Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([CH2:8][NH:9]CC2C=CC=CC=2)[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.[H][H]>CO.[Pd]>[NH2:9][CH2:8][C@@H:7]1[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:3][C@H:2]1[OH:1]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CNCc2ccccc2)[C@H](O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](CN)[C@H](O)C1
Yield: 92.3 %

Procedure:
A mixture of intermediate (25) (0.56 mol) in methanol (700 ml) was hydrogenated at 50° C. with palladium-on-carbon (5 g; 10%) as a catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was solidified in DIPE, filtered off and dried, yielding 119 g (100%) of (+)-1,1-dimethylethyl (trans)-4-(aminomethyl)-3-hydroxy-1-piperidinecarboxylate=+2.43° (c=24.70 mg/5 ml in CH3OH)).
Reaction SMILES: F[C:2]1[C:3]([F:13])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[Cl:14][CH2:15][CH2:16][CH2:17]I.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[Cl:14][CH2:15][CH2:16][CH2:17][N:7]1[C:6]2[CH:12]=[CH:2][C:3]([F:13])=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11]
Reactant: ClCCCI
Reactant: O=C1COc2cc(F)c(F)cc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C1COc2cc(F)ccc2N1CCCCl
Temperature: 25 °C
Reaction time: 40 h
Yield: 95.3 %

Procedure:
A reaction flask was charged with 6,7-difluoro-4H-benzo[1.4]oxazin-3-one (1.5 g, 8.1 mmol), 1-chloro-3-iodopropane (1.44 g, 8.1 mmol), and Cs2CO3 (4.0 g, 12.2 mmol) in MeCN (10 mL) and stirred at rt for 40 h. The reaction mixture was concentrated, water added, and the product extracted into EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiO2; n-heptane/EtOAc 2:1) to give the title compound (1.88 g, 89%). 1H NMR (CDCl3) d 6.99 (dd, J=8.0 Hz, J=5.6 Hz, 1H), 6.79-6.72 (m, 2H), 4.59 (s, 2H), 4.08 (t, J=7.2 Hz, 2H), 3.62 (t, J=6.0 Hz, 2H) 2.18-2.10 (m, 2H); 13C NMR (CDCl3) d 163.9, 159.1 (d, J=244.1 Hz), 146.4 (d, J=11.9 Hz), 124.9 (d, J=3.0 Hz), 115.4 (d, J=9.6 Hz), 109.5 (d, J=22.7 Hz), 105.4 (d, J=26.2 Hz), 67.7, 42.4, 39.2, 30.1.
Reaction SMILES: N1CCCCC1.[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:11]=O.C([CH2:20][C:21]([NH:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=[O:27])=[O:22])(O)=O.Cl>C1(C)C=CC=CC=1>[OH:7][C:8]1[CH:9]=[C:10](/[CH:11]=[CH:20]/[C:21]([NH:23][C:24]2[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26]([OH:28])=[O:27])=[O:22])[CH:13]=[CH:14][C:15]=1[OH:16]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: O=Cc1ccc(O)c(O)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=C(/C=C/c1ccc(O)c(O)c1)Nc1ccccc1C(=O)O
Yield: 83 %

Procedure:
Piperidine (0.39 mL, 4.0 mmol) was added to a suspension of 3,4-dihydroxybenzaldehyde (0.55 g, 4.0 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.74 g, 3.3 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. (E)-2-[[3-(3,4-Dihydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.82 g, 83%) was obtained as a brown crystalline solid; mp 204-206° C.; lit. [24] 204-206° C.; δH (500 MHz, DMSO-d6) 6.50 (d, J=15.5 Hz, 1H, CH═CHCO), 6.77 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.00 (dd, J5′,6′=8.0, =2.0 Hz, 1H, H6′), 7.08 (d, J2′,6′=2.0 Hz, 1H, H2′), 7.14 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.44 (d, J=15.5 Hz, 1H, CH═CHCO), 7.61 (td, J4,5=J5,6=8.0, J3,5=1.5 Hz, 1H, H5), 8.00 (dd, J3,4=8.0, J3,5=1.5 Hz, 1H, H3), 8.58 (d, J5,6=8.0 Hz, 1H, H6), 9.11 (s, 1H, OH), 9.52 (s, 1H, OH), 11.25 (s, 1H, NH).
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].C([O:9][C:10]([C:12]1[S:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])[CH2:19][CH2:18]2)=[N:15][N:16]=1)=O)C>>[CH2:1]([NH:6][C:10]([C:12]1[S:13][C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])[CH2:21][CH2:22]2)=[N:15][N:16]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN
Reactant: CCOC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Product: CCCCCNC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1

