Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](#[N:17])[CH:15]=[CH2:16]>C(O)C>[C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][C@H:10]([NH:13][CH2:16][CH2:15][C:14]#[N:17])[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CC#N
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Solvent: CCO
Product: N#CCCN[C@H]1CCN(Cc2ccccc2)C1
Yield: 102.4 %

Procedure:
A mixture of (S)-1-(phenylmethyl)-3-pyrrolidinamine, (0.115 mol) and 2-propenenitrile (0.115 mol) in ethanol (250 ml) was stirred and refluxed for 2 hours. 2-Propenenitrile (1 g) was added and the reaction mixture was stirred and refluxed for another 2 hours. The solvent was evaporated, yielding 27.0 g of (S)-3-[[1-(phenyl-methyl)-3-pyrrolidinyl]amino]propanenitrile (interm. 5).
Reaction SMILES: [C:1]1([N:7]=[N+:8]=[N-:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([Sn:14]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]#[CH:16])[CH2:11][CH2:12][CH3:13].C(N(CC)CC)C>C1COCC1.[Cu]I>[C:1]1([N:7]2[CH:16]=[C:15]([Sn:14]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=Nc1ccccc1
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(-c2ccccc2)nn1

Procedure:
Phenylazide can be obtained from Pfaltz & Bauer, Inc., or can be synthesized by the method described in J. Biochem., 179, 397-405 (1979). A solution of tributylethynyl stannane (Sigma Aldrich; 400 mg, 1.27 mmol) in THF (4 ml) is treated with phenylazide (169 mg, 1.27 mmol), copper (I) iodide (90 mg, 0.47 mmol), and triethylamine (256 mg, 2.54 mmol) at room temperature over 48 h. The reaction is then filtered through celite to remove copper (I) iodide and chromatographed on silica in a gradient of 5-20% ethyl acetate in petrol. The second fraction is collected and concentrated in vacuo to give the 1-phenyl-4-(tributylstannyl)-1H[1,2,3]triazole as a colourless oil.
Reaction SMILES: [F:1][C:2]1([F:34])[CH2:5][CH:4]([CH:6]([NH:18][C:19]2[CH:20]=[N:21][C:22]([N:25]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:27]=[CH:26]3)=[CH:23][CH:24]=2)[C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.O1CCCC1.CO.[OH-].[Na+]>C(Cl)Cl>[F:34][C:2]1([F:1])[CH2:5][CH:4]([CH:6]([NH:18][C:19]2[CH:20]=[N:21][C:22]([N:25]3[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[N:27]=[CH:26]3)=[CH:23][CH:24]=2)[C:7]2[CH:17]=[CH:16][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1
Reactant: CCOC(=O)c1ccc(C(Nc2ccc(-n3cnc(C(F)(F)F)c3)nc2)C2CC(F)(F)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: O=C(O)c1ccc(C(Nc2ccc(-n3cnc(C(F)(F)F)c3)nc2)C2CC(F)(F)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
To a flask containing impure ethyl 4-((3,3-difluorocyclobutyl)(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-ylamino)methyl)benzoate (35.0 mg, 0.073 mmol) was added tetrahydrofuran (0.180 mL), methanol (0.180 mL), and 1 N sodium hydroxide (0.180 mL, 0.180 mmol) was then added. After 2 h, another 5 equiv. of aqueous sodium hydroxide was added. The suspension was stirred at room temperature for 18 hours. Another 5 equiv. of aqueous sodium hydroxide was added and the reaction was heated to 50° C. After 2 h, the reaction was quenched with 1 N hydrochloric acid to pH 3 and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give crude material. The crude material was azeotrophed three times with methylene chloride and then dried in vacuo for 18 h to provide crude 4-((3,3-difluorocyclobutyl)(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-ylamino)methyl)benzoic acid (24.0 mg). MS (M+1): 453.2.
Reaction SMILES: [Br:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)=[N:5][N:6]2[C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[CH:45]1([C:48](Cl)=[O:49])[CH2:47][CH2:46]1.O>O1CCCC1>[Br:1][C:2]1[C:10]([NH:11][C:48]([CH:45]2[CH2:47][CH2:46]2)=[O:49])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)=[N:5][N:6]2[C:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1ccc2c(c(-c3cccc(F)c3)nn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccc2c(c(-c3cccc(F)c3)nn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1Br)C1CC1

