Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@:13]([CH2:16][O:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])([CH2:14][OH:15])[O:12][C@@H:11]([N:28]2[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]2=[O:30])[C@@H:10]1[OH:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][O:39][C:40]1[CH:61]=[CH:60][C:43]([C:44](Cl)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)=[CH:42][CH:41]=1>N1C=CC=CC=1.ClCCl>[CH2:1]([O:8][C@H:9]1[C@@:13]([CH2:16][O:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])([CH2:14][O:15][C:44]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)([C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)[C:43]2[CH:42]=[CH:41][C:40]([O:39][CH3:38])=[CH:61][CH:60]=2)[O:12][C@@H:11]([N:28]2[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]2=[O:30])[C@@H:10]1[OH:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@]2(CO)O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](O)[C@H]2OCc2ccccc2)cc1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(OC[C@@]2(COS(=O)(=O)c3ccc(C)cc3)O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](O)[C@H]2OCc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 74.5 %

Procedure:
To a solution of nucleoside 6 (3.66 g, 6.88 mmol) in anhydrous pyridine (25 cm3) was added N,N-(dimethylamino)pyridine (0.84 g, 6.81 mmol) and 4,4′-dimethoxytrityl chloride (3.5 g, 13.2 mmol) and the mixture was stirred for 23 h at room temperature. Additional N,N-(dimethylamino)pyridine (0.250 g, 2.06 mmol) and 4,4′-dimethoxytrityl chloride (0.700 g, 2.06 mmol) was added, and stirring was continued for 36 h at room temperature. Ice cold H2O (50 cm3) was added and the reaction mixture was diluted with dichloromethane (150 cm3). The organic phase was separated and washed with saturated aqueous solutions of sodium hydrogen carbonate (25 cm3×3) and brine (40 cm3×3), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol/pyridine (0.75–1.5% methanol; 0.5% pyridine, v/v/v) as eluent to afford nucleoside 7 (4.28 g, 75%) as a white solid material after evaporation of the solvents under reduced pressure.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:13]1[O:18][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][CH2:15][CH:14]1[OH:25].N1C=CC=CC=1>C(Cl)Cl>[C:2]([Cl:1])(=[O:4])[O:25][CH:14]1[CH2:13][O:18][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][CH2:15]1
Reactant: OC1COC(c2ccccc2)OC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cl)OC1COC(c2ccccc2)OC1
Temperature: -40 °C

Procedure:
Triphosgene (bis(trichloromethyl)carbonate (13.35 g, 45.0 mmol) was added under argon at room temperature to a solution of 1,3-O-benzylideneglycerol (18.02 g, 100.0 mmol) in dry CH2Cl2 (300 ml). The reaction mixture was cooled to −40° C. and a solution of pyridine (10.9 ml, 135.0 mmol) was added over 35 min under stirring. Upon completion of the addition the reaction mixture was stirred for 30 min at −40° C. Then it was allowed to warm to 0° C. over 60 min and subsequently warmed to rt over 3.5 h under stirring. The reaction product was used in the next step without any further purification
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1.[F:10][C:11]1[CH:18]=[CH:17][C:16](I)=[CH:15][C:12]=1[C:13]#[N:14].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:16]2[CH:17]=[CH:18][C:11]([F:10])=[C:12]([CH:15]=2)[C:13]#[N:14])[CH:5]=[N:4][CH:3]=1
Reactant: N#Cc1cc(I)ccc1F
Reactant: C#Cc1cncc(Cl)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: N#Cc1cc(C#Cc2cncc(Cl)c2)ccc1F
Temperature: 60 °C
Yield: 90.3 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (77 mg, 0.11 mmol), copper (I) iodide (42 mg, 0.22 mmol), and 3-chloro-5-ethynylpyridine, (prepared as described in PREPARATION 27), (300 mg, 2.2 mmol) to a solution of 2-fluoro-5-iodobenzonitrile (650 mg, 2.6 mmol) in triethylamine (4.6 mL, 33 mmol) and heat at 60° C. for 6 h. Cool to room temperature and concentrate. Purify by silica gel chromatography, eluting with 50:50 dichloromethane:hexanes to 90:10 dichloromethane:ethyl acetate, followed by a second silica gel chromatography eluting with 95:5 to 75:25 hexanes:ethyl acetate, to give the title compound as an off-white