Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[NH:20])[NH2:19])=[CH:14][C:13]=1[Cl:21])(=[O:10])=[O:9].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)C>[CH3:7][S:8]([OH:11])(=[O:10])=[O:9].[C:22]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[NH:20])[NH2:19])=[CH:14][C:13]=1[Cl:21])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CS(=O)(=O)Oc1ccc(C(=N)N)cc1Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CS(=O)(=O)O
Product: N=C(N)c1ccc(OC(=O)c2ccccc2)c(Cl)c1
Reaction time: 0.5 h
Yield: 124.2 %

Procedure:
To 30 ml of anhydrous pyridine, was added 2.7 g of 4-amidino-2-chlorophenol methanesulfonate. To the mixture, while being cooled in ice, was added 1.4 g of benzoyl chloride. The mixture was stirred for 30 minutes, while being cooled in ice, then for 5 hours at room temperature. The reaction mixture was mixed with 100 ml of ethyl ether to allow an oily substance to separate out. The oily substance was dissolved in 20 ml of methanol and poured into a saturated aqueous sodium hydrogencarbonate solution. The precipitated crystals were collected by filtration and washed with water, then with acetone. The washed crystals were added to 20 ml of methanol and admixed with 2.5 g of methanesulfonic acid. The insolubles were removed by filtration and 100 ml of ethyl ether was added to the filtrate. The precipitated colorless crystals were collected by filtration to obtain 2.5 g of 4-amidino-2-chlorophenyl benzoate methanesulfonate.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([OH:41])=O)=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:25][CH2:24]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:42][CH2:43][C:44]1[CH:49]=[N:48][C:47]([CH3:50])=[CH:46][N:45]=1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([NH:42][CH2:43][C:44]4[CH:49]=[N:48][C:47]([CH3:50])=[CH:46][N:45]=4)=[O:41])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[CH2:25][CH2:24]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cnc(CN)cn1
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cnc(CNC(=O)c2ccc3c(C4CCCCC4)c4n(c3c2)CC(C(=O)N2CCC(N3CCOCC3)CC2)=Cc2ccccc2-4)cn1
Yield: 93.2 %

Procedure:
A solution of 13-cyclohexyl-6-[[4-(4-morpholinyl)-1-piperidinyl]carbonyl]-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (40 mg, 0.07 mmol), 2-(aminomethyl)-5-methylpyrazine (12 mg, 0.1 mmol), N,N-diisopropylethylamine (60 μL, 0.34 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (19 mg, 0.1 mmol), and 1-hydroxybenzotriazole (14 mg, 0.1 mmol) in CH2Cl2 (1.5 mL) was stirred at r.t. for 20 h, at which point it was introduced directly to silica gel and chromatographed (gradient elution: 0%→10% MeOH in CH2Cl2) to afford a yellow foam, which was triturated with Et2O and dried to give the title compound as a pale yellow solid (43 mg, 90% yield). LC/MS (ESI) retention time: 1.69 min, m/z 659 (MH+); 1H NMR (400 MHz, CDCl3) δ 1.28-1.44 (m, 3 H) 1.46-1.59 (m, 1 H) 1.61-1.70 (m, 1 H) 1.71-1.81 (m, 2 H) 1.85-1.96 (m, 1 H) 1.97-2.13 (m, 3 H) 2.29 (t, J=10.45 Hz, 1 H) 2.35-2.46 (m, 4 H) 2.55 (s, 3 H) 2.61-2.77 (m, 2 H) 2.77-2.89 (m, 2 H) 3.62 (s, 4 H) 4.38 (s, 1 H) 4.78 (d, J=5.04 Hz, 2 H) 5.00-5.18 (m, 1 H) 6.81 (s, 1 H) 7.32-7.40 (m, 2 H) 7.40-7.50 (m, 3 H) 7.51-7.59 (m, 1 H) 7.88 (d, J=8.56 Hz, 1 H) 8.01 (s, 1 H) 8.39 (s, 1 H) 8.56 (d, J=1.01 Hz, 1 H); 13C NMR (101 MHz, CDCl3) δ 21.18, 26.21, 27.03, 28.08, 33.26, 36.73, 41.91, 42.60, 49.52, 61.59, 67.07, 108.98, 116.90, 120.03, 121.21, 126.98, 127.94, 128.21, 129.27, 130.96, 131.23, 133.27, 134.01, 135.18, 135.25, 136.39, 142.94, 143.40, 149.41, 152.50, 168.10, 168.87.
Reaction SMILES: [NH:1]1[C:5]2[N:6]=[C:7]3[S:13][CH2:12][CH2:11][N:8]3[C:9](=[O:10])[C:4]=2[CH:3]=[N:2]1.[H-].[Na+].[CH2:16](I)[CH3:17].O>CN(C)C=O>[CH2:16]([N:1]1[C:5]2[N:6]=[C:7]3[S:13][CH2:12][CH2:11][N:8]3[C:9](=[O:10])[C:4]=2[CH:3]=[N:2]1)[CH3:17].[CH2:16]([N:2]1[CH:3]=[C:4]2[C:5]([N:6]=[C:7]3[S:13][CH2:12][CH2:11][N:8]3[C:9]2=[O:10])=[N:1]1)[CH3:17]
Reactant: CCI
Reactant: O=c1c2cn[nH]c2nc2n1CCS2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1cc2c(=O)n3c(nc2n1)SCC3
Product: CCn1ncc2c(=O)n3c(nc21)SCC3
Temperature: 25 °C
Reaction time: 6 h
Yield: 22 %
Yield: 53 %

