Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:22]=1B(O)O>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:22]=1[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Reactant: COc1cccc(OC)c1B(O)O
Product: COc1cccc(OC)c1-c1cncc(N2CC3CC4CC2CN(C4)C3)c1

Procedure:
The title compound was prepared from the product of Example 65A and 2,6-dimethoxyphenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 366.0 (M+H)+, retention time 1.34 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:30][C:31]([OH:33])=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]([OH:33])=[O:32])=[CH:4][CH:3]=1
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: O=C(O)CBr
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(CC(=O)O)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) bromo-acetic acid gave the title compound.
Reaction SMILES: [C:1]([C:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:9][C:3]1([C:1]#[C:2][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2/[C:13](=[CH:21]/[C:22]2[NH:23][CH:24]=[CH:25][C:26]=2[O:27][CH3:28])/[C:14](=[O:20])[NH:15]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#CC1(O)CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC3(O)CCCCC3)c21

Procedure:
Using Method C above, 1-ethynyl-1-cyclohexanol (60 mg, 0.48 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and CuI (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h to yield (Z)-1,3-dihydro-4-[(1-hydroxycyclohexyl)ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 94 mg, 65%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[CH:14][O:15]C)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O1CCCC1>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][CH:11]([CH:14]=[O:15])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: COC=C1CCC(c2ccc(Br)cc2)CC1
Solvent: C1CCOC1
Solvent: O
Product: O=CC1CCC(c2ccc(Br)cc2)CC1
Yield: 95.1 %

Procedure:
A mixture of 10.4 g of 1-bromo-4-[4-(methoxymethyli-dene)cyclohexyl]benzene and 100 ml of tetrahydrofuran/2N hydrochloric acid (vol. 4:1) was heated to reflux for 30 minutes in a round flask. Subsequently, the reaction mixture was poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed with 100 ml of water, dried over magnesium sulphate and concentrated. There were obtained 9.4 g of 4-(4-bromophenyl)cyclohexanecarboxaldehyde as white crystals; trans/cis ratio about 5:3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.C[Si]([C:13]#[N:14])(C)C.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[C:3]([C:13]#[N:14])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][n+]1cccc(Cl)c1
Reactant: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ncccc1Cl
Yield: 66.4 %

Procedure:
3-Chloropyridine-1-oxide (2.59 g, 20 mmol), trimethylsilyl cyanide (5.95 g, 60 mmol), and triethylamine (4.05 g, 40 mmol) were combined in 40 mL of acetonitrile and reacted as described in example 763A. The solvent was removed in vacuo and the residue partitioned between CH2Cl2 and 3M potassium carbonate. The organic layer was separated, washed with brine, dried (MgSO4), and concentrated in vacuo. Purification of the crude product by silica gel chomatography using 5% ether/CH2Cl2 as the eluent gave compound 775B (1.84 g, 67%) as a white crystalline solid. HPLC: 100% at 1.64 min(YMC S5 ODS column) eluting with 10-90% aqueous methanol containing 0.2% phosphoric acid over a 4 min gradient monitoring at 220 nm. MS (ES): m/z 139.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[CH:18]([OH:23])[C:19]([CH3:22])([CH3:21])[CH3:20].[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:28][C:27]([Si:24]([CH3:26])([CH3:25])[O:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[C:11]([CH:18]([OH:23])[C:19]([CH3:20])([CH3:22])[CH3:21])[CH:12]=1)([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C(O)C(C)(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C(O)C(C)(C)C)c1
Reaction time: 16 h
Yield: 75.7 %

