Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:21]2[CH2:23][C:22]2([F:25])[F:24])O)=[CH:15][CH:14]=1.[CH3:26][S:27]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:39]=1[NH:38][CH:37]=[CH:36]2)(=[O:29])=[O:28]>ClCCCl.ClCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:21]2[CH2:23][C:22]2([F:25])[F:24])[C:36]2[C:35]3[C:39](=[C:31]([CH2:30][S:27]([CH3:26])(=[O:29])=[O:28])[CH:32]=[CH:33][CH:34]=3)[NH:38][CH:37]=2)=[CH:15][CH:14]=1
Reactant: OC(c1ccc(Cl)cc1)C1CC1(F)F
Reactant: CS(=O)(=O)Cc1cccc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClCCCl
Product: CS(=O)(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)C3CC3(F)F)c[nH]c12

Procedure:
In three parallel batches in each case 3.08 g (13.9 mmol) of indium(III) chloride and 1.6 ml (20.9 mmol) of trifluoroacetic acid were added to in each case 2.54 g (11.6 mmol) of the compound from Example 159A and 2.92 g (13.9 mmol) of the compound from Example 86A in 125 ml of 1,2-dichloroethane, and the mixture was heated under reflux overnight. It was diluted in each case with dichloromethane, and the three batches were combined and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered through kieselguhr and concentrated. The residue was purified by preparative SFC (ethylpyridine column; mobile phase: carbon dioxide/methanol gradient; 150 bar; 35° C.) to result in 995 mg (7% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [O:1]=[C:2]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][CH:25]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:7][C@@H:6]1[C:20]([O:22][CH3:23])=[O:21].[BH4-].[Na+].[Cl-].[NH4+]>CO.ClCCl.CO>[OH:1][CH:2]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][CH:25]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:7][C@@H:6]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)[C@H]1CN(CCSc2ccccn2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H]1CN(CCSc2ccccn2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Reaction time: 0.25 h
Yield: 42.7 %

Procedure:
A stirred solution of 0.77 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-2-ylthio)ethyl]piperidine-3-carboxylate in 15 cm3 of methanol was cooled to a temperature in the region of 0° C. under an inert atmosphere. 0.063 g of sodium borohydride was added and then, after 15 minutes, the temperature was brought back to the region of 20° C. for 16 hours. After adding 5 cm3 of a saturated aqueous ammonium chloride solution, the mixture was stirred for 10 minutes and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was taken up in 10 cm3 of a dichloromethane/methanol (95/5 by volume) mixture and then filtered. The insoluble material was washed with 2 times 5 cm3 of the same mixture. The filtrate was evaporated under the same conditions as above. A foam was obtained, which product was purified by chromatography under a nitrogen pressure of 100 kPa on a column of silica gel (particle size 40-63 μm; diameter 3.5 cm; silica height 35 cm), elution was carried out first with a dichloromethane/methanol (96/4 by volume) mixture, and 35-cm3 fractions were collected. After the first 50 fractions, elution was carried out with a dichloromethane/methanol (90/10 by volume) mixture. Fractions 61 to 90 were combined and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.33 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-2-ylthio)ethyl]piperidine-3-carboxylate was obtained in the form of a lacquer with a beige color.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH:3]1[O:13][CH3:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.O>[CH2:15]([N:1]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH:3]1[O:13][CH3:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)N1CCC(N)C(OC)C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(N(Cc2ccccc2)Cc2ccccc2)C(OC)C1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of racemic ethyl 4-amino-3-methoxypiperidine-1-carboxylate (1 part by mole) in DMF were added benzyl bromide (about 2.2 part by mole), potassium carbonate (about 2.4 part by mole) and potassium iodide (about 0.2 part by mole) respectively. The reaction was heated to about 80° C. After about 6 hours, the reaction was slowly diluted with water (about 12 parts by volume) and extracted with, for example, ethyl acetate. The organic layer was washed with brine and then dried over anhyh Na2SO4. Subsequent filtration and concentration of the solvent provided the 1 as the yellow-orange oil (1 part by mole).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30].C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:23]4[CH:24]=[CH:25][C:20]([F:19])=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:22]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1ccc(F)c(C(F)(F)F)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(F)c(C(F)(F)F)c4)cc3CC[C@@H]12
Yield: 43.2 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 4-fluoro-3-trifluoromethylphenylboronic acid (162 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 18 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 110 mg (43%) of the title compound as an amorphous foam. FDMS: m/e=323. α[D]589 =+51.47 (c=0.52, chloroform).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][C:10]=2[O:12][CH3:13])[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([F:26])[CH:20]=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[C:11]3[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][C:10]=3[O:12][CH3:13])[N:5]=[CH:4][C:3]=2[C:16]#[N:17])=[C:21]([F:26])[CH:20]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1ccc(OC)c2c(Cl)c(C#N)cnc12
Agent: CCOC(C)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(OC)c2c(Nc3ccc(Cl)cc3F)c(C#N)cnc12
Yield: 78.9 %