Procedure:
In 40 ml of dimethylformamide was dissolved 2.07 g (10.7 mmol) of Compound 1 prepared in Example 1, and 0.77 g (19.3 mmol) of sodium hydride (60%) and 2.56 ml (32.0 mmol) of ethyl iodide were added to the solution, followed by stirring at room temperature for 6 hours. After addition of water and evaporation of the solvent, the residue was subjected to partition between chloroform and water, and the chloroform layer was concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (100:1). The first and second main fractions gave 1.24 g (53%) of Compound 26 and 0.51 g (22%) of Compound 27, respectively. Compound 26 and Compound 27 were recrystallized from dimethylformamide/water and ethanol, respectively, for purification.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH3:22])[CH2:13][CH2:12]1.BrB(CC)CC.O>ClCCl>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH3:22])[CH2:13][CH2:12]1
Reactant: COCOc1ccccc1C1(c2ccc(C)cc2OC)CC1
Agent: CCB(Br)CC
Solvent: ClCCl
Solvent: O
Product: COc1cc(C)ccc1C1(c2ccccc2O)CC1
Reaction time: 8 h

Procedure:
A solution prepared from 490 mg (1.64 mmol) of 1-(2-methoxymethoxyphenyl)-1-(2-methoxy-4-methylphenyl)cyclopropane and 6.1 ml of a 1M solution (8.2 mmol) of bromodiethylborane in dichloromethane was stirred overnight under an argon atmosphere. Ten ml of water were added, the phases were separated, and the aqueous phase was extracted twice with 20 ml of dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated by evaporation under reduced pressure to obtain 1-(2-hydroxyphenyl)-1-(2-methoxy-4-methylphenyl)cyclopropane. The proton NMR spectrum was consistent with the assigned structure. This was dissolved in 0.8 ml (8.2 mmol) of a 5M solution of bromodimethylborane and allowed to stir overnight. Nothing happened. The mixture was cooled to 0° C. and 3.3 ml (3.3 mmol) of a 1M solution of boron tribromide was added with stirring under an argon atmosphere. After a short reaction period 2 ml of water was added and the mixture was extracted with 2 ml of 5 percent aqueous sodium bicarbonate then with 2 ml of water, dried over magnesium sulfate and concentrated by evaporation under reduced pressure to obtain 350 mg (84 percent of theory) of the title compound as a foamy brown oil. The proton and carbon NMR spectra were consistent with the assigned structure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:14])=[N:8][C:9](Cl)=[CH:10][C:11]=1[CH3:12])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:14])=[N:8][C:9]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)cc(Cl)nc1Cl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)cc(N2CCOCC2)nc1Cl
Temperature: 95 °C
Reaction time: 18 h
Yield: 29.1 %

Procedure:
A mixture of 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid ethyl ester (29.7 g, 127 mmol), potassium carbonate (26.3 g, 190 mmol), and morpholine (13.3 g, 152 mmol) in dimethylformamide (350 ml) is stirred for 18 h at 95° C. After completion of the reaction, water is added and the mixture is extracted with diethyl ether (3×). The combined organic layers are washed with water (2×) and brine (1×), dried over magnesium sulphate and evaporated to dryness. The crude product is purified by flash chromatography (silica gel, 25% ethyl acetate/cyclohexane) to yield 2-chloro-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid ethyl ester (10.5 g, 36.9 mmol, 29%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17]CC)=[O:16])=[CH:7][C:6]=2[CH:20]=1.[OH-].[Na+]>C1COCC1.C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(-c3cccc(OC)c3)c2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(-c2cc(Cl)cc3c2OC(C(F)(F)F)C(C(=O)O)=C3)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.2 %

