Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[CH2:3][CH2:4][Si:5]([CH3:8])([CH3:7])Cl.[C:20]([Mg]Br)#[CH:21]>C1COCC1>[F:1][C:2]([F:19])([C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[CH2:3][CH2:4][Si:5]([C:20]#[CH:21])([CH3:8])[CH3:7]
Reactant: C#C[Mg]Br
Reactant: C[Si](C)(Cl)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: C1CCOC1
Product: C#C[Si](C)(C)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 60 °C
Yield: 79.1 %

Procedure:
In an oven-dried 250-mL round bottom flask, 3,3,4,4,5,5,6,6,6-nonafluorohexyldimethylchlorosilane (4.58 g, 13.4 mmol) was dissolved in anhydrous THF (10 mL) and cooled in an ice bath. Ethynylmagnesium bromide (34 mL, 17 mmol, 0.5 M in THF) was added slowly, then the mixture was heated to 60° C. for 12 hr. The reaction was quenched with water and dilute sulfuric acid (i.e., a 10 wt % solution of the sulfuric acid (95-98%) in water) to dissolve the salts, then hexane was added and the organic layer was separated. The organic layer was washed with water (5×20 mL), dried over magnesium sulfate, filtered, and concentrated under vacuum to yield the crude product. Purification using chromatography on silica gel with hexane as an eluant yielded a colorless liquid (3.52 g, 10.6 mmol, 80%). Analysis of the colorless product provided the following data: 1H-NMR (200 MHz, CDCl3) δ=2.4 (s, 1H), 2.1 (m, 2H), 0.8 (m, 2H), 0.2 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([C:12]2[C:17]([CH:18]=[CH2:19])=[CH:16][CH:15]=[C:14]([O:20][CH3:21])[C:13]=2[F:22])=[O:11])[C:5](C=C)=[N:6][CH:7]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10](=[O:11])[C:12]3[C:13]([F:22])=[C:14]([O:20][CH3:21])[CH:15]=[CH:16][C:17]=3[CH:18]=[CH:19][C:5]2=[N:6][CH:7]=1
Reactant: C=Cc1ccc(OC)c(F)c1C(=O)c1cc(Cl)cnc1C=C
Solvent: Cc1ccccc1
Product: COc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1F
Temperature: 25 °C

Procedure:
To a stirred solution of (5-chloro-2-vinylpyridin-3-yl)(2-fluoro-3-methoxy-6-vinylphenyl)methanone (6.20 g, 19.5 mmol) in toluene (1 L) was added Zhan IB catalyst (2.0 g, 2.8 mmol). The reaction mixture was purged with N2 for 20 min, heated to reflux overnight, cooled to room temperature, concentrated, and purified by flash chromatography to afford the title compound. LRMS (ESI) calc'd for (C15H9ClFNO2) [M+H]+, 290.0; found 290.0.
Reaction SMILES: FC1C=C(F)C=CC=1C(Cl)=O.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1.C1(C)C=CC=CC=1>C(O)C>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([NH:22][C:23]([NH:44][C:43]1[CH:45]=[CH:46][C:40]([O:39][C:30]2[C:29]3[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:27]([O:26][CH3:25])[CH:28]=3)[N:33]=[CH:32][CH:31]=2)=[CH:41][CH:42]=1)=[S:24])=[O:21]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccc(F)cc1F
Agent: O=C(N=C=S)c1ccc(F)cc1F
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(F)cc4F)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
2,4-Difluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-difluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2,4-Difluoro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (69 mg, yield 82%).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:13][C@H:12]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10][C@H:9]1[C:32](O)=[O:33])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH3:68][NH:69][CH2:70][CH2:71][CH2:72][CH2:73][CH:74]=[CH2:75].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Si:15]([O:14][C@H:12]1[CH2:13][C@@H:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C@H:9]([C:32](=[O:33])[N:69]([CH2:70][CH2:71][CH2:72][CH2:73][CH:74]=[CH2:75])[CH3:68])[CH2:10][CH2:11]1)([C:28]([CH3:29])([CH3:31])[CH3:30])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=CCCCCNC
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCCCCN(C)C(=O)[C@@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a cold solution of compound 38 (1.80 mmol), TBTU (2.17 mmol), and N-methylhex-5-en-1-amine tosylate salt 31a (2.17 mmol) in DMF (100 mL) was added diisopropyl ethyl amine (5.4 mmol) dropwise under nitrogen at 0° C. The reaction mixture was stirred overnight at room temperature, then quenched with water and extracted with diethyl ether. The organic layer was washed with brine, then dried on magnesium sulphate, concentrated under reduced pressure, and purified by chromatography on silica gel to yield compound 39 as a beige solid in 85% yield. MS (ESI, EI+): m/z=578 (MH+).
Reaction SMILES: O[CH:2]([C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[N:10][CH:11]=1)[CH2:3][CH2:4][CH3:5].[Cl:19]C(Cl)Cl>S(Cl)(Cl)=O>[ClH:19].[Cl:19][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[N:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: ClC(Cl)Cl
Reactant: CCCC(O)c1ccc(NC(=O)C(C)(C)C)nc1
Solvent: O=S(Cl)Cl
Product: CCCC(Cl)c1ccc(NC(=O)C(C)(C)C)nc1
Product: Cl
Temperature: 55 °C