solid (510 mg, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl[C:39]([O:41][C:42]1[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=1)=[O:40]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:20]([C:39]([O:41][C:42]4[CH:43]=[CH:44][C:45]([N+:48]([O-:50])=[O:49])=[CH:46][CH:47]=4)=[O:40])[CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:27][CH:28]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (INTERMEDIATE M, 0.200 g, 0.479 mmol) and Hunig's base (0.092 ml, 0.527 mmol) in DCM (2.395 ml) was added 4-nitrophenyl chloroformate (0.097 g, 0.479 mmol) (change from colorless to light yellow solution). The reaction was stirred at RT overnight, at which point starting material remained. Additional 4-nitrophenyl chloroformate (0.097 g, 0.479 mmol) was added and the reaction was stirred overnight once more until completion. After concentration in vacuo, the material was purified via MPLC (12-g Redi Sep Gold) eluting with 0-100% ethyl acetate in heptanes, to yield 4-nitrophenyl 7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate as a white solid. m/z (ESI) 583.0 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:10](Cl)=[O:11])[S:8][CH:9]=1)(=[O:4])=[O:3].[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23]([NH2:25])=[O:24])[C:18](=[O:26])[CH2:17]2>CN(C1C=CN=CC=1)C.C(O)(=O)C>[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23]([NH2:25])=[O:24])[C:18](=[O:26])[CH:17]2[C:10](=[O:11])[C:7]1[S:8][CH:9]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Reactant: CS(=O)(=O)c1csc(C(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Product: CS(=O)(=O)c1csc(C(=O)C2C(=O)N(C(N)=O)c3ccc(Cl)cc32)c1
Yield: 49 %

Procedure:
The title compound was prepared according to the procedure of Example 32. The reaction of 10 ml of thionyl chloride with 1.39 g (6.7 mmoles) of 4-methylsulfonyl-2-thiophenecarboxylic acid (prepared according to Arndt, F., et al., Chem. Ber. 94:1757 (1961)) gave 1.54 g of the crude acid chloride as a solid. The entire amount of 4-methylsulfonyl-2-thiophenecarbonyl chloride was coupled to 1.28 g (6.1 mmoles) of 5-chloro-2-oxindole-1-carboxamide in the presence of 2.24 g (18.3 mmoles) 4-(N,N-dimethylamino)pyridine. Acidic workup gave 2.28 g of crude product as an orange solid. Recrystallization from 2-butanone gave two crops of slightly impure yellow crystalline solid which had a combined mass of 2.18 g. Further purification by recrystallization provided 1.19 g (2.98 mmoles, 49% yield) of pure 5-chloro-3-(4-methylsulfonyl-2-thenoyl)-2-oxindole-1-carboxamide as a yellow crystalline solid, m.p. 228°-30° C. (acetic acid).
Reaction SMILES: [C:1]([S:5]([NH2:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH:15]=O)[CH:10]=1>ClCCl.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](/[CH:15]=[N:7]/[S@:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[O:6])[CH:10]=1
Reactant: CC(C)(C)S(N)=O
Reactant: O=Cc1cc(Cl)ccn1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Liu, G. et al., J. Org. Chem., 64:1278 (1999). To a solution of S-(−)-t-butyl-sulfinamide (0.856 g, 7.06 mmol) in dichloromethane (14.13 mL) was added sequentially copper(II) sulfate (2.481 g, 15.54 mmol) and 4-chloropicolinaldehyde[1.0 g, 7.06 mmol, prepared according to a modified described by Negi (Synthesis, 991 (1996))]. The white suspension was stirred at rt. After 3 h, the brown suspension was filtered through CELITE®, eluting with DCM, to give a clear brown filtrate. Concentration gave a brown oil weighing 1.85 g. Purification by normal phase chromatography gave 1.31 g of 1A as a clear, yellow oil. MS (ESI) m/z: 245.0 (M+H)+.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[Cl:18][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:9][CH:10]=1
Reactant: OCc1ccc(Oc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCc1ccc(Oc2ccccc2)cc1
Yield: 92.6 %

Procedure:
To a solution of (4-(phenyloxy)phenyl)methanol (8 g, 40.0 mmol) in chloroform (20 ml) was added thionyl chloride (36 ml, 500 mmol) and the mixture was heated under reflux overnight. The reaction solution was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to give 1-(chloromethyl)-4-(phenyloxy)benzene (8.1 g, 93%).