Procedure:
The ester from Step 1 (0.300 g, 0.727 mmol) was dissolved in THF-ethanol-water (7:2:1, 10 mL). It was treated with sodium hydroxide (0.29 mL of a 2.5 N solution, 0.727 mmol), and stirred at room temperature for 18 hours. The solvent was evaporated and the residue was dissolved in water (10 mL). Ether (10 mL) was added, followed by a few drops of concentrated HCl. The ether layer was separated, and the aqueous phase was extracted with ether (2×10 mL). The ether extracts were combined, dried over MgSO4, filtered, and concentrated in vacuo to yield a white solid, which was recrystallized in diethyl ether-hexane to afford the title compound as a white solid (0.23 g, 81%): mp 173.1–177.4° C. 1H NMR (CDCl3/300 MHz) 7.81 (s, 1H), 7.39–7.37 (m, 2H ), 7.05–7.04 (m, 2H), 6.97–6.94 (m, 1H), 5.71 (q, 1H, J=6.7 Hz), 3.85 (s, 3H). ESHRMS m/z 383.0278 (M−H, Calc'd. 383.029796). Anal. Calc'd. for C18H12ClF3O4: C, 56.20; H, 3.14; Cl, 9.21. Found: C, 55.90; H, 3.11; Cl, 9.48.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.[O:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[C:15]([O:14][C:12]([N:5]1[CH2:6][CH2:7][CH2:8][CH:9]([OH:10])[CH:4]1[CH2:3][OH:2])=[O:11])([CH3:18])([CH3:17])[CH3:16]
Reactant: OCc1ncccc1O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(O)C1CO
Temperature: 25 °C
Reaction time: 20 h
Yield: 24.7 %

Procedure:
A suspension of 5 g (31.00 mmol) of 2-hydroxymethyl-pyridin-3-ol hydrochlorid and 2.50 g 5% Rh/Alox in 100 ml AcOEt was stirred under hydrogen atmosphere 20 h at 25° C. and 8 bar. The suspension was filtered and evaporated to give an yellow oil. The crude product was treated with 8.78 g (40.00 mmol) BOC2O and 12 ml (93.00 mmol) Hunig's base in 30 ml DMF under ice cooling for 25 h. An extraction (water/brine/AcOEt) and two crystallizations (AcOEt, MeCN/CH2Cl2) gave 1.77 g (25%) of the title compound as a white solid. MS: 232.0 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[C:25](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:25])=[CH:21][CH:22]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
32.94 g (100 mmol) of N-benzyloxycarbonyl-tyrosine methyl ester is mixed in 200 ml of DMF with 27.64 g (200 mmol) of ground potassium carbonate. 15.6 g (110 mmol) of iodomethane is instilled in this suspension and stirred overnight at room temperature. The solution is concentrated by evaporation, dispersed between ethyl acetate and water, and the organic phase is mixed with hexane after drying (Na2SO4). The title compound crystallizes out.
Reaction SMILES: C([O:8][C:9](=O)[CH2:10][C@@H:11](NC(OC(C)(C)C)=O)[C:12]([NH:14][C@H:15]([C:20](=[O:23])NC)[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1.CC(C)(C)[C@H](NC(=O)[C@H]([N:45]1[CH:49]=[CH:48][C:47]([C:50]2[CH:55]=[CH:54][C:53]([C:56]3[CH:61]=[CH:60][N:59]=[CH:58][CH:57]=3)=[CH:52][CH:51]=2)=[CH:46]1)CC(O)=O)CO.[O:65]([NH2:83])[Si:66]([C:79]([CH3:82])([CH3:81])[CH3:80])([C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CO.C(Cl)Cl>[O:65]([NH:83][C:9](=[O:8])[C@H:10]([N:45]1[CH:49]=[CH:48][C:47]([C:50]2[CH:55]=[CH:54][C:53]([C:56]3[CH:57]=[CH:58][N:59]=[CH:60][CH:61]=3)=[CH:52][CH:51]=2)=[CH:46]1)[CH2:11][C:12]([NH:14][C@H:15]([CH2:20][OH:23])[C:16]([CH3:18])([CH3:19])[CH3:17])=[O:13])[Si:66]([C:79]([CH3:80])([CH3:82])[CH3:81])([C:73]1[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Reactant: CC(C)(C)[Si](ON)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[C@@H](CO)NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[C@@H](CO)NC(=O)C[C@H](C(=O)NO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Yield: 43 %