Procedure:
To a solution of N-[5-(1-hydroxy-butyl)-pyridin-2-yl]-2,2-dimethyl-propionamide (1.025 g, 4.09 mmol) in trichloromethane (12 mL), thionylchloride (6 mL) was added and the mixture was heated to 55° C. for 1 h. Then the solution was concentrated under reduced pressure to leave crude N-[5-(1-chloro-butyl)-pyridin-2-yl]-2,2-dimethyl-propionamide hydrochloride as a colourless solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.[CH3:14][O:15][C:16]1[C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=[C:18]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[N:17]=1>>[Cl:13][C:12]1[C:3]2[CH2:2][N:23]([CH2:22][C:21]3[C:16]([O:15][CH3:14])=[N:17][C:18]([O:24][CH2:25][C:26]([F:27])([F:28])[F:29])=[CH:19][CH:20]=3)[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: COc1nc(OCC(F)(F)F)ccc1CN
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Product: COc1nc(OCC(F)(F)F)ccc1CN1Cc2c(ccnc2Cl)C1=O
Yield: 80 %

Procedure:
The title compound is prepared in 80% yield (177 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and (2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine (155 mg, 0.57 mmol, Amine-13) in a similar manner to Intermediate-2.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8]([O:10]C)=[O:9])=[CH:5][C:4]2[CH2:12][O:13][C:14]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:15]=3[C:16](=[O:17])[C:3]1=2.[OH-].[Na+]>CO.O>[CH3:1][N:2]1[C:6]([CH2:7][C:8]([OH:10])=[O:9])=[CH:5][C:4]2[CH2:12][O:13][C:14]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:15]=3[C:16](=[O:17])[C:3]1=2
Reactant: COC(=O)Cc1cc2c(n1C)C(=O)c1ccc(C)cc1OC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc2c(c1)OCc1cc(CC(=O)O)n(C)c1C2=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
To an ice-cooled suspension of 1.74 g (0.006 m) of methyl 4,10-dihydro-1,7-dimethyl-10-oxo-1H[1]-benzoxepino[4,3-b]pyrrole-2-acetate in a mixture of methanol (50 ml) and water (5 ml) under a nitrogen atmosphere was added 2.5 N sodium hydroxide solution (2.6 cc, 0.0066 m) over 1 minute. After 30 minutes the ice-bath was removed, and the mixture stirred at ambient temperatures for five hours. The mixture was diluted to ca. 150 ml with water, aged, filtered, and the filtrate acidified dropwise with 2.0 N hydrochloric acid. After filtration, washing and drying, 1.5 g of product was obtained which upon recrystallization from i-propanol-water yielded pure 4,10-dihydro-1,7-dimethyl-10-oxo-1H[1]-benzoxepino[4,3-b]-pyrrole-2-acetic acid, m.p. 196°-197° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1)=[O:4].C(N(CC)CC)C.[C:18]1([C:24](Cl)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:4]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1C[C@@H](O)CN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 99.3 %