Procedure:
To a stirred solution of 66.13G (0.500 g, 2 mmol) in DCM (10.00 mL) at 23° C. was added tert-butyidimethylsilyl chloride (0.3 mL, 2 mmol), followed by TEA (0.3 mL, 2 mmol) and DMAP (0.02 g, 0.2 mmol). The reaction was then stirred for 16 hours and concentrated in vacuo. The product was purified on silica gel (0-10% EtOAc in hexanes) to yield 69.16A as a colorless oil (0.655 g, 96% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH:17]2[CH2:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.[NH2:20][C:21]([CH3:27])([CH3:26])[C:22]([NH:24][CH3:25])=[O:23]>>[CH3:26][C:21]([NH:20][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH:17]2[CH2:19][CH2:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:22](=[O:23])[NH:24][CH3:25])[CH3:27]
Reactant: CNC(=O)C(C)(C)N
Reactant: O=C(O)c1ccc(C2CC2)c(-c2cccc(Cl)c2)n1
Product: CNC(=O)C(C)(C)NC(=O)c1ccc(C2CC2)c(-c2cccc(Cl)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid (Example 48 e) and 2-amino-N,2-dimethyl-propanamide (CAN 106914-07-2) as starting materials, MS (EI) m/e: 372.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9](=[O:12])(=[O:11])[NH:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:13]C(C)([O-])C.[K+].CI>CN(C)C=O>[CH3:13][N:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[S:9]1(=[O:12])=[O:11]
Reactant: CC(C)(C)[O-]
Reactant: O=S1(=O)NCc2cccc(Cl)c21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1Cc2cccc(Cl)c2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
A solution of 16.6 g of 7-chloro-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide in 85 mls of dry dimethylformamide was cooled and treated with 10 g of potassium t-butoxide at such a rate that the temperature remained below 6° C. The resulting suspension was stirred at 5° to 10° C. for 30 minutes, treated with 6.1 mls of methyl iodide at 10° to 15° C. and stirred at room temperature for 16 hours. The mixture was poured into ice water and the resulting solid was filtered, washed with water and dried in vacuo at 50° C. for 1.5 hours to give 15.4 g of the title compound as a pinkish solid, m.p. 95°-97° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]=[C:10]=[S:11])[CH2:3][CH2:2]1.[N-:12]=[N+:13]=[N-:14].[Na+]>C(O)C.O>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][N:9]2[C:10](=[S:11])[NH:14][N:13]=[N:12]2)[CH2:5][CH2:6]1
Reactant: [N-]=[N+]=[N-]
Reactant: S=C=NCCN1CCOCC1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: S=c1[nH]nnn1CCN1CCOCC1
Temperature: 20 °C
Yield: 53 %

Procedure:
To a mechanically stirred slurry of 25.8 g (0.15 mole) of 2-morpholinoethylisothiocyanate (S-7) in 250 ml ethanol under a nitrogen atmosphere was added in a slow stream 19.5 g (0.3 mole) of sodium azide dissolved in 600 ml water. The resultant solution was refluxed for 16 hrs, cooled to room temperature (20° C.) and filtered. The filtrate was extracted twice with ether, and then acidified to pH=1 with concentrated hydrochloric acid. The resultant solution was extracted three times with ether. The pH of the aqueous solution was adjusted to 4.5 using a 50% NaOH solution and a fine white precipitate formed. The precipitate was collected by filtration to yield 17.1 grams of intermediate S-8 with a melting point of 226°-8° C.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[C:21](=[O:39])[N:22]([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29]([C:35]([F:38])([F:37])[F:36])[CH:28]=2)[C:23](=[O:26])[C:24]=1[CH3:25]>O1CCCC1.C(OCC)(=O)C>[C:31]([C:30]1[CH:33]=[CH:34][C:27]([N:22]2[C:23](=[O:26])[C:24]([CH3:25])=[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]3)[C:21]2=[O:39])=[CH:28][C:29]=1[C:35]([F:38])([F:37])[F:36])#[N:32]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC1=C(CCCCCI)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1=C(CCCCCN2CCN(C(=O)OC(C)(C)C)CC2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 25 °C
Reaction time: 168 h
Yield: 98 %

