCl solution. A white solid precipitated. The reaction mixture was filtered and the organic layer was washed twice with 1N aqueous HCl solution, once with 2N aqueous NaOH solution and once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated to leave 70 mg (33%) product as a colorless oil. MS (ISP) 429.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)=[CH:5][CH:4]=1.C(O)C.Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+]>O>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=[N:22][OH:23])=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(Oc2cccc(C=O)c2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(Oc2cccc(C=NO)c2)cc1
Temperature: 85 °C
Yield: 102.8 %

Procedure:
3-(4-Methoxyphenoxy)benzaldehyde (Aldrich, Cat. #195898) (0.10 g, 0.44 mmol) was dissolved in ethanol (2.1 mL, 37 mmol) and water (0.43 mL) at r.t., and the hydroxylamine hydrochloride (0.061 g, 0.88 mmol) and sodium acetate (0.072 g, 0.88 mmol) were added. The reaction was heated in a sealed tube to 85° C. for 2 h., and allowed to cool to r.t. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 3-(4-methoxyphenoxy)benzaldehyde oxime (0.11 g, 100%) as an oily residue.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12](/[CH:15]=[C:16](\[CH3:19])/[CH:17]=[O:18])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:20]1([CH2:26][CH2:27][CH2:28][Mg]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(CCCC(O)CCCC2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Si:1]([O:8][C@H:9]1[CH2:10][CH2:11][C@H:12](/[CH:15]=[C:16](\[CH3:19])/[CH:17]([OH:18])[CH2:28][CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:13][CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C/C(C=O)=C\[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Reactant: Br[Mg]CCCc1ccccc1
Agent: OC(CCCc1ccccc1)CCCc1ccccc1
Solvent: C1CCOC1
Product: C/C(=C\[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1)C(O)CCCc1ccccc1

Procedure:
The alcohol 137 was prepared from the crude aldehyde 136. and 1.5 mL (0.75 mmol) of 120 in 2.0 mL of THF as described above for the synthesis of alcohol 121 in Example 1 to give 220 mg of the crude diastereomeric alcohol 137. Flash chromatography (elution with 20% ethyl acetate in hexane) afforded 146 mg of the alcohol 137 as an oil. 1H NMR consistent with structure.