Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([Cl:12])[CH:6]=1.F[C:15]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=1[CH:17]=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][C:15]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=2[CH:17]=[O:18])[CH:8]=[C:7]([Cl:12])[CH:6]=1
Reactant: COC(=O)Cc1cc(O)cc(Cl)c1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc(Cl)cc(Oc2ccc([N+](=O)[O-])cc2C=O)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
(3-Chloro-5-hydroxy-phenyl)-acetic acid methyl ester (2.9 g, 14.5 mmol), 2-fluoro-5-nitrobenzaldehyde (2.7 g, 15.9 mmol), and potassium carbonate (4.0 g, 28.9 mmol) were combined in 1,4-dioxane (20 mL) and stirred at 100° C. overnight. Once no starting material was seen by analyical LCMS and tlc, the mixture was worked up with EtOAc and 10% aqueous HCl, and the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([C:8]1[CH:9]=[C:10](C#C[Si](C)(C)C)[C:11]2[C:12](=[O:22])[C:13]3[C:18]([NH:19][C:20]=2[CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:7])([CH3:4])[CH3:3].[CH2:29]1COC[CH2:30]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CCOC(C)=O>[CH3:3][C:2]([NH:5][C:6]([C:8]1[C:9]([C:29]#[CH:30])=[CH:10][C:11]2[C:12](=[O:22])[C:13]3[C:18]([NH:19][C:20]=2[CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:7])([CH3:1])[CH3:4]
Reactant: CC(C)(C)NC(=O)c1cc(C#C[Si](C)(C)C)c2c(=O)c3ccccc3[nH]c2c1
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Product: C#Cc1cc2c(=O)c3ccccc3[nH]c2cc1C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A one dram vial was charged with compound 145A (13 mg, 0.033 mmol), THF (0.5 mL) and TBAF (33 L, 0.033 mmol) under argon. The reaction mixture was stirred at RT for 20 min., and then diluted with EtOAc (10 mL), washed with sat. NaHCO3 (10 mL), water (10 mL) and brine (10 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to give 145B as a yellow solid (12 mg). HPLC retention time=2.74 min. (Condition A), M+=319.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9]1[N:10]=[C:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:12](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1>CCOCC>[C:2]1([NH:1][C:9]2[N:10]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC1=NC(Cl)(c2ccccc2)C(c2ccccc2)=N1
Reactant: Nc1ccccc1
Solvent: CCOCC
Product: c1ccc(NC2=NC(Nc3ccccc3)(c3ccccc3)C(c3ccccc3)=N2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 43.1 %

Procedure:
11.2 g (0.12 mol) of aniline are added dropwise, whilst stirring, to 8.7 g (0.03 mol) of 2,4-dichloro-4,5-diphenyl-4H-imidazole in 150 ml of ether. The mixture was then stirred for 20 hours at room temperature. The precipitate produced was filtered off and dried. After adding methylene chloride, the solution was repeatedly washed with water and then dried over sodium sulphate, and the solvent was distilled off. The oily residue crystallised on addition of a little ether. The product obtained was recrystallised from benzene/petroleum ether. 5.2 g (44% of theory) of 2,4-diphenylamino-4,5-diphenyl-4H-imidazole of melting point 153° - 156° C were obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:19][C:20](=[O:46])[CH:21]([N:25]([C:27](=[O:45])[CH:28]([NH:37]C(OCCCC)=O)[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH3:26])[CH:22]([CH3:24])[CH3:23])[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:19][C:20](=[O:46])[CH:21]([N:25]([C:27](=[O:45])[CH:28]([NH2:37])[CH2:29][C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[CH3:26])[CH:22]([CH3:24])[CH3:23])[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCOC(=O)NC(Cc1ccc(F)cc1)C(=O)N(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nccs1)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nccs1)N(C)C(=O)C(N)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46.8 %

