Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.Br[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([F:11])[C:5]=1[F:12].[Li]CCCC.[C:18](=O)=[O:19].S(C)C>CCOCC.CC(=O)OCC.Cl.C1COCC1.O>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:18][OH:19])=[C:5]([F:12])[C:6]=1[F:11]
Reactant: O=C=O
Reactant: Fc1c(Br)ccc(Br)c1F
Agent: Cl
Agent: N#N
Agent: [Li]CCCC
Solvent: CSC
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(Br)c(F)c1F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1,4-dibromo-2,3-difluorobenzene (490 mg, 1.80 mmol) in dry Et2O (6 mL) was added to a n-BuLi (0.72 mL of a 2.5M solution in hexanes, 1.80 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 2 h before solid CO2 was added. The reaction mixture was stirred at −78° C. for 10 min and then allowed to warm up to rt. The mixture was then diluted with EA and aq. 1N HCl was added. The layers separated and the org. layer dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the crude carboxylic acid as a pale yellow solid. The crude material (360 mg, 1.52 mmol) was dissolved in dry THF (7 mL) and treated with BH3.Me2S complex (1.0 M in THF, 3.0 mL, 3.00 mmol) at 0° C. The reaction mixture was then warmed to 50° C. and stirred at this temperature until completion of the reaction. The mixture was cooled to 0° C. and water was added followed by EA. The layers were separated and the aq. layer extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA 9:1 to 2:1) to give the title compound as a colorless oil. TLC:rf (1:1 EA-hept)=0.50.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[N:10]([CH2:13][CH3:14])[CH2:9][CH2:8][N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1>O1CCOCC1.C1COCC1>[CH2:15]([N:7]1[C:6]2[CH:17]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=2[CH2:11][N:10]([CH2:13][CH3:14])[CH2:9][CH2:8]1)[CH3:16]
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1=O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCN1CCN(CC)c2cc(N)ccc2C1
Temperature: 75 °C
Reaction time: 18 h
Yield: 77.3 %

Procedure:
To a solution of 8-Amino-1,4-diethyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5one (22.0 g, 0.0944 mol) in dioxane (400 mL) was added borane dimethyl sulfide complex solution (2 M in THF, 118 mL, 0.236 mol) and heated at 75° C. for 4 hr. The reaction was quenched with ethanol (100 mL) and stirred at room temperature for 18 hr., then evaporated. To the residue was added hydrazine hydrate (100 mL) and heated at 95° C. for 4 hr. After evaporation, toluene (50 mL) and ethanol (50 mL) werer added, distilled and the reaction evaporated. The residue was extracted with DCM, evaporated, dissolved in ether, filtered and evaporated to give 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine as an oil (16.0 g, 84%). LCMS (m/e) 220 (M+1); 1H-NMR (DMSO, 400 MHz) δ 6.79-6.71 (d, 1H, J=7.83 Hz), 6.49 (br, 1H,), 6.01-5.99 (d, 1H, J=7.83 Hz), 4.79 (s, 2H), 3.07-3.02 (q, 2H, J=6.82 Hz), 2.85-2.83 (t, 2H, J=8.08 Hz), 2.70-2.68 (t, 2H, J=8.09 Hz), 1.13-1.10 (t, 3H, J=7.07 Hz), 1.00-0.97 (t, 3H, J=7.32 Hz),
Reaction SMILES: Cl.[NH2:2][CH:3]([C:6]1[S:7][C:8]([CH:11]2[O:16]CC(C)(C)CO2)=[CH:9][CH:10]=1)[CH2:4][OH:5].C(N(CC)CC)C.Cl[Si](C)(C)C.Cl[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33].Cl>ClCCl.O.CCOC(C)=O.CO>[CH2:35]([O:34][C:32](=[O:33])[NH:2][C@@H:3]([C:6]1[S:7][C:8]([CH:11]=[O:16])=[CH:9][CH:10]=1)[CH2:4][OH:5])[CH:36]=[CH2:37]
Reactant: C=CCOC(=O)Cl
Reactant: CC1(C)COC(c2ccc(C(N)CO)s2)OC1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)N[C@H](CO)c1ccc(C=O)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2R)-2-amino-2-[5-(5,5-dimethyl-1,3-dioxan-2-yl)thiophen-2-yl]ethanol hydrochloride in dichloromethane (6.8 mL) was treated with triethylamine (0.57 mL, 4.08 mmol) and cooled to 0° C. Chlorotrimethyl silane (0.14 mL, 1.123 mmol) was added and, after stirring the mixture for 30 minutes, allyl chloroformate (0.11 mL, 1.072 mmol) was added. After the mixture was stirred overnight at room temperature, 1 N HCl (100 mL) and MeOH (50 mL) were added and the solution was stirred at room temperature overnight. EtOAc and water were then added and the phases were separated. The organic phase was washed with brine, dried and concentrated under reduced pressure. The crude product was used without further purification. 1H NMR ((CD3)2CO) δ 9.90 (1H), 7.82 (1H), 7.25 (1H), 6.90 (1H), 5.96-5.87 (1H), 5.30 (1H), 5.15 (1H), 5.09 (1H), 4.52 (2H), 3.90 (2H), 3.39 (2H), 0.86 (3H).
Reaction SMILES: Cl.[C:2]([NH:6][OH:7])([CH3:5])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.CCN(CC)CC.[O-]S([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[C:2]([N+:6]([O-:7])=[CH:13][C:12]1[CH:15]=[CH:16][C:9]([Br:8])=[CH:10][CH:11]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NO
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)[N+]([O-])=Cc1ccc(Br)cc1