Procedure:
According to the procedure described in Example 1(b) for the preparation of 3(R)-t-butyloxycarbonylamino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester, N-(2,2-dimethyl-1(S)-hydroxymethyl-propyl)-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid (prepared as described in Example 5(a)) and t-butyldiphenylsiloxyamine were coupled with TBTU. Flash column chromatography with 0-5% MeOH/CH2Cl2 gradient eluant furnished in 43% yield N1-t-butyldiphenylsiloxy-N4-[2,2-Dimethyl-1(S)-(hydroxymethyl)propyl]-2(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamide as an amorphous solid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:19]([N:27]3[CH2:32][C@@H:31]([CH3:33])[N:30]([CH2:34][CH:35]=[CH2:36])[CH2:29][C@@H:28]3[CH3:37])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.O>C1COCC1.CO>[CH2:34]([N:30]1[C@H:31]([CH3:33])[CH2:32][N:27]([C@@H:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[O:38])[C@@H:28]([CH3:37])[CH2:29]1)[CH:35]=[CH2:36]
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N3CCC(C(=O)OCC)CC3)c2)C[C@H]1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N3CCC(C(=O)O)CC3)c2)C[C@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a solution of 1-{3-[(R)-((2S,5R)-4-allyl-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperidine-4-carboxylic acid ethyl ester (512 mg, Example 119) in THF (5 mL) was added 1 N NaOH solution (4 mL). The reaction was stirred at room temperature overnight. The reaction solution was neutralized by the addition of 1 N HCl solution (4 mL). The reaction solution was concentrated to dryness under vacuum to give crude product, which was subjected to reverse phase C-18 column chromatography conducted on CombiFlash™ Sq 16×(gradient: 100% H2O to 100% MeOH) to give 1-{3-[(R)-((2S,5R)-4-allyl-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperidine-4-carboxylic acid (445 mg; 92%). 1H NMR (300 MHz, CD3OD) δ 7.52-7.37 (m, 3H), 7.28 (m, 1H), 7.19 (dd, J=8.0, 8.0 Hz, 1H), 6.72 (m, 3H), 5.93 (m, 1H), 5.45 (m, 2H), 5.30 (s, 1H), 4.48 (m, 1H), 3.69 (m, 2H), 3.39 (m, 1H), 3.19-2.99 (m, 4H), 2.79 (m, 2H), 2.65 (m, 1H), 2.47 (m, 1H), 2.13 (m, 1H), 1.98 (m, 1H), 1.79 (m, 1H), 1.64 (m, 2H), 1.27 (d, J=6.0 Hz, 3H), 1.20 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:19]([NH2:21])=[O:20])[CH3:2].Br[CH2:27][CH2:28][CH2:29][CH2:30]Cl.C([O-])([O-])=O.[Cs+].[Cs+].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>CS(C)=O.O>[CH2:1]([C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:27][CH2:28][CH2:29][CH2:30][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:19]([NH2:21])=[O:20])[CH3:2]
Reactant: ClCCCCBr
Reactant: CCc1ccccc1Nc1c(C(N)=O)cnc2cc(O)c(OC)cc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CCc1ccccc1Nc1c(C(N)=O)cnc2cc(OCCCCN3CCOCC3)c(OC)cc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 22 %

Procedure:
4-(2-Ethylanilino)-7-hydroxy-6-methoxy-3-quinolinecarboxamide (0.064 g, 0.19 mmol) was dissolved in DMSO (4 ml), 1-bromo-4-chlorobutane (22 μl, 0.19 mmol) and Cs2CO3 (0.18 g, 0.55 mmol) were added and the mixture was stirred at ambient temperature for three days. The mixture was poured into water and extracted with methylenechloride. The residue was chromatographed on silica using ethylacetate/methanol (1:0–>1:1) as eluent. The resulting oil was dissolved in DME, morpholine (25 μl, 0.29 mmol) and a catalytic ammount of KI was added, mixture was heated at reflux for four days. After cooling the mixture was poured out on water and extracted with methylenechloride. The crude product was purified on preparative HPLC, affording 20 mg (22% yield) of the titled compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=O.ClC(OCC(C)C)=O.[N+:18]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])([O-:20])=[O:19].C(=O)(O)[O-].[Na+]>O1CCCC1.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([NH:24][C:23]1[CH:25]=[CH:26][CH:27]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=1)=[O:9]
Reactant: COCCOCC(=O)O
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCOCC(=O)Nc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
5 g of (2-methoxyethoxy)-acetic acid is dissolved in 500 ml of tetrahydrofuran. 9.7 ml of triethylamine and 5.6 ml of isobutyl chloroformate are added at 0° C., and it is stirred for 30 minutes at 0° C. 5.0 g of 3-nitroaniline is added, and it is stirred for another 15 hours at room temperature. The reaction mixture is mixed with semi-saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic solution is washed with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation and, after purification by chromatography on silica gel, 7.5 g of the title compound is obtained.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[C:11]1(=[O:21])[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[Cl-].[NH4+]>O1CCCC1>[CH3:10][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:11]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])=[O:21]
Reactant: COc1ccccc1Br
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)c1ccccc1C(=O)O
Temperature: -70 °C
Reaction time: 2.5 h
Yield: 88.4 %