Procedure:
To a solution of 2-((2-butoxycarbonylamino-3-(4-fluorophenyl)propionyl)-N-methylamino)-3-methylbutyric acid 2-(3-tert-butyl-4-hydroxyphenyl)-1-(thiazol-2-yl)ethylamide (B) (1.48 g, 2.26 mmol) in methylene chloride (20 ml), TFA (10 ml) was added and stirred at room temperature for 1.5 hours. The reaction mixture was evaporated to remove the solvent under reduced pressure; the thus obtained residue was mixed with methylene chloride, washed with a 2N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure. The thus obtained residue was subjected to silica gel column chromatography (developing solvent: methanol:aqueous ammonia:methylene chloride=3:0.1:100), giving the titled compound (587 mg).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:22][CH:21]=2)[N:15]=1.Br[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>O1CCCC1.CCCCCC.O>[F:13][C:14]1[C:19]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:18][CH:17]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:22][CH:21]=2)[N:15]=1
Reactant: CCCCCCCCOc1ccc(-c2cccc(F)n2)cc1
Reactant: CCCCCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ccc(CCCCCCCC)c(F)n2)cc1
Temperature: -78 °C
Reaction time: 4 h
Yield: 3.6 %

Procedure:
0.74 g (7.3 mmol) of diisopropylamine in 30 ml of tetrahydrofuran is stirred at 0° C. with 4.56 ml (7.3 mmol) of a 1.6-molar n-butyllithium solution in hexane under argon for 1 hour. After cooling to -78° C., 2.00 g (6.64 mmol) of 2-fluoro-6-(4-octyloxyphenyl)pyridine in 30 ml of tetrahydrofuran are added dropwise at such a rate that the temperature does not exceed 70° C. After 4 hours at -78° C., 1.35 g (7.00 mmol) of 1-bromooctane in 10 ml of tetrahydrofuran are added dropwise while also maintaining a temperature ≤-70° C. The reaction mixture is stirred overnight, during which it warms to room temperature, 5 ml of water are added, and the mixture is evaporated to dryness. The residue is taken up in ether, the resulting solution is washed twice with water, the organic phase is dried over sodium sulfate, filtered, the solvent is distilled off, the residue is purified by chromatography (silica gel, 9:1 hexane/ethyl acetate) and recrystallized from acetonitrile, giving 0.10 g of 2-fluoro-3-octyl-6-(4-octyloxyphenyl)pyridine, whose physical properties are identical to those of the product prepared by Example 1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([Cl:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH:26]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27]1>>[Cl:19][C:17]1[CH:18]=[C:13]([CH:11]([NH:10][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:30]([CH:26]3[CH2:29][CH2:28][CH2:27]3)=[O:31])[N:7]=2)=[O:9])[CH3:12])[CH:14]=[N:15][C:16]=1[O:20][CH2:21][C:22]([F:24])([F:23])[F:25]
Reactant: CC(NC(=O)c1ccnc(N)n1)c1cnc(OCC(F)(F)F)c(Cl)c1
Reactant: O=C(Cl)C1CCC1
Product: CC(NC(=O)c1ccnc(NC(=O)C2CCC2)n1)c1cnc(OCC(F)(F)F)c(Cl)c1

Procedure:
The title compound is prepared from 2-amino-N-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carb oxamide (20 mg, 0.05 mmol, Step-1 of Example 210, single enantiomer) and cyclobutanecarbonyl chloride (32 mg, 0.27 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:9]=1[CH2:10]Br.[OH:17][C:18]1[N:19]=[C:20]([S:36][CH3:37])[N:21]([C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=2[CH3:35])[C:28]([O:30][CH3:31])=[O:29])[C:22](=[O:24])[CH:23]=1>>[F:7][C:8]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:9]=1[CH2:10][O:17][C:18]1[N:19]=[C:20]([S:36][CH3:37])[N:21]([C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=2[CH3:35])[C:28]([O:30][CH3:31])=[O:29])[C:22](=[O:24])[CH:23]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(SC)nc(O)cc2=O)c1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(C)c(-n2c(SC)nc(OCc3ccc(F)cc3F)cc2=O)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 64 %