Procedure:
Following the procedure as described in Example 3, making variations only as required to use n-pentylamine in place of isoamylamine to react with 5-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl][1,3,4]thiadiazole-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid (0.85 g, yield 77%). 1H NMR (300 MHz, CDCl3) δ 7.70-7.73 (m, 1H), 7.51-7.64 (m, 2H), 7.29-7.35 (m, 1H), 6.97-7.06 (m, 1H), 3.99-4.10 (m, 1H), 3.81-3.92 (m, 1H), 3.62-3.70 (m, 2H), 3.48-3.56 (m, 2H), 3.29-3.44 (m, 4H), 1.50-1.63 (m, 2H), 1.26-1.38 (m, 4H), 0.83-0.91 (m, 3H). 13C NMR (75 MHz, CDCl3) δ 174.6, 167.6, 158.3, 156.1, 133.1, 132.5, 129.7, 127.7, 126.9, 125.4, 121.8. MS (ES+) m/z 455.9 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH2:4]Br.[CH3:11][NH2:12]>CO>[CH3:11][NH:12][CH2:4][C:3]1[CH:6]=[C:7]([Br:10])[CH:8]=[CH:9][C:2]=1[F:1]
Reactant: CN
Reactant: Fc1ccc(Br)cc1CBr
Solvent: CO
Product: CNCc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 25 ml flask, under a nitrogen atmosphere, 2-fluoro-5-bromobenzylbromide (755 mg, 2.82 mmol) was dissolved in methanol (10 ml). Methylamine (0.99 ml, 14.1 mmol) was added and the mixture was stirred at ambient temperature for about three hours. The progress of the reaction was monitored by thin layer chromatography. The solvents were removed by evaporation. The residue was partitioned between 1 M potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The title intermediate was further purified by liquid chromatography.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].Cl>C(O)C>[CH2:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: ClCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COC(=O)Cc1ccc(OCc2ccccc2)cc1

Procedure:
Benzyl ethers may conveniently be used to protect --YH groups. For example, methyl 4-hydroxyphenylacetate (0.2 mol) is heated at reflux with 25 g benzyl chloride (0.2 mol) and 25 g K2CO3 (0.2 mol) in 100 ml ethanol. The product is added to dilute aqueous HCl, extracted with ether, and purified by silica gel chromatography to yield methyl 4-benzyloxyphenylacetate (7).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[H-].[Na+].Cl[C:8]1[C:9]([CH:23]2[CH2:26][CH2:25][CH2:24]2)=[CH:10][C:11]2[N:12]([C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][N:16]=2)[N:13]=1>CN(C=O)C>[CH:23]1([C:9]2[C:8]([O:4][CH2:1][C:2]#[CH:3])=[N:13][N:12]3[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:15][N:16]=[C:11]3[CH:10]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: C#CCO
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOc1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Reaction time: 0.08 h

Procedure:
To a stirred solution of propargyl alcohol (47 mg, 0.84 mmol) in DMF (2 ml) was added 60% sodium hydride suspension in oil (31 mg, 0.77 mmol). Left to stir for 5 minutes prior to the addition of 6-chloro-7-cyclobutyl-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (200 mg, 0.70 mmol). Left to stir for 90 minutes. Quenched (120), extracted (ethyl acetate), washed (H2O, brine), dried (MgSO4) and evaporated in vacuo. The residue was purified via silica gel chromatography using 50/50 ethyl acetate/hexane to elute. The title compound was obtained as a white solid. 1H NMR (250 MHz, CDCl3) δ2.19-2.26 (1 H, m), 2.37-2.55 (3 H, m), 2.69-2.80 (2 H, m), 2.90 (1 H, m), 3.97 (1 H, m), 5.35 (2 H, d, J=2.4 Hz), 7.77-7.89 (3 H, m), 8.13 (1 H, s), 8.80 (1 H, s), 8.86 (1 H, s). Mass spec. ES+(M+1)=305.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:6]=1)=[O:4].[H-].[Na+].[CH2:26](I)[CH2:27][CH3:28]>C1COCC1.C(OCC)(=O)C>[CH2:26]([O:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)[N:6]=1)=[O:4])[CH2:27][CH3:28]
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NO)c1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCONC(=O)c1cc(OC)cc(Oc2cccc(C(F)(F)F)c2)n1