Procedure:
By anaolgy to the procedure for the synthesis described above, 5.024 g (40.0 mmol) of N-tert-butylhydroxylamine hydrochloride (1) were reacted with 6.476 g (35.0 mmol) of 4-bromobenzaldehyde (2c) in 100 mL of anhydrous toluene, and in the presence of 4.554 g (45 mmol, 6.27 mL) of Et3N and 8.425 g (70.0 mmol) of MgSO4. Purification of the crude yellow oil by column chromatography (silica gel, EtOAc/hexanes=1:6 to 1:3) yielded 8.95 g (quant.) of colorless crystals. Rf: 0.25 (EtOAc/hexanes=1:4, UV254-quenching). 1H NMR (300 MHz, CDCl3, room temp.): δ8.14 (dt, J=8.7,2.4 Hz, 2H, Ar-H), 7.49 (dt, superimposed, J=8.7,2.4 Hz, 2H, Ar-H), 7.48 (s, superimposed, 1H, HC(═N)), 1.56 (s, 9H, C(CH3)3) ppm. 13C NMR (75 MHz, CDCl3, room temp.): δ131.53, 130.06, 129.81, 128.92, 123.73, 71.09, 28.20 ppm.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[C:5]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:10][N:9]([CH3:18])[CH2:8][CH2:7][C:6]=12>C(O)(=O)C.[Zn]>[Br:1][C:2]1[S:3][CH:4]=[C:5]2[CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:10][N:9]([CH3:18])[CH2:8][CH2:7][C:6]=12
Reactant: CN1CCc2c(Br)sc(Br)c2C(c2ccccc2)C1
Agent: [Zn]
Solvent: CC(=O)O
Product: CN1CCc2c(csc2Br)C(c2ccccc2)C1

Procedure:
Zinc powder (0.19 g) was added to a stirred solution of 1,3-dibromo-6-methyl-4-phenyl-5,6,7,8-tetrahydro-4H-thieno[3,4-d]azepine (0.58 g) in acetic acid (10 ml) and the mixture heated under reflux for 5 hours under nitrogen. The mixture was evaporated, water (20 ml), 0.880 ammonia solution (5 ml) added, and extracted with dichloromethane (2×20 ml). The extracts were dried, filtered, evaporated and the residue chromatographed (silica, 1% methanol in dichloromethane) to give 1-bromo-6-methyl-4-phenyl-5,6,7,8-tetrahydro-4H-thieno [3,4-d]azepine as an oil. Later column fractions contained 6-methyl-4-phenyl-5,6,7,8-tetrahydro-4H-thieno[3,4-d]azepine.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH:13]([CH2:21][OH:22])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH:13]([CH2:21][O:22][CH3:23])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CC(CO)Oc2ccccc21
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CI
Product: COCC1CN(C(=O)OCc2ccccc2)c2ccccc2O1

Procedure:
The title compound is prepared analogously to Example 87b) starting from 3.0 g of N-benzyloxycarbonyl-2(R,S)-hydroxymethyl-3,4-dihydro-2H-1,4-benzoxazine, 2.4 g of sodium bis(trimethylsilyl)amide and 0.94 ml of methyliodide: Rf (3:1 mixture of toluene and ethyl acetate)=0.56; Rt (I)=27.9 min.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C1C(I)=C(I)C(C(O)=O)=CC=1I.[H][H]>C1(C)C=CC=CC=1.CCCCCCC>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [H][H]
Agent: C=CCCCCCCCC
Agent: O=C(O)c1cc(I)cc(I)c1I
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CCCCCCCCCC
Temperature: 90 °C