Procedure:
To a solution of methyl 3-[4-hydroxy-2-(methylthio)-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (1.0 g, 0.0033 mol) in DMF (10.0 mL) obtained from step 2, was added potassium carbonate (0.7 g, 0.005 mol) followed by the addition of 2,4 difluorobenzyl bromide (0.8 g, 0.0039 mol) and stirred at 0° C. for 15 min. After stirring at room temperature for 30 min, DMF was distilled in vacuo and the residue was portioned between EtOAc (25 mL) and water (25 mL). The organic phase was washed with water, (2×20 mL), dried (Na2SO4) and concentrated. The resulting material was purified by flash chromatography using EtOAc/hexane (1:1 v/v) to afford the title compound (0.9 g, 64%) as a white powder: 1H NMR (CD3OD/400 MHz) δ 8.08 (dd, 1H, J=8.4 Hz, & 1.6 Hz), 7.83 (d, 1H, J=1.6 Hz), 7.55 (m, 2H), 6.99 (m 2H), 5.64 (s, 1H), 5.48 (s, 2H), 3.89 (s, 3H), 2.50 (s, 3H), and 2.15 (s, 3H); ES-HRMS m/z 433.1016 (M+H calcd for C21H19N2O4SF2 requires 433.1028).
Reaction SMILES: C(OC(=O)[C:5]([C:15](=[O:17])[CH3:16])([CH2:12][CH2:13][CH3:14])[CH2:6][C:7]([O:9]CC)=[O:8])C.Cl>[Cl-].[Na+].O>[C:15]([CH:5]([CH2:12][CH2:13][CH3:14])[CH2:6][C:7]([OH:9])=[O:8])(=[O:17])[CH3:16]
Reactant: CCCC(CC(=O)OCC)(C(C)=O)C(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCCC(CC(=O)O)C(C)=O
Temperature: 105 °C

Procedure:
To 35 g of 2-acetyl-2-propyl-succinic acid diethyl ester, is added concentrated HCl (200 ml). The mixture is refluxed (oil bath 105° C.) overnight and to it is added brine (100 ml). The mixture is extracted with EtOAc (4×150 ml) and the combined extracts are extracted with 2N aqueous NaOH solution (4×100 ml). The NaOH solution is then cooled to 0° C. and acidified with concentrated HCl. The mixture is extracted with EtOAc (4×200 ml) and the combined extracts are washed with brine (200 ml), dried (Na2SO4) and evaporated in vacuo, which provides the title product as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]1[C@H:56]2[C@@H:51]([CH2:52][CH2:53][CH2:54][CH2:55]2)[CH2:50][CH2:49][NH:48]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:48]4[CH2:49][CH2:50][C@@H:51]5[C@H:56]([CH2:55][CH2:54][CH2:53][CH2:52]5)[CH2:47]4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: C1CC[C@H]2CNCC[C@@H]2C1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CC[C@H]3CCCC[C@@H]3C2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with trans-decahydroisoquinoline (TCI-US) to give the title product. LC-MS (ES+) 786 [(M+H)+].
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([F:22])=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[C:23]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(=[O:25])[CH3:24]>>[F:22][C:13]1[C:12]([CH2:11][C:8]2[N:6]3[N:7]=[C:2]([N:29]4[CH2:30][CH2:31][N:26]([C:23](=[O:25])[CH3:24])[CH2:27][CH2:28]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2
Reactant: CC(=O)N1CCNCC1
Reactant: Fc1c(Cc2cnc3ccc(Cl)nn23)ccc2ncccc12
Product: CC(=O)N1CCN(c2ccc3ncc(Cc4ccc5ncccc5c4F)n3n2)CC1

Procedure:
The title compound was prepared in analogy to Example 38 using 6-(6-chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-5-fluoro-quinoline (Intermediate N, 70 mg, 0.224 mmol) and 1-acetylpiperazine (57.4 mg, 0.448 mmol) (tR 3.40 min (conditions 5), MH+=405, 1H-NMR in DMSO-d6: 8.92 (m, 1H); 8.49 (d, 1H); 7.83 (d, 1H); 7.79 (d, 1H); 7.67 (m, 1H); 7.61 (m, 1H); 7.45 (s, 1H); 7.13 (d, 1H); 4.41 (s, 2H); 3.47 (s, 4H); 3.41 (m, 1H); 3.28 (m, 1H); 2.00 (s, 3H)).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:4]([OH:5])[C:3]=1[OH:11].[C:12]1([C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(Cl)Cl)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>>[Br:1][C:2]1[C:3]2[O:11][C:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:5][C:4]=2[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1
Reactant: ClC(Cl)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(Br)c(O)c1O
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(Br)c2c1OC(c1ccccc1)(c1ccccc1)O2

Procedure:
3-Bromo-6-methoxycatechol (3.87 g) and diphenyl-dichloromethane (4.61 g) were heated at 170° C. with stirring without a solvent. After being allowed to stand for cooling, a saturated aqueous solution of sodium bicarbonate was added to the mixture, followed by extraction with ether. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was triturated with methanol to give Compound IIbl-a (4.7 g, 69%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]([NH2:7])C.[OH-].[Na+].[C:10](Cl)([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>CN(C=O)C.O>[NH2:7][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:10](=[O:11])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(N)CCCN
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: NCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.2 %