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.[C:29]([C:31]1[CH:32]=[C:33]([NH:42][C:43](=[O:54])[O:44][CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50](Br)=[CH:49][CH:48]=2)[CH:34]=[CH:35][C:36]=1[S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])#[N:30]>>[C:29]([C:31]1[CH:32]=[C:33]([NH:42][C:43]([O:44][CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([B:25]([OH:27])[OH:26])=[CH:49][CH:48]=2)=[O:54])[CH:34]=[CH:35][C:36]=1[S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])#[N:30]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)OCCc2ccc(Br)cc2)cc1C#N
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Product: CCS(=O)(=O)c1ccc(NC(=O)OCCc2ccc(B(O)O)cc2)cc1C#N
Yield: 82 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 26A (600 mg, 2.54 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 26B (455 mg, 82%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.24 (t, J=7.47 Hz, 3 H) 3.01 (t, J=6.81 Hz, 2 H) 3.35 (q, J=7.32 Hz, 2 H) 4.42 (t, J=6.59 Hz, 2 H) 7.29 (d, J=7.91 Hz, 2 H) 7.56 (d, J=7.91 Hz, 2 H) 7.86 (dd, J=9.01, 1.98 Hz, 1 H) 7.99 (d, J=8.79 Hz, 1 H) 8.11 (d, J=2.20 Hz, 1 H) 10.12 (s, 1 H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]([N:9]([CH3:30])[C:10](=[O:29])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:28])[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[O:26]C)[CH:12]=1)[CH2:6][CH2:7][CH3:8]>C(Cl)Cl>[CH2:5]([N:9]([CH3:30])[C:10](=[O:29])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:28])[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[OH:26])[CH:12]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCN(C)C(=O)c1cccc(NC(=O)c2ccc(Cl)cc2OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCN(C)C(=O)c1cccc(NC(=O)c2ccc(Cl)cc2O)c1
Reaction time: 17 h
Yield: 81.9 %

Procedure:
AlCl3 (307 mg, 2.30 mmol) was added to a solution of N-butyl-N-methyl-3-{(4-chloro-2-methoxybenzoyl)amino}benzamide (345 mg, 0.92 mmol) in CH2Cl2 (3.7 mL) at 25°. The mixture was kept at 25° for 17 h. The mixture then was partitioned between EtOAc (75 mL) and aqueous 1 N HCl (50 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (10-40μ silica gel, EtOAc:hexane, 1:1) to give the title compound (272 mg, 82% yield) as a white foam:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:22][C:23]([C:25]3[NH:29][C:28](=[O:30])[N:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:26]=3)=[O:24])[CH2:16][C@@H:17]([OH:21])[C:18]([OH:20])=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:37](=[O:44])([O:41][CH2:42][CH3:43])[O:38][CH2:39]Cl.N1C(C)=CC=CC=1C.[Na+].[I-]>CN(C=O)C>[CH2:42]([O:41][C:37]([O:38][CH2:39][O:19][C:18](=[O:20])[C@H:17]([OH:21])[CH2:16][C@H:15]([NH:22][C:23]([C:25]1[NH:29][C:28](=[O:30])[N:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:26]=1)=[O:24])[CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:13][CH:12]=1)=[O:44])[CH3:43]
Reactant: CCOC(=O)OCCl
Reactant: O=C(N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)O)c1nn(-c2ccccc2)c(=O)[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: CCOC(=O)OCOC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1nn(-c2ccccc2)c(=O)[nH]1