Procedure:
A solution of 100 g of purified 1-decene, 1.301 g of a TIBA stock solution (20 mg TIBA/g toluene solution) and 0.445 g of Metallocene A stock solution (1 mg Metallocene A/g toluene solution) was charged into a clean 600 ml autoclave equipped with an agitator, at room temperature. The reactor was then pressurized with 30 psig hydrogen. The mixture was then heated to 90° C. with stirring. A second solution made by adding a) 0.641 g of Activator A stock solution (1 mg Activator A/g toluene solution) and b) 20 g toluene solvent and was added and the reaction temperature was maintained at 90° C. overnight, then cooled down to room temperature, and any reactor pressure was vented. The liquid product was diluted with 50 ml heptane, stirred with 5 g activated alumina for half an hour and filtered to remove solids. The filtrate was analyzed by gas chromatography using an internal standard to obtain the wt % of normal-decane (n-C10) formation from 1-decene hydrogenation, wt % conversion to lubes and wt % lube yield. The lube product was then isolated by flashing the light ends (solvents, unreacted C10 fraction, and any fractions lighter than C30) and distilled at 180° C. under high vacuum (1 millitorr) for two hours to isolate the lube product.
Reaction SMILES: [CH2:1]([NH:8][S:9]([CH2:12][C@:13]12[C:19]([CH3:21])([CH3:20])[C@H:16]([CH2:17][CH2:18]1)[CH2:15][C:14]2=[N:22]O)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.C(N)(C)(C)C>C(O)C.C(OCC)(=O)C>[CH2:1]([NH:8][S:9]([CH2:12][C@:13]12[C:19]([CH3:20])([CH3:21])[C@H:16]([CH2:17][CH2:18]1)[CH2:15][C@H:14]2[NH2:22])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)NCc1ccccc1)C(=NO)C2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)(C)N
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)NCc1ccccc1)[C@H](N)C2
Temperature: 0 °C

Procedure:
A solution of (1S,4R)—N-benzyl-2-hydroxyimino-7,7-dimethylbicyclo[2.2.1]hept-1-ylmethanesulfonamide (IXa) (45.0 g, 134 mmol) in ethanol (360 mL) was added dropwise to a solution of sodium acetate (94.5 g, 1150 mmol) and TiCl3 (460 mmol) in 10.5% wt. aq. HCl (320 mL) at −20 to −10° C. The addition was conducted below 0° C., and the reaction mixture was then stirred at 0° C. for an hour prior to addition of neat t-BuNH2.BH3 (29.1 g, 335 mmol) in portions. The mixture was stirred at 0-10° C. for 30 minutes and then at ambient temperature. After the reaction was completed, the solution was diluted with ethyl acetate (675 mL) and was extracted with water (450 mL). Following separation of the layers, the organic layer was washed with sat. aq. NH4Cl (675 mL), 1 M aq. Na2CO3 (900 mL) and finally with 10% aq. NaCl (450 mL). The organic solution was concentrated to give the crude amine product (1S,2R,4R)—N-benzyl-2-amino-7,7-dimethylbicyclo[2.2.1]hept-1-ylmethanesulfonamide (VIa) as light yellow powder. The crude product was dissolved in ethanol (180 mL) at 70-75° C. and was hot-filtered. The filter cake was washed with hot ethanol (45 mL), and the filtrate was slowly cooled allowing recrystallization to occur at about 50° C. After stirring for an hour at 0° C., the white suspension was filtered and washed with cold ethanol (45 mL) to give pure (1S,2R,4R)—N-benzyl-2-amino-7,7-dimethylbicyclo[2.2.1]hept-1-ylmethanesulfonamide (VIa) as a white powder (23.5 g; 54%; >99.9% pure as assessed by HPLC).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Cl)[CH:17]=2)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].BrC1C(OC)=C(C(CSC2C=CC=C([F:44])C=2)=CC=1)C(OC)=O>>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:44])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(CS(=O)(=O)c2cccc(Cl)c2)ccc(Br)c1OC
Reactant: COC(=O)c1c(CSc2cccc(F)c2)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)c2cccc(F)c2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 68, starting from methyl 3-bromo-6-(3-fluorophenylthiomethyl)-2-methoxybenzoate (Intermediate 103).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[CH2:12][N:11]1[C:23]([N:25]([CH3:32])[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:24])(C(C)(C)C)(C)C.C(N(CC)CC)C.[CH:46]([S:48]([CH3:51])(=[O:50])=[O:49])=C.FC(F)(F)C(O)=O>CCO>[F:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[C:13]1[CH2:12][N:11]([C:23]([N:25]([CH3:32])[CH:26]2[CH2:31][CH2:30][N:29]([CH2:46][S:48]([CH3:51])(=[O:50])=[O:49])[CH2:28][CH2:27]2)=[O:24])[C:10]([CH2:9][OH:8])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:14]=1
Reactant: CN(C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO[Si](C)(C)C(C)(C)C)c1ccccc1)C1CCNCC1
Reactant: C=CS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CN(C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO)c1ccccc1)C1CCN(CS(C)(=O)=O)CC1
Reaction time: 1 h