Procedure:
0.6 g (0.0018 mol) of N-hydroxy-4-methoxy-6-{3-(trifluoromethyl)phenoxy)-2-pyridine carboxamide was dissolved in THF, and the obtained solution was mixed with 0.08 g (ca. 60% in mineral oil; 0.0018×1.1 mol) of NaH and then with 0.62 g (0.0018×2.0 mol) of n-propyl iodide, followed by treating the solution under reflux for about 2 hours. The reaction solution was distributed in ethyl acetate-saturated sodium bicarbonate water and then washed with saturated brine. The organic phase of the solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15](B4OC(C)(C)C(C)(C)O4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11]([CH3:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH2:37])=[O:36])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([C:31]4[CH:39]=[CH:38][C:34]([C:35]([NH2:37])=[O:36])=[CH:33][CH:32]=4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11]([CH3:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)c1ccc(Br)cc1
Reactant: CN1Cc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2cc(-c3ccc(C(N)=O)cc3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 90 °C
Yield: 42.8 %

Procedure:
A mixture of 4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (1.0 g mg, 2.3 mmol), 4-bromobenzamide (690 mg, 3.45 mmol) and cesium carbonate (2.25 g, 6.9 mmol) in water (6 mL) and N,N-dimethylformamide (20 mL) was degassed with argon and then [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (88 mg, 0.12 mmol) was added. The mixture was degassed again and then heated to 90° C. for 2 hours. The mixture was partitioned between water and ethyl acetate (3×) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was partially purified by column chromatography (7:3 hexanes/ethyl acetate to ethyl acetate, then ethyl acetate to 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to give 4-(4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide (423 mg, 43%) as a brown solid: ESI MS m/z 429 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[F:24][C:25]([F:38])([F:37])[O:26][C:27]1[CH:36]=[CH:35][C:30]([C:31](=[O:34])[CH2:32]Br)=[CH:29][CH:28]=1>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:32]=1[C:31](=[O:34])[C:30]1[CH:35]=[CH:36][C:27]([O:26][C:25]([F:24])([F:37])[F:38])=[CH:28][CH:29]=1
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2ccc(OC(F)(F)F)cc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans 4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 4-(trifluoromethoxy)phenacyl bromide*.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N#N.C1C[O:23][CH2:22]C1.C([Li])CCC>CCCCCC.CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=2)=[C:9]([CH:10]=1)[CH:22]=[O:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC1(C)COC(c2ccc(C(C)(C)C)cc2)=N1
Agent: N#N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC1(C)COC(c2ccc(C(C)(C)C)cc2C=O)=N1

Procedure:
An oven dried 250 mL 3-neck round bottom flask was fitted with a thermometer, stir bar, septum, and nitrogen inlet. Added 8.02 g (34.7 mmol) of 2-(4-tert-butyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole. Established and maintained N2 atmosphere. Added 100 mL of anhydrous THF. Cooled the clear solution to −78°. Stirred rapidly and added 17 mL (43 mmol) of a 2.5 M solution of n-butyllithium in hexane dropwise over 10 minutes. Stirred the clear amber solution at −20° for 4 hr. The reaction mixture became red-amber and cloudy. Cooled the mixture to −78°. Stirred rapidly and added 12 mL of DMF dropwise at a rate to keep the temperature below −60°. Stirred at −78° for 15 min. Stirred at −20° for 1 hr. Stirred at room temperature for 1 hr. Quenched with 100 mL of 0.5 M aqueous KHSO4. The aqueous phase was still strongly basic. Added more 1.0 M KHSO4 until the pH was ˜2. Diluted the two phase solution with 300 mL Et2O. Separated phases and extracted the aqueous phase with 100 mL Et2O. Washed the combined organic phases with 200 mL brine and dried over K2CO3. Filtered through 120 g of silica gel and washed through with 300 mL Et2O to remove baseline impurities. Removed the solvent on rotavap to obtain 8.18 g of the title compound as a clear yellow liquid. MS (ESI) 260 (M+H)+.
Reaction SMILES: [I-].[C:2]1([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[CH2:13][N+:14]([CH3:17])([CH3:16])C)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1C=CN=[CH:19]1.[ClH:23]>C(O)C.CCOCC>[ClH:23].[C:2]1([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[CH2:13][N:14]2[CH:16]=[CH:19][N:18]=[CH:17]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1c[nH]cn1
Reactant: C[N+](C)(C)Cc1cccn1-c1ccccc1
Agent: Cl
Agent: [I-]
Solvent: CCO
Solvent: CCOCC
Product: c1ccc(-n2cccc2Cn2ccnc2)cc1