Procedure:
Into a solution of 1 (10 g, 55 mmol) in anhydrous CHCl3 (100 mL) was added triethylamine (19 mL, 138 mmol) and triphenylmethyl chloride (14.5 g, 52 mmol). The mixture was stirred at RT for 3d before concentrating and redissolving in EtOAc. The solution was washed sequentially with 10% aq. citric acid, water, and brine before drying over MgSO4 and concentrating under reduced pressure to give 2 (20 g, 100%) as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10](=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[C:19](=[O:27])[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:9])(C)(C)C>Cl.CO>[NH2:7][C@H:8]([C:10]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:19](=[O:27])[C:13]2[C:12]([CH:11]=1)=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:18])[CH3:9]
Reactant: Cc1cccc(CC(=O)C(C)NC(=O)OC(C)(C)C)c1C(=O)Nc1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1cccc2cc([C@H](C)N)n(-c3ccccc3)c(=O)c12

Procedure:
Tert-Butyl 4-(3-methyl-2-(phenylcarbamoyl)phenyl)-3-oxobutan-2-ylcarbamate (compound 4703) (4.61 g, 0.012 mol) was dissolved in HCl/MeOH (50 mL) and stirred at reflux for 30 min. The mixture was concentrated in vacuo and then saturated Na2CO3 solution was added to adjust PH to about 7-8. The resulting solid was collected by filtration and further dried in vacuo to afford the desired product, 3-(1-aminoethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 4704) (2.9 g, 90% yield, where the ratio of isomers is S:R=5:1) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=O)[CH2:12][C:11]3([CH3:20])[CH3:19])[CH:5]=[CH:6][CH:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[S:22])[CH2:12][C:11]3([CH3:20])[CH3:19])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=O)Nc2ccc(-c3cccc(F)c3)cc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CC1(C)CC(=S)Nc2ccc(-c3cccc(F)c3)cc21

Procedure:
Prepared by heating under reflux overnight a mixture of 6-(3-fluorophenyl)-4,4-dimethyl-3,4-dihydroquinoline-2(1H)-one and an equal weight of phosphorus pentasulfide was stirred in pyridine. Workup as in the previous example gave a yellow solid, mp 209-211° C. 1H-NMR (DMSO-d6) δ 12.34 (s, 1H), 7.65 (d, 1H J=2.2 Hz) 7.57 (dd, 1H J1=8.24 J2=2.2 Hz), 7.51 (m, 3H), 7.18 (m, 2H), 2.84 (s, 2H), 1.26 (s, 6H). MS m/z 284 [M−H]− Anal. Calc. For C17H16FlNS: C, 71.55, H, 5.65, N, 4.91. Found: C, 71.18, H, 5.59, N, 4.82.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:15]=[CH:14][C:8]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1.I[CH3:17]>>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH3:17])[C:11](=[O:13])[CH3:12])=[CH:14][CH:15]=1
Reactant: CI
Reactant: COc1ccc(CNC(C)=O)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(CN(C)C(C)=O)cc1
Reaction time: 8 h
Yield: 90 %

Procedure:
Sodium hydride (60% in mineral oil) (1.11 grams, 27.4 mmol) was measured into a round bottom flask and triturated with hexanes. To this was added pure N-(4-methoxybenzyl)-acetamide (1.23 grams, 6.9 mmol) followed by iodomethane (1.95 grams, 13.7 mmol)and the resulting mixture stirred overnight. The reaction was filtered and the solvent removed under vacuum. The crude product was purified by flash column chromatography (SiO2, 2% EtOH in methylene chloride) to yield 1.2 grams of a colorless oil. HRMS (M+H) calcd for C11H16NO2: 194.1181; found: 194.1177. 1H NMR and 13C NMR show a mixture of rotamers at room temperature. 1H NMR (500 MHz, CDCl3) δ: 2.13 (s), 2.15 (s), 2.89 (s), 2.90 (s), 3.78 (s), 3.80 (s), 4.45 (s), 4.50 (s), 6.86 (m), 7.08 (d, J=9), 7.17 (d, J=9). 13C NMR (125 MHz, CDCl3) δ: 21.50, 21.91, 33.49, 35.33, 49.95, 53.72, 55.28, 113.95, 114.32, 127.66, 128.46, 129.44, 129.52, 158.95, 159.13, 170.63, 170.91.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH:55]1([C:58]2[O:62][N:61]=[CH:60][C:59]=2[C:63](O)=[O:64])[CH2:57][CH2:56]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:63]([C:59]2[CH:60]=[N:61][O:62][C:58]=2[CH:55]2[CH2:57][CH2:56]2)=[O:64])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(O)c1cnoc1C1CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2cnoc2C2CC2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 18 %