Procedure:
A total of 513 mg of 4-bromo-3-(3-fluoro-phenyl)-1-trityl-1H-indazol-5-yl-amine obtained in Production Example II-21 was dissolved in 19 ml of tetrahydrofuran. Under ice-cooling and stirring, 0.261 ml of triethylamine and 0.089 ml of cyclopropanecarbonyl chloride were added, and the mixture was stirred at room temperature for 90 minutes. Water was added to the reaction mixture, followed by extracting with ethyl acetate. The resulting organic layer was washed with brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified and, separated by silica gel column chromatography (ethyl acetate:hexane=1:2), to give 471 mg of the title compound as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15](O)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.[CH2:57]([C:59]1[CH:60]=[C:61]([CH:63]=[CH:64][CH:65]=1)[NH2:62])[CH3:58]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:62][C:61]3[CH:63]=[CH:64][CH:65]=[C:59]([CH2:57][CH3:58])[CH:60]=3)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CCc1cccc(N)c1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cccc(NC(=O)c2cccc(N3CCc4nc(N)ncc4C3)c2)c1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 37.5 %

Procedure:
A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (41 mg, 0.15 mmol), N,N-diisopropylethylamine (0.105 mL, 0.60 mmol), and COMU (68 mg, 0.158 mmol) in 1.5 mL DMF was stirred at room temperature for 2 minutes, then 3-ethylaniline (0.127 mL, 0.90 mmol) added and the reaction continued for 4 hours at room temperature. The reaction mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was chromatographed eluting with portions of CHCl3, then 1:1 CHCl3:EtOAc, and then 5% MeOH/CHCl3. The obtained solid was then triturated with an EtOAc/hexane mixture to give the title compound as a light beige solid (21 mg, 38%). 1H NMR (DMSO-d6) δ: 10.08 (s, 1H), 8.13 (s, 1H), 7.61-7.64 (m, 1H), 7.57-7.61 (m, 1H), 7.49-7.52 (m, 1H), 7.32-7.40 (m, 2H), 7.18-7.29 (m, 2H), 6.93-6.98 (m, 1H), 6.41 (s, 2H), 4.29 (s, 2H), 3.65 (t, J=6.0 Hz, 2H), 2.77 (t, J=5.9 Hz, 2H), 2.61 (q, J=7.6 Hz, 2H), 1.20 (t, J=7.6 Hz, 3H)
Reaction SMILES: O1CCOCC1.Br[C:8]1[C:12]([CH3:14])([CH3:13])[O:11]/[C:10](=[C:15]2/[C:16](=[O:26])[NH:17][C:18]3[C:23]/2=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)/[CH:9]=1.[CH:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28].C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.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>[F:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[F:25])[NH:17][C:16](=[O:26])/[C:15]/2=[C:10]1\[CH:9]=[C:8]([C:32]2[CH:33]=[CH:34][C:29]([CH:27]=[O:28])=[CH:30][CH:31]=2)[C:12]([CH3:14])([CH3:13])[O:11]\1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)c(F)cc32)C=C1Br
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)c(F)cc32)C=C1c1ccc(C=O)cc1
Temperature: 80 °C

Procedure:
To 10 mL of 1,4-dioxane was added (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-5,6-difluoro-1,3-dihydro-2H-indol-2-one (85 mg, 0.25 mmol), 4-formylphenylboronic acid (45 mg, 0.30 mmol), PdCl2(PPh3)2 (10 mg, 0.014 mmol), 2M Na2CO3 aqueous solution (0.5 mL, 10 mmol). The mixture was heated at 80° C. under N2 for 30 minutes. After cooling to room temperature, the mixture was diluted with EtOAc (80 mL). The EtOAc solution was washed with brine (2×50 mL), dried over Na2SO4, and concentrated to give 4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzaldehyde as the crude product, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17](F)=[CH:18][CH:19]=2)[C:3]=1[CH3:21].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:19]=2)[C:3]=1[CH3:21]
Reactant: C1CCNC1
Reactant: Cc1c(-c2ccc(F)nc2)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccc(N3CCCC3)nc2)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C
Reaction time: 22.6 h
Yield: 38.5 %