Procedure:
1.56 g of 1,1-dimethylethyl piperazine-1-carboxylate was added under a nitrogen atmosphere to a solution of 2.0 g of 4-[2,5-dihydro-3-(5-iodopentyl)-4-methyl-2,5-dioxo-1H-pyrrol-1-yl]-2-(trifluoromethyl)benzonitrile in 53 ml of tetrahydrofuran, and this mixture was stirred for 7 days at room temperature. For working-up, it was diluted with ethyl acetate and washed with semi-saturated sodium bicarbonate solution. After drying on sodium sulfate and concentration by evaporation, it was chromatographed with methanol/dichloromethane on silica gel, and thus 2.2 g of the title compound was obtained as a yellowish oil.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[N:12]=[CH:11][C:10]2=[O:28])=[C:4]([O:29][CH3:30])[CH:3]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[F:8][C:7]1[CH:6]=[C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[N:12]=[CH:11][C:10]2=[O:28])[C:4]([O:29][CH3:30])=[CH:3][C:2]=1[C:35]1[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=1
Reactant: COc1cc(Br)c(F)cc1-n1c(=O)cnc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reactant: OB(O)c1ccc(F)cc1
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1cc(-c2ccc(F)cc2)c(F)cc1-n1c(=O)cnc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 80 °C
Yield: 51.5 %

Procedure:
A vial was charged with 1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoxaline-6-sulfonamide (201.5 mg, 0.407 mmol), (4-fluorophenyl)boronic acid (114 mg, 0.814 mmol), 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (28.8 mg, 0.041 mmol), and potassium phosphate (259 mg, 1.221 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (1627 μl) and water (407 μl) were added. The vial was sealed and heated to 80° C. for 30 min. The mixture was cooled, the layers were separated, and the aq. layer was extracted with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in MeOH and filtered through a 0.2 micron filter. The filtrate was purified by reverse-phase HPLC (25-70% CH3CN/H2O with 0.1% TFA). Fractions containing clean desired product were combined and lyophilized to give 1-(2,4′-difluoro-5-methoxy-4-biphenylyl)-N-3-isoxazolyl-2-oxo-1,2-dihydro-6-quinoxalinesulfonamide (107 mg, 82% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=11.76 (s, 1H), 8.76 (d, J=1.9 Hz, 1H), 8.50 (s, 1H), 8.32 (d, J=2.2 Hz, 1H), 7.95 (dd, J=2.3, 8.9 Hz, 1H), 7.76 (ddd, J=1.5, 5.4, 8.8 Hz, 2H), 7.56 (d, J=10.3 Hz, 1H), 7.46-7.37 (m, 3H), 7.01 (d, J=8.9 Hz, 1H), 6.49 (d, J=2.0 Hz, 1H), 3.80 (s, 3H). m/z (ESI) 511.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:3][CH2:4][S:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[CH3:54][CH:55]([CH3:59])[CH2:56][CH2:57][NH2:58]>O1CCCC1>[F:22][C:2]([F:1])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:3][CH2:4][S:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH:58][CH2:57][CH2:56][CH:55]([CH3:59])[CH3:54])=[O:10]
Reactant: CC(C)CCN
Reactant: O=C(O)c1ccccc1SCCC(F)(F)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)CCNC(=O)c1ccccc1SCCC(F)(F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 56.2 %

Procedure:
To a stirred solution of 2-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-benzoic acid (0.24 g, 0.73 mmol) in dry tetrahydrofuran (10 ml) are added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.30 g, 0.80 mmol) and triethylamine (0.38 ml, 2.2 mmol) at RT. The reaction mixture is stirred for 5 min at RT followed by the addition of 3-methyl-butyl-amine (0.1 ml, 0.88 mmol). The reaction mixture is stirred at RT for 2 h. After completion of the reaction, the solvent is distilled off and the residue is diluted with saturated sodium hydrogen carbonate solution (20 ml) before extraction with EtOAc (3×30 ml). The organic layer is washed with saturated ammonium chloride solution (30 ml), water (30 ml), brine (30 ml), dried over anhydrous sodium sulfate and evaporated in vacuo to get the crude product, which is purified by column chromatography (silica gel, 50% EtOAc/hexane) to yield 2-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-(3-methyl-butyl)-benzamide (example 1) (0.16 g, 0.41 mmol, 56%). [M+H]+ 396.1.
Reaction SMILES: [O:1]([C:8]([NH:10][C@H:11]([C:19]([OH:21])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9])C1C=CC=CC=1.[C:22]([OH:25])(=[O:24])C>C(#N)C>[C:22]([NH:10][C@H:11]([C:19]([O:21][C:19](=[O:20])[C@H:11]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:10][C:8]([OH:1])=[O:9])=[O:20])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([OH:25])=[O:24]
Reactant: CC(=O)O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)Oc1ccccc1
Solvent: CC#N
Product: O=C(O)N[C@@H](Cc1ccccc1)C(=O)OC(=O)[C@H](Cc1ccccc1)NC(=O)O
Temperature: 80 °C
Reaction time: 29 h
Yield: 99 %