Procedure:
The desired compound was prepared according to the procedure of Example A27 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 5-cyclopropylisoxazole-4-carboxylic acid as starting materials in 18% yield. LCMS for C31H32ClN8O3 (M+H)+: m/z=599.2.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][N:15]=1)[C:9]([O:11][CH3:12])=[O:10]>C(O)(=O)C.[Pt](=O)=O>[F:20][C:2]([F:1])([F:21])[C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][CH:6]1[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[CH2:13][CH2:14][NH:15]1
Reactant: COC(=O)c1ccnc(Cc2ccccc2C(F)(F)F)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COC(=O)C1CCNC(Cc2ccccc2C(F)(F)F)C1
Reaction time: 3 h
Yield: 89.2 %

Procedure:
Methyl 2-(2-(trifluoromethyl)benzyl)isonicotinate (4.613 g, 15.62 mmol) was dissolved in acetic acid (40 mL) and platinum(IV) oxide (0.26 g, 1.14 mmol) added. The resulting mixture was hydrogenated in a Büchi hydrogenator for 3 h at room temperature and 5 bar. More platinum(IV) oxide (160 mg) was added and the hydrogenation continued at room temperature at 5 bar for 2 h. The catalyst was filtered off and washed with MeOH and the eluate evaporated. DCM and 10% K2CO3 were added and the phases separated. The water phase was extracted with DCM and the combined organic phase washed with water, passed through a phase separator and evaporated to yield methyl 2-(2-(trifluoromethyl)benzyl)-piperidine-4-carboxylate (4.20 g, 89%) as a yellow oil. MS m/z 302 (M+H)+
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]([O:28][CH3:29])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]([O:28][CH3:29])[CH:11]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CCCCCC(=CC(=O)OCC)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCC(CC(=O)OCC)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1OC