Procedure:
To a solution of 1,4-diaminopentane (25 g, 155 mmol) in 100 mL DMF/H2O (1:1) was added 5N NaOH to adjust the pH to 9. CBZ-Cl (3.7 mL, 26 mmol) was added as one portion and stirred at room temperature for 16 hrs. The reaction was acidified to pH 1.25 and washed with diethyl ether. The pH of the reaction was then adjusted to 9.5 and the reaction extracted with EtOAc. The organic layer was washed with H2O, brine, dried over Na2SO4 and evaporated to give title compound (1.57 g, 30%).
Reaction SMILES: [F:1][C:2]([F:55])([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]/[C@H:11]([C:25](N1[C@@H](C(C)C)C(C2C=CC=CC=2)(C2C=CC=CC=2)SC1=O)=[O:26])[C@@:12]([OH:24])([CH2:20][CH2:21][O:22][CH3:23])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH2:56][C@@H:57]([CH2:62][C:63]1[CH:68]=[CH:67][C:66]([O:69][CH2:70][CH2:71][CH2:72][CH3:73])=[CH:65][CH:64]=1)[C:58]([O:60][CH3:61])=[O:59]>ClCCl>[CH2:70]([O:69][C:66]1[CH:65]=[CH:64][C:63]([CH2:62][C@H:57]([NH:56][C:25]([C@@H:11](/[CH:10]=[CH:9]/[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:55])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C@@:12]([OH:24])([CH2:20][CH2:21][O:22][CH3:23])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:26])[C:58]([O:60][CH3:61])=[O:59])=[CH:68][CH:67]=1)[CH2:71][CH2:72][CH3:73]
Reactant: CCCCCCCC(F)(F)CCCCCC/C=C/[C@H](C(=O)N1C(=O)SC(c2ccccc2)(c2ccccc2)[C@@H]1C(C)C)[C@@](O)(CCOC)C(=O)OC(C)(C)C
Reactant: CCCCOc1ccc(C[C@H](N)C(=O)OC)cc1
Solvent: ClCCl
Product: CCCCCCCC(F)(F)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)OC)[C@@](O)(CCOC)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 60 h
Yield: 87 %

Procedure:
tert-Butyl (E)-(2S,3S)-12,12-difluoro-2-hydroxy-3-((S)-4-isopropyl-2-oxo-5,5-diphenyl-thiazolidine-3-carbonyl)-2-(2-methoxy-ethyl)-nonadec-4-enoate (No. 5552816; 17.0 mg, 0.0216 mmol) and methyl (S)-2-amino-3-(4-butoxy-phenyl)-propionate (8.2 mg, 0.0324 mmol) were dissolved in dichloromethane and the solvent was distilled off. The resulting mixture was stirred at 50° C. for 2.5 days, cooled to room temperature, and subsequently the residue was purified by preparative TLC (33% ethyl acetate/n-hexane, Rf=0.6) to obtain tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-(2-methoxy-ethyl)-nonadec-4-enoate (No. 5552820; 13.9 mg, 87% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:17][C:18]([CH3:26])([CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:19]#[N:20]>>[C:19]([C:18]([NH:17][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:26])[CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])#[N:20]
Reactant: CC(N)(C#N)CS(C)(=O)=O
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(Cl)cn1
Product: CC(C#N)(CS(C)(=O)=O)NC(=O)c1cc(OCC(F)(F)F)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 78e, using 5-Chloro-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 24c) and 2-Amino-3-methanesulfonyl-2-methyl-propionitrile (Example 80a) as starting materials and isolated (583 mg, 56%) as a white solid; MS (ESI, m/z): 400.9 (M+H+).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[C:4]([CH2:16][CH3:17])[CH:3]=1.C([Li])CCC.[CH:23](=[O:26])[CH2:24][CH3:25].[Cl-].[NH4+]>C1COCC1>[Si:7]([O:6][C:5]1[CH:14]=[CH:15][C:2]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:3][C:4]=1[CH2:16][CH3:17])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CCc1cc(Br)ccc1O[Si](C)(C)C(C)(C)C
Reactant: CCC=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1cc(C(O)CC)ccc1O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
11.9 g (38 mmol) of (4-bromo-2-ethylphenoxy)-tert-butyldimethylsilane are placed in 200 ml of THF in a round-bottomed flask and under a stream of nitrogen. The reaction medium is cooled to −78° C. and 16.6 ml (41 mmol) of n-butyllithium (2.5 M/THF) are added dropwise. 30 minutes later, 3.2 ml (45 mmol) of propionaldehyde are added dropwise. The medium is stirred for 3 hours at −78° C. It is then poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and then evaporated. 11.1 g (100%) of the expected product are obtained in the form of a colorless oil.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:16]=1[CH:17]=[O:18])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH:36]1([Mg]Br)[CH2:39][CH2:38][CH2:37]1.Cl>O1CCCC1>[F:33][C:30]([F:31])([F:32])[C:28]1[CH:27]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:29]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:16]=1[CH:17]([CH:36]1[CH2:39][CH2:38][CH2:37]1)[OH:18])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C=O)n1
Reactant: Br[Mg]C1CCC1
Agent: Cl
Solvent: C1CCOC1
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(O)C2CCC2)n1
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 25 %