Procedure:
A mixture of 0.148 g of 4-chloro-5,8-dimethoxy-3-quinolinecarbonitrile, 0.102 g of 4-chloro-2-fluoroaniline, and 5 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 30 minutes. The mixture was cooled and added to 50 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, dried, and washed with 10 ml of hexanes-ethyl acetate (4:1) to give 0.168 g of 4-(4-chloro-2-fluoro-phenylamino)-5,8-dimethoxy-quinoline-3-carbonitrile as a solid, mp 197-199° C.; mass spectrum (EI, m/e): M 329.7609.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]([CH:19]2[CH2:24][CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][CH2:20]2)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[C:27]([NH:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)(=[O:29])[CH3:28].C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].N#N>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[C:27]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]([CH:19]3[CH2:20][CH2:21][C:22]([CH3:25])([CH3:26])[CH2:23][CH2:24]3)[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[CH:4][CH:3]=2)=[CH:33][CH:32]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Reactant: CC1(C)CCC(N(CCOc2ccc(Br)cc2)C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: ClCCl
Solvent: COCCOC
Product: CC(=O)Nc1ccc(-c2ccc(OCCN(C(=O)OC(C)(C)C)C3CCC(C)(C)CC3)cc2)cc1

Procedure:
A mixture of 1,1-dimethylethyl {2-[(4-bromophenyl)oxy]ethyl}(4,4-dimethylcyclohexyl)carbamate (0.085 g; 0.20 mmol; Example V-8), [4-(acetylamino)phenyl]boronic acid (0.040 g; 0.22 mmol), PdCl2(dppf).CH2Cl2 (0.005 g; 0.006 mmol), Na2CO3 (2 mL of a 2M solution) and DME (2 mL) was sparged with N2 for 10 minutes at room temperature and heated at 80° for 1 h (until consumption of the aryl bromide, as judged by LC/MS). Upon cooling, the mixture was partitioned between EtOAc/H2O, layers were separated and the aqueous layer was extracted with EtOAc (×2). Combined organics were washed (brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a pale yellow solid. LC/MS (method A) tR 3.29 min, m/z 481 (M+H, 53%), 381 ([M−Boc]+H, 100%).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.Br[C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[NH2:24].C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl.O.CN(C=O)C>[CH3:10][N:7]1[CH2:8][CH2:9][N:4]([CH2:1][CH2:2][CH2:3][C:21]2[CH:22]=[C:23]([NH2:24])[CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=2)[CH2:5][CH2:6]1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: C=CCN1CCN(C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: B1C2CCCC1CCC2
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(CCCc2cc(N)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C

Procedure:
A solution of 1-allyl-4-methylpiperazine (2.12 g, 14.0 mmol) and 9-BBN (0.5 M in THF, 1.7 g, 28 mL, 14.0 mmol) was heated at reflux for 3 h and then cooled to RT. The solution was added to a mixture of 3-bromo-5-(trifluoromethyl)aniline (3.0 o g, 12.5 mmol), potassium carbonate (8.64 g, 62.5 mmol), PdCl2(PPh3)2—CH2Cl2 adduct (0.457 g, 0.6 mmol), DMF (30 mL) and water (2 mL). The mixtre was heated to 75° C. for 24. The mixture was concentrated, triturated with dichloromethane, and filtered. The filtrate was concentrated and the residue was purified via column chromatography on silica gel (gradient elution with 0-20% methanol-dichloromethane) to afford 3-(3-(4-methylpiperazin-1-yl)propyl)-5-(trifluoromethyl)benzenamine as a brown oil. MS m/z=302 [M+H]+. Calc'd for C15H22F3N3: 301.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[NH:17][C:16]=1[CH3:24].CC1(C)C(C)(C)OB(C2C=CC3OCOC=3C=2)O1>>[O:9]1[C:8]2[CH:7]=[CH:6][C:5]([C:15]3[C:23]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[NH:17][C:16]=3[CH3:24])=[CH:4][C:3]=2[O:2][CH2:10]1
Reactant: Cc1[nH]c2ncccc2c1Br
Reactant: COc1ccc(B(O)O)cc1OC
Agent: CC1(C)OB(c2ccc3c(c2)OCO3)OC1(C)C
Product: Cc1[nH]c2ncccc2c1-c1ccc2c(c1)OCO2