Procedure:
A solution of [1-phenyl-pyrrol-2-yl]methyl trimethylammonium iodide (J.A.C.S., 73, 4921, (1951) (3.42 g) and imidazole (0.68 g) in ethanol (70 ml) was heated under reflux for 7 hours. The solution was evaporated and the residue was chromatographed on silica gel. Elution with chloroform gave an oil which was dissolved in ether. Addition of an excess of ethereal hydrogen chloride gave a precipitate which was filtered off and crystallised from methanol/ethyl acetate to give 1-phenyl-2-(imidazol-1-ylmethyl) pyrrole hydrochloride (0.65 g), m.p. 140°-141°.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([O:16][C:17]([NH:19][C@@H:20]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH:21]=[O:22])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH2:9]([O:16][C:17]([NH:19][C@H:20]([CH:21]1[CH2:4][O:22]1)[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[S+](C)(C)=O
Reactant: O=C[C@H](CC1CCCCC1)NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(N[C@@H](CC1CCCCC1)C1CO1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
18.9 g of sodium hydride dispersion (55% in oil) are freed of oil in a dry reaction flask under argon by stirring three times in 50 ml of petroleum ether (b.p. 40°-60°) and subsequently decanting off the solvent each time. After drying under a high vacuum, a grey powder is obtained which is placed in 500 ml of THF; 55.6 g of trimethylsulphoxonium iodide are added thereto, the temperature increasing to approximately 40°. The grey suspension is boiled under reflux for 1 hour and then, within a period of 50 minutes at -70°, a solution of 108.6 g of 2(S)-benzyloxycarbonylamino-3-cyclohexylpropanal in 250 ml of THF is added. The yellow suspension is stirred at 0° for 2 hours. The yellowish turbid solution is poured onto 500 g of ice. The aqueous solution is extracted with 2.5 liters of ether, and the organic phase is washed with water and, after being dried over sodium sulphate, concentrated by evaporation. The oily residue is separated by means of flash chromatography (2.5 kg of silica gel 60, 40-63 μm, eluant C). The product-containing fractions are combined, concentrated by evaporation and dried under a high vacuum. The title compound (diastereoisomeric mixture, approximately 4:1) is obtained in the form of a slightly yellowish oil. Rf (K)=0.71; Rf (C)=0.16.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[CH:9][N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[N:15][N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:12]2[CH2:13][CH2:14][N:10]([CH:9]=[N:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:11]2=[N:15][N+:16]([O-:18])=[O:17])=[CH:22][N:21]=1
Reactant: O=[N+]([O-])N=C1NCCN1C=Nc1ccc(F)cc1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])N=C1N(C=Nc2ccc(F)cc2)CCN1Cc1ccc(Cl)nc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
A mixture of 0.70 g of 1-(4-fluorophenyliminomethyl)-2-nitroiminoimidazolidine, 0.45 g of 2-chloro-5-chloromethylpyridine, 0.77 g of potassium carbonate and 5 ml of dimethylsulfoxide were agitated at 70° C. for 1 hour. The reaction mixture was, as it is, subjected to purification by column chromatography [silica gel, eluent: hexane-ethyl acetate (1:2)] to give 0.45 g of 1-(2-chloropyridin-5-ylmethyl)-2-nitroimino-3-(4-fluorophenyliminomethyl)imidazolidine.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[F:13][C:14]([F:21])([F:20])[CH2:15][O:16][CH2:17][CH2:18][OH:19].[H-].[Na+]>>[F:13][C:14]([F:21])([F:20])[CH2:15][O:16][CH2:17][CH2:18][O:19][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: OCCOCC(F)(F)F
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Product: O=C(O)c1ccc(OCCOCC(F)(F)F)nc1
Reaction time: 0.05 h
Yield: 71 %