Procedure:
To a solution of 2-{[(3,5-bis-trifluoromethyl-benzyl)(2-methyl-2H-tetrazol-5-yl)amino]-methyl}-4-trifluoromethyl-benzaldehyde (1.5 g; 2.9 mmol) in tetrahydrofuran (14 mL) at −10° C. was added dropwise cyclobutylmagnesium bromide (9 mL; 5.4 mmol; 0.6M solution in tetrahydrofuran). The reaction was stirred at −10° C. for 1.5 hours. To quench the reaction, at 0° C. was added aqueous 2N hydrochloric acid. Reaction extracted with ethyl acetate. The organic was washed with aqueous 2N hydrochloric acid, water and brine. It was dried sodium sulfate and concentrated under reduced pressure. The residue was purified by 40 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 15-70% ethyl acetate in heptane) to give 420 mg (25% yield) as a gum. MS (ES−): Calc; 567.4, Found: 612.6 (M+HCO2). 1H NMR (400 MHz, CDCl3) δ ppm 7.78 (s, 1H), 7.66 (s, 2H), 7.52 (d, J=8.30 Hz, 1H), 7.49 (d, J=8.30 Hz, 1H), 7.35 (s, 1H), 4.86 (q, J=15.77 Hz, 2H), 4.86 (s, 1H), 4.77 (q, J=15.77, 16.18 Hz, 2H), 4.20 (s, 3H), 2.68 (m, 1H), 2.05-1.96 (m, 2H), 1.93-1.76 (m, 3H), 1.70 (m, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[C:15]([OH:17])=O.S(Cl)([Cl:20])=O>>[CH3:1][O:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[C:15]([Cl:20])=[O:17]
Reactant: COCc1onc(-c2ccccc2)c1C(=O)O
Reactant: O=S(Cl)Cl
Product: COCc1onc(-c2ccccc2)c1C(=O)Cl
Temperature: 60 °C
Yield: 100 %

Procedure:
A suspension of 5-methoxymethyl-3-phenyl-isoxazole-4-carboxylic acid (10.0 g, 43.0 mmol) in thionyl chloride (20 mL) was heated at 60° C. for 3 h. The resulting mixture was concentrated under reduced pressure to afford the crude title compound (11.16 g, 100%) which was obtained as a light yellow liquid. The crude product was directly used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][OH:11].CS(O[CH2:17][CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=O)=O.O>COCCOC>[C:21]1([CH2:20][O:19][CH2:18][CH2:17][O:11][CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCCc1ccccn1
Reactant: CS(=O)(=O)OCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: c1ccc(COCCOCCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.4 %

Procedure:
Sodium hydride (80% dispersion in oil, 1.68 g) was added portionwise to a solution of 2-pyridineethanol (6.88 g) in 1,2-dimethoxyethane (50 ml) and stirred under nitrogen for 18 h at room temperature. A solution of 2-(phenylmethoxy)ethanol methanesulphonate (8.25 g) in 1,2-dimethoxyethane (100 ml) was added and the mixture stirred at room temperature for 7 h, then poured into water (400 ml) and extracted with diethyl ether (3×200 ml). The ethereal extracts were washed with 2N hydrochloric acid (250 ml). The aqueous phase was re-extracted with diethyl ether (100 ml) and the aqueous phase carefully basified with 8% sodium bicarbonate to pH8. Extraction with diethyl ether (2×200 ml) and drying and evaporation in vacuo of the organic extracts gave an oil. Purification by FCC eluting with System F (4.1→1.1) gave the title compound (2.71 g) as an oil. T.l.c. (diethyl ether) Rf 0.54