Procedure:
3-Benzo[1,3]dioxol-5-yl-2-methyl-1H-pyrrolo[2,3-b]pyridine 142 was prepared using the same protocol as described in Example 8, substituting 3-Bromo-1H-pyrrolo[2,3-b]pyridine and 3,4-dimethoxy-phenyl boronic acid with 3-Bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine and 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[1,3]dioxole respectively.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]3[CH2:23][N:22](C(OC(C)(C)C)=O)[C@H:21]([C:31]([O-:33])=[O:32])[CH2:20]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[S:34](=[O:38])(=[O:37])([OH:36])[OH:35].[CH3:39]O>>[S:34]([OH:38])([OH:37])(=[O:36])=[O:35].[CH:5]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]3[CH2:23][NH:22][C@H:21]([C:31]([O:33][CH3:39])=[O:32])[CH2:20]3)=[O:17])[C:11]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]=2[CH:2]=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)[C@@H]1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)CN1

Procedure:
850 mg 1-tert.butyl (2S,4R)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-1,2-dicarboxylate and 60 μl sulphuric acid are placed in 12 ml abs. methanol. The reaction mixture is then refluxed for 48 hours with stirring and then evaporated to dryness. 1.0 g product is obtained as a foam. Analytical HPLC-MS (method B): RT=1.80 min.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([N:16]([CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:17][C:18]([OH:20])=O)=[O:15])[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:26]([O:30][C:31](=[O:41])[C@H:32]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH2:33])([CH3:29])([CH3:28])[CH3:27].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>CN(C)C=O>[C:26]([O:30][C:31](=[O:41])[C@H:32]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH:33][C:18](=[O:20])[CH2:17][N:16]([C:14](=[O:15])[C@H:12]([CH3:13])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)O)C1CCCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C)C1CCCC1
Temperature: 0 °C
Yield: 112 %

Procedure:
N-Carbobenzoxy-L-alanyl-N-cyclopentylglycine (4 g) and L-phenylalanine tert-butyl ester (2.4 g) are dissolved in 20 ml of dimethylformamide and under ice-cooling and stirring, a solution of 1.9 g of diethyl cyanophosphate in 5 ml of dimethylformamide is added, followed by addition of 1.6 ml of triethylamine. The mixture is stirred at room temperature for 3 hours. Then, 200 ml of ice water is added and the mixture is extracted twice with 50 ml portions of ethyl acetate. The extract is washed with 1N hydrochloric acid and water and dried. The solvent is then distilled off under reduced pressure to give 6.7 g of N-carbobenzoxy-L-alanyl-N-cyclopentylglycyl-L-phenylalanine tert-butyl ester as colorless oil.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([O:13][C:14](=O)[CH3:15])(=[O:12])[CH3:11].[CH3:17][O:18][C:19]([C:21]1[CH:22]=[N+:23]([O-])C(C)=[CH:25][CH:26]=1)=[O:20].C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:17][O:18][C:19]([C:21]1[CH:22]=[N:23][C:15]([CH2:14][O:13][C:10](=[O:12])[CH3:11])=[CH:25][CH:26]=1)=[O:20]
Reactant: COC(=O)c1ccc(C)[n+]([O-])c1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(COC(C)=O)nc1
Temperature: 120 °C
Reaction time: 2.25 h
Yield: 48 %