Procedure:
Under a nitrogen atmosphere, 571 mg (2 mmol) of N-phenoxycarbonyl-L-phenylalanine, 360 mg (6 mmol) of acetic acid, and 20 mL of acetonitrile were loaded into a two-necked round bottom flask having a volume of 100 mL and mounted with a Dimroth condenser, and then the mixture was stirred at 80° C. for 29 hours. The fact that N-carboxy-phenylalanine anhydride was obtained in a yield of 99% or more was confirmed by subjecting the reaction mixture to NMR determination. After the reaction mixture had been cooled to room temperature, 2 mL of a 1M aqueous solution of hydrochloric acid and 2,400 mg of activated carbon were added to the resultant, and then the mixture was stirred for 1 hour. The activated carbon was removed by filtration, and then the resultant filtrate was concentrated under reduced pressure. Thus, N-carboxy-phenylalanine anhydride was obtained. An isolation amount and an isolation yield were 302.5 mg and 78%, respectively.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][O:9]2)=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(O)C>[OH:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:10][N:30]1[CH2:29][CH2:28][N:27]([CH2:26][CH2:25][CH2:24][CH2:23][C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:21]=[CH:22][C:13]=2[O:12][CH3:11])[CH2:32][CH2:31]1
Reactant: COc1ccc2ccccc2c1CCCCN1CCNCC1
Reactant: Fc1ccc(C2CO2)cc1
Solvent: CCO
Product: COc1ccc2ccccc2c1CCCCN1CCN(CC(O)c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
0.80 g of the optically active form of 2-(4-fluorophenyl)oxirane was dissolved in ethanol, and 3.2 g of 1-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine was added, followed by reflux with heating or 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in chloroform and washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Chromatorex NH, hexane:ethyl acetate=2:1) to give 1.2 g of optically active 1-[2-hydroxy-2-(4-fluorophenyl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazin as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:58])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[C:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[NH:36][C:37]([CH:40]5[CH2:44][C:43]([F:46])([F:45])[CH2:42][N:41]5[C:47](=[O:57])[CH:48]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:49]([CH3:51])[CH3:50])=[N:38][CH:39]=4)=[CH:31][CH:30]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].CO[C:61](=O)[NH:62]C(C(N1CCCC1C1NC(C2C=CC(Br)=CC=2)=CN=1)=O)C(C)C.COC(=O)NC(C(N1CC(F)(F)CC1C1NC(C2C=CC(C#C)=CC=2)=CN=1)=O)C(C)C.COC(=O)NC(C(N1CCCC1C1NC(C2C=CC(C#C)=CC=2)=CN=1)=O)C(C)C>>[CH3:1][O:2][C:3](=[O:58])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH:14]([C:61]#[N:62])[CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[C:28][C:29]3[CH:30]=[CH:31][C:32]([C:35]4[NH:36][C:37]([CH:40]5[CH2:44][C:43]([F:45])([F:46])[CH2:42][N:41]5[C:47](=[O:57])[CH:48]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:49]([CH3:51])[CH3:50])=[N:38][CH:39]=4)=[CH:33][CH:34]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(C#Cc3ccc(-c4cnc(C5CC(F)(F)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Agent: C#Cc1ccc(-c2cnc(C3CC(F)(F)CN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1
Agent: C#Cc1ccc(-c2cnc(C3CCCN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1
Product: COC(=O)NC(C(=O)N1CC(C#N)CC1c1ncc(-c2ccc(C#Cc3ccc(-c4cnc(C5CC(F)(F)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C