Yield: 4.3 %

Procedure:
A solution of (2R,4R)-5-(3′-chlorobiphenyl-4-yl)-2-hydroxy-4-[(5-oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl)amino]pentanoic acid (253 mg, 0.5 mmol), chloromethyl ethyl carbonate (69 mg, 0.5 mmol), 2,6-lutidine (165 mg, 1.5 mmol) and NaI (150 mg, 1 mmol) in DMF (20 mL) was stirred for 15 hours at 50° C. The mixture was quenched with water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were collected and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/EtOAc=3:1) to yield the title compound as a white solid (13 mg). LC-MS: 608.8 [M+H]+. 1H NMR: (CDCl3, 400 MHz) δ 1.27 (t, J=8.0 Hz, 3H), 2.03-2.33 (m, 2H), 3.02-3.05 (m, 2H), 4.18 (q, J=8.0 Hz, 2H), 4.49 (br, 1H), 4.85 (br, 1H), 5.57-5.76 (m, 2H), 7.03 (d, J=12 Hz, 1H), 7.25-7.40 (m, 4H), 7.42-7.51 (m, 3H), 7.53-7.61 (m, 3H), 7.93 (d, J=8.0 Hz, 2H).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:35])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([OH:34])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[C:16]=2[CH:33]=1)([CH3:3])[CH3:2].[CH3:36]I>>[CH:1]([O:4][C:5](=[O:35])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([O:34][CH3:36])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)[C:16]=2[CH:33]=1)([CH3:3])[CH3:2]
Reactant: CI
Reactant: Cc1ccc(-n2c(-c3ccccc3)nc3cc(O)c(OCCCCCC(=O)OC(C)C)cc32)cc1
Product: COc1cc2nc(-c3ccccc3)n(-c3ccc(C)cc3)c2cc1OCCCCCC(=O)OC(C)C

Procedure:
6-[[5-Hydroxy-1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester was methylated with methyl iodide according to general operating instructions 8.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].C([Li])CCC.CCCCCC.[I:27]I.[Cl-].[NH4+]>C1COCC1>[CH2:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=[C:6]1[I:27])[CH2:2][CH2:3][CH3:4]
Reactant: II
Reactant: CCCCn1cnc(-c2ccccc2)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCn1cc(-c2ccccc2)nc1I
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of 1-butyl-4-phenylimidazole (4.0 g, 20 mmol) in 60 ml of anhydrous THF at −78° C. under nitrogen is added a solution of n-butyllithium in hexane (1.6M, 13.13 ml, 21 mmol, 1.05 eq.) dropwise. The resulting mixture is stirred at −78° C. for 1 h followed by dropwise addition of a solution of iodine (5.33 g, 21 mmol, 1.05 eq.) in 40 ml of THF. The resulting solution is stirred at −78° C. for 30 min. and then warmed to room temperature. Saturated ammonium chloride (30 mL) is added to quench the reaction. The resulting mixture is evaporated a reduced pressure to remove THF, extracted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered and evaporated. Purification by silica gel chromatography (hexanes/ethyl acetate, from 8:1 to 5:1) affords 5.73 g of 1-butyl-2-iodo-4-phenylimidazole. 1H NMR (400 MHz, CDCl3) δ 7.73 (2H, dd, J=1.2, 8.4 Hz), 7.36 (2H, m), 7.30 (1H, s), 7.24 (1H, m), 3.92 (2H, t, J=7.2 Hz), 1.79 (2H, m), 1.41 (2H, m), 0.98 (3H, t, J=7.2 Hz); MS (+VE) m/z 327 (M+1).