Procedure:
N,N-Diisopropylethylamine (2.2 mL, 13 mmol) and acetic anhydride (3.5 mL, 38 mmol) were added to a solution of 6-methylpyridine-3-carboxylic acid methyl ester N-oxide (Reference Compound No. 8-1, 2.1 g, 13 mmol) in acetic acid (14 mL), and then the reaction mixture was stirred at 120° C. for 135 minutes. After cooling, saturated aqueous sodium hydrogen carbonate solution (100 mL) was added thereto, and then sodium hydrogen carbonate was added until foam formation was ended. The whole was extracted with ethyl acetate (100 mL, 50 mL), the organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), and then the resulting solid was collected by filtration with hexane and ethyl acetate to give 1.2 g of the title reference compound as a pale yellow solid. (Yield 48%)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[NH:19]1[CH2:29][CH2:28][CH2:27][C@H:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20]1>>[CH2:25]([O:24][C:22]([C@H:21]1[CH2:27][CH2:28][CH2:29][N:19]([C:13]([C:11]2[S:12][C:8]([C:5]3[C:4]([CH3:16])=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20]1)=[O:23])[CH3:26]
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: CCOC(=O)[C@H]1CCCNC1
Product: CCOC(=O)[C@H]1CCCN(C(=O)c2ccc(-c3noc(C(F)(F)F)c3C)s2)C1

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (S)-(+)-nipecotic acid, ethyl ester (TCI America, Portland Oreg., USA) by the method described in Example 2 Method B. Colorless solid (415 mg, 91%). 1H NMR (CDCl3) 1.19 (t, J=7.0, 3H), 1.50-1.60 (m, 1H), 1.66-1.82 (m, 2H), 2.02-2.12 (m, 1H), 2.29 (d, J=1.4, 3H), 2.46-2.56 (m, 1H), 3.13 (t, J=11.0, 1H), 3.28 (br s, 1H), 4.08 (q, J 7.0, 3H), 4.10 (obs m, 1H), 4.34 (br s, 1H), 7.28 (d, J=4.0, 1H), 7.39 (d, J=3.5, 1H). 19F NMR −63.12. LC/MS 6.74 min, [M+1]+ 417.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1.[CH2:9]([S:11]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:28]3[C:23](=[C:24]([C:38]([NH2:40])=[O:39])[CH:25]=[C:26](B4OC(C)(C)C(C)(C)O4)[CH:27]=3)[NH:22][CH:21]=2)[CH2:16][CH2:15]1)(=[O:13])=[O:12])[CH3:10].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[CH2:9]([S:11]([N:14]1[CH2:15][CH2:16][CH:17]([C:20]2[C:28]3[C:23](=[C:24]([C:38]([NH2:40])=[O:39])[CH:25]=[C:26]([C:2]4[S:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=4)[CH:27]=3)[NH:22][CH:21]=2)[CH2:18][CH2:19]1)(=[O:13])=[O:12])[CH3:10]
Reactant: O=Cc1csc(Br)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(C=O)cs4)cc23)CC1
Reaction time: 0.33 h
Yield: 161.8 %

Procedure:
To a solution of 5-bromo-3-thiophenecarbaldehyde (250 mg, 1.29 mmol) in dioxane (4.5 mL) and H2O (1.5 mL) was added 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (200 mg, 0.43 mmol), potassium carbonate (250 mg, 2.58 mmol) and tetrakis(triphenylphosphine)palladium (0) (56 mg, 0.049 mmol). The reaction was run in the microwave at 150° C. for 20 min. It was then treated with EtOAc and H2O to obtain the crude product. This was then treated with MeOH (10 mL) and the solid was filtered and collected to give 310 mg of the desired title compound.
Reaction SMILES: [Cl:1][C:2](C)=[CH:3][C:4]1[CH:13]=[C:12]2C(C(C)=CC(=O)[O:11]2)=CC=1.[C:17]([O:22][C:23](=[O:27])[CH2:24][CH2:25][CH3:26])(=O)[CH2:18][CH2:19][CH3:20]>>[Cl:1][CH2:2][CH:3]=[CH:4][C:13]1[C:12]([OH:11])=[CH:20][CH:19]=[C:18]2[C:17]=1[O:22][C:23](=[O:27])[CH:24]=[C:25]2[CH3:26]
Reactant: CCCC(=O)OC(=O)CCC
Reactant: CC(Cl)=Cc1ccc2c(C)cc(=O)oc2c1
Product: Cc1cc(=O)oc2c(C=CCCl)c(O)ccc12
Temperature: 180 °C