Procedure:
Title compound was prepared according to the method employed to prepare [1-(2-{5-[4-(4-{2-[4,4-Difluoro-1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (Example AB1) substituting (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-cyano-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester for (1-{2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (400 mg, 0.89 mmol), and (1-{2-[5-(4-ethynyl-phenyl)-1H-imidazol-2-yl]-4,4-difluoro-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester for (1-{2-[5-(4-ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester. 1H NMR (MeOH-d4, 400 MHz) δ: 7.71-7.61 (m, 4H) 7.46-7.34 (m, 4H), 5.30 (m, 1H), 5.14 (m, 1H), 4.55-4.45 (m, 2H), 4.20-3.94 (m, 5H), 3.61 (s, 6H), 3.47-3.40 (m, 2H), 2.84-2.76 (m, 3H), 2.52 (m, 1H), 1.96-1.91 (m, 2H), 0.96-0.83 (m, 12H); MS (ESI) m/z 824 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8]C(C)(C)C)=[O:7])=[CH:4][CH:3]=1.Br[C:16]1[S:17][CH:18]=[CH:19][N:20]=1.Cl.O1CCOCC1>C(O)(C)C>[S:17]1[CH:18]=[CH:19][N:20]=[C:16]1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: Brc1nccs1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: O=C(O)c1ccc(Nc2nccs2)cc1
Temperature: 100 °C
Yield: 56.9 %

Procedure:
To a suspension of tert-butyl 4-aminobenzoate (1.93 g, 10 mmol) and 2-bromothiazole (1.2 g, 7.3 mmol) in isopropanol (60 mL) was added 4 N HCl solution in 1,4-dioxane (0.5 mL, 2 mmol). The mixture was refluxed at 100° C. for 50 h, and then allowed to cool to room temperature. The mixture was concentrated to one third of the initial volume. The resulting precipitate was isolated by filtration to yield the first crop of the title compound as a brown solid (915 mg). The mother liquor was dried in vacuo. The obtained residue was dissolved in ethyl acetate (50 mL), washed with water (2×15 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was triturated with isopropanol (8 mL) to yield the second crop of the title compound (341 mg) (total 1.25 g, 78% yield). HPLC/MS (Method D): retention time=0.57 min, [M+H]+=221.3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][C:13]([CH3:15])=[O:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:16]I.[OH-].[K+].O>C(COC)OC>[Cl:1][C:2]1[C:3]([CH:12]([CH3:16])[C:13](=[O:14])[CH3:15])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CI
Reactant: CC(=O)Cc1ncc(C(F)(F)F)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: CC(=O)C(C)c1ncc(C(F)(F)F)cc1Cl
Yield: 9.9 %

Procedure:
6.00 g of 1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]acetone (Int-11) (27 mMol) (synthesis according to P10 and comm av.) and 5.75 g of methyl iodide (40.5 mMol) were diluted in 120 mL of dimethoxyethane. 3.03 g of potassium hydroxide were added portionwise at room temperature. After cooling, 100 mL of water were added to the reaction mixture which was extracted twice with 150 mL of ethyl acetate. The organic phase was washed twice with 100 mL of water, dried over magnesium sulfate and concentrated. After purification on silica, 0.67 g (39%) of desired product 3-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]butan-2-one (Int-12) were obtained, [M+1]=252.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]#[C:24][CH2:25][N:26]([CH3:28])[CH3:27])=[C:10]1[C:29]([O:31][CH2:32][CH3:33])=[O:30].[H][H]>N1C=CC=CC=1.[Pd]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][N:26]([CH3:28])[CH3:27])=[C:10]1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: [H][H]
Reactant: CCOC(=O)C1=C(COCC#CCN(C)C)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Agent: [Pd]
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(COC/C=C\CN(C)C)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 17.7 %

Procedure:
A solution of 4-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}-1-dimethylaminobut-2-yne (1.10 g) in pyridine (75 ml) was stirred at room temperature in the presence of 5% palladium on calcium carbonate under one atmosphere of hydrogen for 45 minutes. The mixture was evaporated and the residue twice taken up in toluene and evaporated. The residue was purified by chromatography on SiO2 (20 g) using dichloromethane plus 1-5% of 10% 0.880 aqueous ammonia in methanol as eluant. Appropriate fractions were combined and evaporated. The residue was dissolved in methanol (20 ml) and the solution treated with fumaric acid (74 mg). The mixture was then evaporated and the residue crystallised from ethyl acetate to give the fumarate salt of the title compound (0.195 g) as a hemihydrate, m.p. 142°-146°.