Procedure:
The title compound was synthesized as described for Intermediate example I-92 in 71% yield starting from ethyl 6-chloronicotinate and 2-(2,2,2-trifluoroethoxy)ethanol. The reaction between sodium hydride and 2-(2,2,2-trifluoroethoxy)ethanol was performed at 0° C. for 3 min, then ambient temperature for 15 min and then cooled to 0° C. before ethyl 6-s chloronicotinate was added; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (d, 1 H), 8.15 (dd, 1 H), 6.93 (d, 1 H), 4.42-4.52 (m, 2 H), 4.14 (q, 2 H), 3.92-3.97 (m, 2 H); MS (APPI/APCI) m/z 266[M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]#[N:11])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][OH:14].N1C=CC=CC=1.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>C(Cl)Cl>[CH3:24][S:21]([O:14][CH2:13][CH2:12][C:3]1[CH:4]=[CH:5][C:6]([C:10]#[N:11])=[C:7]([O:8][CH3:9])[C:2]=1[Cl:1])(=[O:23])=[O:22]
Reactant: COc1c(C#N)ccc(CCO)c1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(C#N)ccc(CCOS(C)(=O)=O)c1Cl
Reaction time: 2 h

Procedure:
A solution of 2-(2-chloro-4-cyano-3-methoxyphenyl)ethanol (205 mg, 0.969 mmol) DIPEA (0.846 mL, 4.84 mmol) and pyridine (0.078 mL, 0.969 mmol) in DCM (3 mL) was treated dropwise with mesyl chloride (0.110 mL, 1.417 mmol). The reaction was stirred for 2 hours and was then diluted with DCM and washed twice with aq. citric acid, then washed with brine, and dried over sodium sulfate. The residue was purified by flash chromatography (20-50% ethyl acetate/hexanes) to afford the title intermediate.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O1CCCC1>[Cl:2][CH2:3][C:4]1[CH:5]=[C:6]([NH:7][S:19]([CH3:18])(=[O:21])=[O:20])[CH:8]=[CH:9][CH:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(CCl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
873 mg (4.903 mmol) of 3-(chloromethyl)aniline hydrochloride (Example 89A) were initially charged in 4 ml of tetrahydrofuran, and 2.48 g (24.514 mmol) of triethylamine were added. A solution of 421 mg (3.677 mmol) of methanesulfonyl chloride in 3 ml of tetrahydrofuran was slowly added dropwise, and the reaction solution was stirred at RT for 2 h. The reaction solution was concentrated using a rotary evaporator and the residue was purified by preparative HPLC (Chromasil, water/acetonitrile).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]2[N:29]=[C:30]([CH:32]([OH:34])[CH3:33])[NH:31][C:26]2=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[N:28]=[C:27]3[N:29]=[C:30]([CH:32]([OH:34])[CH3:33])[NH:31][C:26]3=[CH:25][CH:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(O)c1nc2nc(Cl)ccc2[nH]1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(O)c1nc2nc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)ccc2[nH]1

Procedure:
The title compound was prepared as described in Example 1 Step 5 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol), and 1-(5-chloro-1H-imidazo[4,5-b]pyridin-2-yl)ethanol (95 mg, 0.48 mmol) as starting materials.
Reaction SMILES: [C:1]([OH:9])(=[O:8])C1C=CC=CC=1.Br[C:11]1[CH:12]=[CH:13][C:14]([C:25]([CH3:28])([CH3:27])[CH3:26])=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:16]=1>>[C:25]([C:14]1[CH:13]=[CH:12][C:11]([C:1]([OH:9])=[O:8])=[CH:16][C:15]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1ccc(Oc2cc(Br)ccc2C(C)(C)C)cc1
Reactant: O=C(O)c1ccccc1
Product: Cc1ccc(Oc2cc(C(=O)O)ccc2C(C)(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of 4-tert-butyl-3-(4'-trifluoromethyl)phenoxy]benzoic acid (Compound P), 1.02 g (3.2 mmol) of 5-bromo-2-tert-butyl-1-[(4'-methyl)phenoxy]benzene (Compound J) was converted into the title compound using 4.7 mL (8.0 mmol) of tert-butyllithium solution (1.7M in pentane) and 10 mL of tetrahydrofuran. Purification by flash chromatography (silica, 3% methanol in chloroform) gave the title compound as a creme solid.