Procedure:
A solution of 7-(2-chloro propenyl)-4-methyl coumarin (120 g, 0.48 mol) in a mixture of p-disopropyl-benzene (1 L) and n-butyric anhydride 160 mL was heated to 180° C. for 24 hours. The organic layer was evaporated under reduced pressure and residue recrystallizated from ethanol to afford 75 g of the desired compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6](=[O:29])[O:7][C@H:8]([CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:9]=1[OH:10])[CH:2]=[CH2:3]>CO>[OH:10][C:9]1[C@@H:8]([CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:7][C:6](=[O:29])[C:5]=1[O:4]/[CH:1]=[CH:2]/[CH3:3]
Reactant: C=CCOC1=C(O)[C@@H](CC/C=C\CCCCCCCCCCCCCC)OC1=O
Solvent: CO
Product: C/C=C/OC1=C(O)[C@@H](CC/C=C\CCCCCCCCCCCCCC)OC1=O

Procedure:
(R)-4-Hydroxy-5-[(Z)-3-octadecenyl]-3-[(E)-propenyloxy]-2(5H)-furanone was prepared as for the S-isomer from (R)-3-Allyloxy-4-hydroxy-5-[(Z)-3-octadecenyl]-2(5H)-furanone in similar yield: mp 42°-45° C.; [α]D25 12.8° (c=0.3, CH3OH); IR (neat, cm-1) 3079 (br), 3004, 2919, 1739, 1681, 1658, 738, 721; 1H NMR (CD3COCD3) δ 6.43-6.36 (m, 1H), 5.49-5.31 (m, 2H), 5.05-4.91 (m, 1H), 4.77 (dd., J=3.5, 7.8 Hz, 1H), 2.24-1.62 (m, 6H), 1.51 (dd, J=1.7, 6.9 Hz, 3H), 1.44-1.24 (m, 24H), 0.87 (t, J=6.8 Hz, 3H); HRMS calculated for C25H42O4 (M+) 406.3083, found 406, 3076.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6].[CH3:31][CH:32]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]1>>[CH:25]1([CH2:24][NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:11]([CH3:14])=[CH:12][CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:28]=[CH:29][N:30]=[C:2]([N:34]5[CH2:35][CH2:36][CH2:37][CH:32]([CH3:31])[CH2:33]5)[CH:3]=4)[CH:9]=3)=[CH:16][CH:17]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: CC1CCCNC1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC(C)C3)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
A solution of 2-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide (50 mg, 0.12 mmol) in 3-methylpiperidine (1 ml) was heated at 120° C. for 18 h in a sealed tube. The reaction was concentrated under vacuum, the residue chromatographed on an SPE (C18) eluting with a water/acetonitrile gradient, to give, after evaporation of the solvents under vacuum N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-(3-methylpiperidin-1-yl)isonicotinamide (16 mg). NMR; δH [2H6]—DMSO includes 10.28,(1H, s), 8.62,(1H, t), 8.21,(1H, d), 7.93,(2H, d), 7.70,(1H, dd), 7.65,(1H, d), 7.44,(2H, d), 7.30,(1H, d), 7.20,(1H, s), 6.98,(1H, d), 4.26,(2H, m), 3.16,(2H, t), 2.80,(1H, m), 2.20,(3H, s), 1.78,(1H, m), 1.68,(1H, m), 1.57,(1H, m), 1.45,(1H, m), 1.15,(1H, m), 1.04,(1H, m),0.91,(2H, d), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.54 min, MH+483.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].Cl[CH2:12][CH:13]=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([CH3:10])[C:3]=1[NH:4][CH2:12][CH:13]=[O:14]
Reactant: O=CCCl
Reactant: Cc1ccc(C)c(N)c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(C)c(NCC=O)c1C
Temperature: 150 °C

Procedure:
2,3,6-Trimethylaniline (0.3 mole), the dimethyl acetal of 2-chloroacetaldehyde (0.3 mole) and sodium carbonate (20 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at about 150° C. for a period of about 8 hours. After this time the mixture is filtered and the filtrate is distilled to yield the desired product the dimethyl acetal of 2-(2,3,6-trimethylanilino)acetaldehyde.