Procedure:
To 40 mg (0.07 mmol) of amine 7-2 in EtOH was added 15 μL (0.11 mmol) of triethylamine and 10 μL (0.11 mmol) of methyl vinyl sulfone. After stirring for 60 min, ˜500 μL of trifluoroacetic acid was added and the mixture was stirred for 1 h. The reaction was partitioned between EtOAc and 15% aqueous Na2CO3, the layers were separated, the organic phase was washed with saturated NaHCO3, water, brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel with 20:1:1 EtOH/NH4OH/H2O in EtOAc to provide 13-1 as a white solid. Data for 13-1: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.3 (s, 1H), 5.3 (m, 1H), 4.8 (m, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 4.0 (m, 1H), 3.75 (m, 1H), 3.15 (m, 2H), 3.05 (s, 3H), 3.0 (m, 2H), 2.9 (s, 3H), 2.85 (m, 2H), 2.2 (m, 2H), 1.9-1.7 (m, 4H) ppm. HRMS (ES) calc'd M+H for C27H33F2N3O4S1: 534.2233. Found: 534.2218.
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[N:18]1([CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][C:34](OC)=O)=[CH:29][CH:28]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.O>C(O)C.CCOCC.C(O)(=O)C>[CH:2]1([N:7]2[C:11]3=[N:12][C:34]([CH2:33][C:30]4[CH:31]=[CH:32][C:27]([O:26][CH2:25][CH2:24][N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[CH:28][CH:29]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)Cc1ccc(OCCN2CCOCC2)cc1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccc(OCCN4CCOCC4)cc3)nc(=O)c1-2
Yield: 41.1 %

Procedure:
Sodium (414 mg) was dissolved in ethanol (30 ml) and 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.0 g) and methyl 4-[2-(4-morpholinyl)ethoxy]phenylacetate (5.03 g, 18 mmol) were added. The reaction mixture was refluxed overnight, the solvent was stripped, water was added to the residue, followed by sufficient acetic acid to adjust the pH to 8-9. An oil separated which was collected by decantation and treated with water and saturated NaHCO3. The mixture was extracted with ethyl acetate and washed with water and then saturated NaHCO3 (2×). The aqueous layer was extracted with additional ethyl acetate and the combined organic layers were washed with 2N NaOH and brine. The organic layer was dried over MgSO4, filtered and stripped to afford crude product which was digested with ether and collected by filtration. The crude product was purified by several acid/base work-ups, followed by recrystallization from ether to afford 1.67 g of 1-cyclopentyl-3-ethyl-6-[4-[2-(4-morpholinyl)ethoxy]phenylmethyl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 136-137° C.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[NH:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:21][CH2:20]2)[C:16](O)=[O:17])=[CH:11][CH:10]=1.[F:34][C:35]([F:51])([F:50])[C:36]1[CH:37]=[C:38]([S:46]([NH2:49])(=[O:48])=[O:47])[CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH:27]1([NH:26][C:25]([CH:22]2[CH2:21][CH2:20][N:19]([CH:15]([C:12]3[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=3)[C:16]([NH:49][S:46]([C:38]3[CH:37]=[C:36]([C:35]([F:51])([F:50])[F:34])[CH:41]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:39]=3)(=[O:47])=[O:48])=[O:17])[CH2:24][CH2:23]2)=[O:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(NC1CCCCC1)C1CCN(C(C(=O)O)c2ccc(Cl)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)C1CCN(C(C(=O)NS(=O)(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
140 mg of triethylamine and 0.32 ml of 50% propylphosphonic acid anhydride (solution in DMF) are added to a solution of 150 mg of (4-chlorophenyl)-(4-cyclohexylcarbamoyl-piperidin1-yl)-acetic acid, 174 mg of 3,5-bis(trifluoromethyl)-benzenesulfonamide and 24 mg of DMAP in 6 ml of anhydrous DMF at 10°. The mixture obtained is stirred for ca. 60 hours at RT, solvent is evaporated off and the evaporation residue obtained is treated with EtAc and H2O. Two phases obtained are separated and the organic layer obtained is washed, dried and solvent is evaporated. The evaporation residue obtained is subjected to chromatography on silica gel. 1-[2-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-2-oxo-(4-chloro-phenyl)-ethyl]-piperidine-4-carboxylic acid cyclohexylamide is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].Cl[CH2:17][C:18]1[CH:37]=[CH:36][CH:35]=[CH:34][C:19]=1[O:20][CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27].CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:17][C:18]2[CH:37]=[CH:36][CH:35]=[CH:34][C:19]=2[O:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])[N:5]=1)[CH3:2]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccccc1CCl
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccccc2OCc2nc(-c3ccccc3)oc2C)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
To a mixture of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl]propionate (509 mg), 4-(2-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (753 mg), and N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 96.0 mg) was added at 0° C., and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (1.09 g, yield: 93%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Cl[CH2:32][CH2:33][O:34][CH2:35][CH2:36][OH:37]>O1CCCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:32][CH2:33][O:34][CH2:35][CH2:36][OH:37])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: OCCOCCCl
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC(=O)c1cnc2c(OCCOCCO)cccc2c1Nc1ccccc1C
Yield: 57.8 %