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[CH:7]=[C:8]([CH2:12]O)[CH:9]=[CH:10][CH:11]=2)[CH3:5])[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:34]>>[Cl:34][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:4]([CH:1]2[CH2:3][CH2:2]2)[CH3:5])[CH:7]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(c1cccc(CO)c1)C1CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(c1cccc(CCl)c1)C1CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of [3-(1-cyclopropylethyl)phenyl]methanol (0.128 g, 0.73 mmol) in carbon tetrachloride (20 mL) was added polystyrene bound triphenyl phosphine (2.15 mmol/g, 0.68 g, 1.5 mmol). After stirring at 100° C. overnight the resin was filtered of and the solvent was removed under vacuum to afford the desired product.
Reaction SMILES: [CH2:1]1[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:4][S:3][CH2:2]1>C1CCCCC1.C(OCC)(=O)C>[CH2:1]1[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:4][S:3][CH2:2]1
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(O)CCCCC1CCSS1
Temperature: -7.5 °C
Yield: 102.6 %

Procedure:
A solution which contained 11.7 g R-(+)-thioctic acid and 5.0 g S-(-)-thioctic acid in a mixture of 225 ml cyclohexane and 25 ml ethyl acetate was cooled off from 35 to 40° C. down to -5 to -10° C., filtered and dried. 12.0 g thioctic acid were obtained in the novel modification as first crystallizate. The R-(+)-thioctic acid content was 65.8% with a melting range of 54 to 58° C.
Reaction SMILES: [OH:1][C@:2]12[C@H:11]3[CH2:12][C:13]4[C:18]5[C@@:7]1([CH2:8][CH2:9][NH:10]3)[C@@H:6]([O:19][C:17]=5[C:16]([O:20][CH3:21])=[CH:15][CH:14]=4)[C:5](=[O:22])[CH2:4][CH2:3]2.C([O-])([O-])=O.[K+].[K+].[CH:29]1([CH2:32]Br)[CH2:31][CH2:30]1>CC#N>[CH:29]1([CH2:32][N:10]2[CH2:9][CH2:8][C@@:7]34[C:18]5[C:13]6[CH2:12][C@@H:11]2[C@:2]3([OH:1])[CH2:3][CH2:4][C:5](=[O:22])[C@@H:6]4[O:19][C:17]=5[C:16]([O:20][CH3:21])=[CH:15][CH:14]=6)[CH2:31][CH2:30]1
Reactant: BrCC1CC1
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)NCC[C@]314
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314

Procedure:
To a suspension of Compound 3 (9.5 g, 31.5 mmol) in 80 mL of CH3CN was added K2CO3 (10.9 g, 79.0 mmol) portionwise followed by cyclopropylmethyl bromide (3.97 mL, 41.0 mmol) dropwise via syringe. The suspension was heated at reflux for 18 h. LC-MS showed a single peak corresponding to the desired product (Tr=0.830 min, M+H=356). The mixture was cooled to ambient temperature and the solid was filtered off and washed with CH3CN. The filtrate was concentrated and the golden yellow residue was diluted with CH2Cl2 and H2O. The layers were separated and the aqueous was further extracted with CH2Cl2. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated to provide 9.76 g (87%) of Compound 4 as a white foam that turned to a light yellow oily foam overnight. LC/MS, m/z=356.2 [M+H]+ (Calc: 356.43).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([O:22][C:23](=[O:28])[C:24](Br)([CH3:26])[CH3:25])[CH3:21]>CN(C)C=O.O>[CH2:20]([O:22][C:23](=[O:28])[C:24]([CH3:26])([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:3]=1)[CH3:25])[CH3:21]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1cccc(-c2cccnc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1cccc(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(3-hydroxyphenyl)pyridine (40.91 g, 0.239 mol) in 500 mL dimethylformamide was added potassium carbonate (148.62 g, 1.075 mol) and ethyl-2-bromoisobutyrate (157.8 mL, 1.075 mol). The mixture was heated to reflux under N2 with stirring for 18 h and cooled to ambient