Procedure:
A solution in tetrahydrofuran (17 ml) of a Grignard's reagent prepared from magnesium (120 mg, 5.1 mmol) and 2-bromoanisole (0.55 ml, 4.4 mmol) was added dropwise to a solution of phthalic anhydride (500 mg, 3.4 mmol) in tetrahydrofuran (12 ml) in an atmosphere of nitrogen at −70° C. over a period of 10 minutes. The reaction mixture was stirred at −70° C. for 2.5 hours, and aqueous saturated ammonium chloride solution was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with aqueous saturated sodium chloride solution, dried and concentrated under reduced pressure to obtain crude 2-(2-methoxybenzoyl)benzoic acid (770 mg, yield: 90%).
Reaction SMILES: [H-].[Na+].[CH:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:8]([O:15][CH2:16][C:17](OCC)=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOCC>[CH2:8]([O:15][CH:16]([CH:17]=[O:18])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)COCc1ccccc1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(C=O)OCc1ccccc1

Procedure:
To a suspension of sodium hydride (3.3 g, 60% in paraffin oil, 82.5 mmol) in dry ether (100 mL) and dry ethyl formate (5.55 g, 75 mmol) was added ethyl (benzyloxy)acetate (14.57 g, 75 mmol) dropwise with stirring. The resulting mixture solution was then refluxed for 2 h and concentrated to give crude ethyl 2-(benzyloxy)-3-oxopropanoate which was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1OC1C.CS([C:20]1[CH:25]=[CH:24][C:23]([O:26]C2C=CC=CC=2)=[CH:22][CH:21]=1)(=O)=O>>[F:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH2:1][CH:22]2[CH2:21][CH2:20][CH2:25][CH2:24][CH:23]2[OH:26])(=[O:4])=[O:3])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: CC1CO1
Product: O=S(=O)(CC1CCCCC1O)c1ccc(F)cc1

Procedure:
The desired product was prepared by substituting cyclohexene oxide and 4-fluorophenyl methyl sulfone for propylene oxide and 1-(methylsulfonyl)-4-phenoxybenzene, respectively, in Example 120A.
Reaction SMILES: [Mg].O1CCCC1.CO[CH:9]([O:19]C)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Cl.Cl.[C:22]1(C)[CH:27]=[CH:26]C=[CH:24][CH:23]=1>C(Cl)CCC>[CH:9](=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:24][CH:23]=[CH:22][CH2:27][CH3:26]
Reactant: COC(CCCCCCCCCl)OC
Reactant: Cc1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCCCCl
Product: CCC=CCCCCCCCCCC=O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To 0.85 gm of magnesium in a thoroughly dried flask equipped with condensor and magnetic stirrer was added 5 mls of anhydrous tetrahydrofuran and 1.06 mls of butyl chloride and 5 mls of dry toluene. This mixture was heated with stirring at 70° C. for about two hours. A solution of 4.44 gms of 1,1-dimethoxy-9-chloro nonane in 50 mls of toluene was added all at once. The temperature was maintained at 75°±5° for one and one quarter hours. The Grignard reagent was decanted into another flask and 3.12 gms of a mixture (approximately 60:40) of 1-chloro-2-pentene and 3-chloro-1-pentene was added. The reaction was maintained at 75°±5° with stirring. The reaction mixture became cloudy within one-half to three-quarters of an hour indicating the initiation of the coupling reaction. This was confirmed by GLC of a hydrolysed aliquot of reaction mixture. The reaction was allowed to continue until a test for Grignard reagent was negative (approximately 2 hours). 50 mls of 3 N hydrochloric acid was then added, the reaction mixture was then stirred and heated at reflux for 1 hour. The aqueous layer was separated, washed two times with toluene. The organic layer and the toluene washes were combined and dried over sodium sulphate. The solvents were removed on the rotary evaporator and the residue was distilled. The majority of the material distilled at 95° at 0.35 torr yielding 2.48 gms of crude 11-tetradecenal. For physical constants see Example 5.