Procedure:
A solution of 27.92 g (66.4 mmol) of ethyl 3-(4-t-butyldimethylsilyloxymethyl-2-methoxyphenyl)-2-octenoate [prepared as described in step (iii) above] in 200 ml of ethyl acetate was vigorously stirred for 8 hours in the presence of 1.58 g of 10% palladium-on-charcoal in a stream of hydrogen. At the end of this time, the catalyst was filtered off, and the filtrate was concentrated by evaporation under reduced pressure, to give 28.25 g (a quantitative yield) of the title compound as an oily substance.
Reaction SMILES: [CH2:1]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[C:27]([CH3:32])([CH3:31])[C:28](Br)=[O:29].[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[CH2:20]([C:7]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:19]2[CH:18]=[C:17]3[C:28](=[O:29])[CH:27]([CH3:32])[CH2:31][C:16]3=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCC1(CCCCCC)c2ccccc2-c2ccccc21
Reactant: CC(C)(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCCCCCC1(CCCCCC)c2ccccc2-c2cc3c(cc21)C(=O)C(C)C3
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
A 2000 mL round flask was charged with 9,9-dihexyl-9H-fluorene (79 g, 236.2 mmol) and 2-bromo-2-methylpropanoyl bromide (54.3 g, 236.2 mmol), and then dissolved with 600 mL of carbon disulfide inputted thereto. Then, the reactor was cooled with ice water. Under nitrogen atmosphere, aluminum trichloride (78.7 g, 590.4 mmol) was slowly added thereto in ten lots over 2 hours. The mixture was stirred at room temperature for 8 hours, and then the reaction was terminated by addition of 500 mL of distilled water, followed by washing 3 times with 500 mL of distilled water. The organic layer was dried over magnesium sulfate, followed by removal of volatile materials and drying, to thereby obtain 89.0 g of 9,9-dihexyl-2-methyl-2,3-dihydrocyclopenta[b]fluoren-1(9H)-one (yield: 93.6%) as highly viscous oil.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:10]=2)=CC=1>OS(O)(=O)=O>[F:18][C:15]([F:16])([F:17])[C:13]1[CH:12]=[C:11]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][CH:20]=2)[N:10]=[C:9]([NH2:8])[CH:14]=1
Reactant: COc1ccc(CNc2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)n2)cc1
Agent: O=S(=O)(O)O
Product: Nc1cc(C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
To (4-methoxy-benzyl)-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-amine (6.4 g, 15 mmol) immersed in an icebath was added icecold conc. H2SO4 (30 mL) [immediate development of a deep red color!] and the mixture was stirred at 5° C. for 5 min, then the cooling bath was removed and stirring was continued at 23° C. for 2 h until all gummy material had dissolved into a clear deep red solution. Poured onto ice, made alkaline with 32% NaOH-sol., saturated with solid NaCI, extracted thrice with THF/TBME, dried over Na2SO4. Removal of the solvent in vacuum left the title compound as a light yellow solid (4.537 g, 99%). MS (ISP) 307.1 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:6][O:5][C:4]([C:7]2[C:12]([F:13])=[CH:11][C:10]([F:14])=[CH:9][C:8]=2F)=[N:3]1.[CH3:17][Mg]Br>O1CCCC1>[F:13][C:12]1[CH:11]=[C:10]([F:14])[CH:9]=[C:8]([CH3:17])[C:7]=1[C:4]1[O:5][CH2:6][C:2]([CH3:1])([CH3:16])[N:3]=1
Reactant: CC1(C)COC(c2c(F)cc(F)cc2F)=N1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1cc(F)cc(F)c1C1=NC(C)(C)CO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (ice bath) solution of 4,4-dimethyl-2-(2,4,6-trifluorophenyl)-4,5-dihydrooxazole (16.8 g, 73.3 mmol) in dry tetrahydrofuran (150 ml) was added a solution of methyl magnesium bromide (73.3 ml, 3M in ether) via slow drop-wise addition. The mixture was stirred for 2 hours at 0° C. and then warmed to ambient over 6 hours. The reaction was carefully quenched via the addition a saturated aqueous solution of ammonium chloride (30 ml) and the material was taken up in water (200 ml) and ethyl acetate (150 ml), transferred to a separatory funnel and the organic phase was collected. The organic phase was washed with water (200 ml) and the ethyl acetate phase collected. The aqueous phases were back extracted with ethyl acetate (2×120 ml) and the organic phases were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to provide the desired product as a light yellow oil (16.31 g). (M+H)+=226 m/e.
Reaction SMILES: [C:1]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:13])[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38]>C1COCC1>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38])[C:1]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)C(CCCN1C(=O)c2ccccc2C1=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
A solution of dibenzyl malonate (20 g) in anhydrous THF (200 ml) was treated at 0° C. with sodium hydride (60% dispersion in mineral oil, 3.1 g). The mixture was allowed to warm to room temperature and stirred for 30 minutes under nitrogen. The mixture was then treated with a solution of N-(3-bromopropyl)phthalimide (20.5 g) in THF (100 ml) and heated at reflux for 12 hours. The reaction was then cooled, filtered, and the filtrate evaporated in vacuo. The residue was partitioned between ethyl acetate (200 ml) and saturated aqueous ammonium chloride (150 ml). The organic layer was washed with water (100 ml), brine (100 ml), dried (MgSO4), filtered and the filtrate evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with 20% ethyl acetate in hexane to yield the title compound (17.5 g, 50%) as a white solid.
Reaction SMILES: C(O[C:4](=[O:25])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][CH2:22][CH2:23][CH3:24])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.CO.[CH3:28][NH:29][C:30]([NH2:32])=[O:31]>C[O-].[Mg+2].C[O-]>[CH2:21]([S:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[C:4]([NH:32][C:30]([NH:29][CH3:28])=[O:31])=[O:25])=[CH:17][CH:16]=1)(=[O:19])=[O:20])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)OCC)cc1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CCCCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)NC(=O)NC)cc1
Temperature: 110 °C
Yield: 46.1 %

Procedure:
A solution of 2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-propionic acid ethyl ester (125.3 mg, 0.34 mmol) in magnesium methoxide in methanol (7.4 wt %, 0.98 mL, 0.68 mmol) was treated with methyl urea (38 mg, 0.51 mmol). This mixture was refluxed at 110° C. for 12 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 1-{2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-propionyl}-3-methyl-urea (61.8 mg, 45.8%) as a white solid: mp 189-191° C.; EI-HRMS m/e calcd for C20H30N2O4S (M+) 395.2005, found 395.2008.