temperature. The resultant brown suspension was diluted with 1 L water and extracted with diethyl ether (3×500 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated to a volume of 1 L. The organic solution was diluted with 1 L water and made acidic with 6N HCl. The layers were separated and the organic phase extracted with 500 mL water. The acidic extractions were combined and made basic with 5N aqueous sodium hydroxide. This basic layer was extracted with diethyl ether (4×500 mL) and the extracts were combined, washed with 500 mL brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield crude 2-methyl-2-(3-pyridin-3-yl-phenoxy)-propionic acid ethyl ester as a pale yellow oil which was taken on to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19]([C:21]3[C:22]([CH3:28])=[N:23][CH:24]=[N:25][C:26]=3[CH3:27])=[O:20])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH:46]1([C:49](Cl)=[O:50])[CH2:48][CH2:47]1>C(Cl)Cl>[C:37]([C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][N:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:49]([CH:46]2[CH2:48][CH2:47]2)=[O:50])=[CH:7][CH:6]=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19]([C:21]2[C:26]([CH3:27])=[N:25][CH:24]=[N:23][C:22]=2[CH3:28])=[O:20])[CH2:11][CH2:10]1)#[N:38]
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(N)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(NC(=O)C3CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.6 %

Procedure:
To a solution of the above aniline (51 mg, 0.10 mmol) in CH2Cl2 (1 mL) and Et3N (28 μL, 0.20 mmol) was added cyclopropanecarbonyl chloride (14 μL, 0.15 mmol) and the solution was stirred at room temperature for 16 hours to afford COMPOUND 154 as a white solid (56 mg, 96%) following work-up and purification. 1H NMR (CDCl3) δ 0.74-0.79 (m, 2H), 0.98-1.15 (m, 7H), 1.43 (m, 1H), 1.56 (m, 1H), 1.74-1.79 (m, 3H), 2.19 (m, 1H), 2.50 (s, 6H), 2.58 (m, 1H), 2.75-2.87 (m, 3H), 3.32 (m, 1H), 3.57 (m, 1H), 3.82 (m, 1H), 3.89 (s, 2H), 6.52 (d, 2H, J=8.4 Hz), 7.26 (m, 3H), 7.39-7.44 (m, 1H), 7.49-7.53 (m, 3H), 8.64 (br s, 1H), 8.85 (s, 1H). 13C NMR (CDCl3) δ 7.64, 13.36, 15.44, 21.95, 29.04, 30.17, 30.77, 39.86, 43.64, 48.46, 51.94, 56.68, 60.10, 112.48, 114.66, 118.98, 121.61, 129.27, 129.43, 130.06, 130.58, 130.84, 131.12, 141.85, 144.86, 157.51, 163.09, 166.38, 171.62. ES-MS m/z 580 (M+H). Anal. Calcd. for C34H41N7O2.0.45CH2Cl2: C, 66.96; H, 6.83; N, 15.87. Found. C, 66.99; H, 7.02; N, 15.55.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:29]=[CH:28][C:27]4[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=4[CH:21]=3)[N:19]=2)[CH2:11][CH2:10]1)C.O.[OH-].[Li+].Cl>C1COCC1>[CH3:30][C:26]1([CH3:31])[CH2:25][CH2:24][C:23]([CH3:32])([CH3:33])[C:22]2[CH:21]=[C:20]([C:18]3[N:19]=[C:15]([N:12]4[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:34])=[O:3])[CH2:10][CH2:11]4)[S:16][CH:17]=3)[CH:29]=[CH:28][C:27]1=2
Reactant: CCOC(=O)CCCCN1CCN(c2nc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cs2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCN(CCCCC(=O)O)CC4)n3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60 mg of 5-{4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperazin-1-yl}pentanoic acid ethyl ester from step a was dissolved in 2.5 ml of THF, 250 μl of water and 11 mg (0.43 mmol) of lithium hydroxide were added, and the mixture was stirred at room temperature overnight. The reaction mixture was neutralised using a 1N hydrochloric acid solution, evaporated to dryness and purified by means of preparative HPLC. The product is in the form of the trifluoroacetate salt.