Procedure:
3-butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (2.40 g, 7.5 mmol) and potassium t-butoxide (1.22 g, 10 mmol) were dissolved in tetrahydrofuran (40 ml), 2-(2-chloroethoxy)ethanol (1.58 ml, 15 mmol) added, and the mixture heated at reflux for 18 hours. The solvent was evaporated, the residue taken up in dichloromethane, washed with water and brine, dried and evaporated. Chromatography (silica gel, 3-5% methanol in dichloromethane) and recrystallisation from ethyl acetate gave 3-butyryl-4-(2-methylphenylamino)-8-(2-(2-hydroxyethoxy)ethoxy)quinoline (1.77 g, 60%), m.p. 144°-146°.
Reaction SMILES: Br[CH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[C:18]([F:27])[CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[Mg].Cl[Si:30]1([CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C1COCC1>[CH2:36]([Si@H:30]1[CH2:31][CH2:32][C@H:33]([CH2:2][CH2:3][C@H:4]2[CH2:9][CH2:8][C@H:7]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[C:18]([F:27])[CH:17]=4)=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[CH2:34][CH2:35]1)[CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCC[Si]1(Cl)CCCCC1
Reactant: Fc1cc(-c2ccc([C@H]3CC[C@H](CCBr)CC3)cc2)ccc1OC(F)(F)F
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(OC(F)(F)F)c(F)c4)cc3)CC2)CC1

Procedure:
44.5 g (0.1 mol) of 4-(trans-4-(2-bromoethyl)cyclohexyl)-3'-fluoro-4'-trifluoromethoxybiphenyl was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 20.5 g (0.1 mol) of 1-chloro-1-n-pentyl-silacyclohexane. After a conventional after treatment, 4-(trans-4-(2-(trans-4-n-pentyl-4-silacyclohexyl)ethyl)cyclohexyl)-3'-fluoro-4'-trifluoromethoxybiphenyl was obtained. The silacyclohexane rings of the product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 44.9 g (yield 84.1%) of the trans isomer.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C[O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1>>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:14]([OH:22])=[O:13])=[CH:16][CH:17]=2)=[CH:3][CH:4]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: Fc1ccc(C(F)(F)F)cc1
Product: O=C(O)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Yield: 84 %

Procedure:
4-(4-Trifluoromethyl-phenoxy)benzoic acid (474 mg, 80%) was prepared from 1-fluoro-4-trifluoromethyl benzene (328 mg, 2.0 mmol) and 4-hydroxy benzoic acid methyl ester (304 mg, 2.0 mmol) following general procedure B, then hydrolyzed following general procedure C to give the corresponding acid (450 mg, 80%). 3-(4′-Trifluoromethyl-biphenyl-4-yl)-(2S)-[4-(4-trifluoromethyl-phenoxy)-benzoylamino]-propionic acid methyl ester (121 mg, 82%) was prepared starting from the above acid (70 mg, 0.25 mmol) and 2-amino-3-(4′-trifluoromethyl-biphenyl-4-yl)-(2S)-propionic acid methyl ester (108 mg, 0.30 mmol) according to general procedure A. The ester was hydrolyzed following general procedure C to give the title compound (105 mg, 89%)