Procedure:
To a stirred solution of 4-chloro-5,7-difluoro-2-(6-fluoropyridin-3-yl)-3-methylquinoline (0.2 g, 0.65 mmol) in DMF (1.3 mL) was added pyrrolidine (0.046 g, 0.65 mmol) followed by potassium carbonate (0.180 g, 1.3 mmol). The reaction was stirred at 100° C. for 22.6 h. After which, the reaction mixture is cooled to rt and water was added. The crude reaction was extracted with EtOAc, dried over magnesium sulfate and concd in vacuo. The crude material was purified on silica gel, eluting with 0-30% EtOAc in hexanes to provide 4-chloro-5,7-difluoro-3-methyl-2-(6-(pyrrolidin-1-yl)pyridin-3-yl)quinoline (0.09 g, 0.250 mmol, 38.6% yield). Mass Spectrum (ESI) m/e=360.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[C:13](I)[C:14]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=4[N:16]=3)=[N:9][N:8]([CH2:24][C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[C:5]2=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.Cl.[F:42][CH:43]1[CH2:46][NH:45][CH2:44]1>CN1CCCC1=O>[F:42][CH:43]1[CH2:46][N:45]([C:13]2[C:14]3[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=3[N:16]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=4)[N:8]([CH2:24][C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=4)[N:9]=3)[N:12]=2)[CH2:44]1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ncccc4F)c4ncc(F)cc34)nc(I)c21
Reactant: FC1CNC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ncccc4F)c4ncc(F)cc34)nc(N3CC(F)C3)c21
Temperature: 150 °C

Procedure:
150 mg (0.155 mmol, approx. 55% purity) of the compound obtained in example 21A was dissolved in 1-methyl-2-pyrrolidone (2.7 ml) in a reaction vessel suitable for a microwave, and 0.423 ml (2.430 mmol) of N,N-diisopropyl ethylamine and 270 mg (2.420 mmol) of 3-fluoroazetidine hydrochloride were added. Then it was sealed with a corresponding septum and it was heated in the microwave at 150° C. for 3 h. After cooling, the reaction mixture was purified by preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 30 mg of the title compound was obtained (40% of theor.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[C:21]#[CH:22].C(NCC)C.C(OCC)(=O)C>CN(C=O)C.[Pd](Cl)Cl.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.[Cu]I>[NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:22]#[C:21][C:15]1[C:16]([CH3:20])=[CH:17][CH:18]=[CH:19][C:14]=1[CH3:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(I)c(N)c1
Reactant: C#Cc1c(C)cccc1C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCNCC
Product: COC(=O)c1ccc(C#Cc2c(C)cccc2C)c(N)c1

Procedure:
A mixture of methyl 3-amino-4-iodobenzoate (920 mg, 3.32 mmol), 2,6-dimethylphenylacetylene (540 mg, 4.15 mmol),), bis-(triphenylphosphine) palladium (II) chloride (47 mg, 67 μmol), diethylamine (486 mg, 66 mmol), and copper (I) iodide (19 mg, 100 μmol) in DMF (10 mL) was heated at 120° C. in a microwave apparatus for 10 min. The mixture was poured into ethyl acetate and extracted six times with brine. The organic phase was dried, filtered, and the solvent was removed under reduced pressure to leave a residue that was chromatographed using a gradient of 0-30% heptane/ethyl acetate to afford methyl 3-amino-4-(2,6-dimethylphenylethynyl)-benzoate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([C:12]2[C:13]([CH2:22][S:23]([CH3:25])=[O:24])=[C:14]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=2)=[O:11])[N:3]=1.[OH:26]O>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([C:12]2[C:13]([CH2:22][S:23]([CH3:25])(=[O:26])=[O:24])=[C:14]([S:18]([NH2:21])(=[O:19])=[O:20])[CH:15]=[CH:16][CH:17]=2)=[O:11])[N:3]=1
Reactant: Cc1cc(C)nc(NC(=O)c2cccc(S(N)(=O)=O)c2CS(C)=O)n1
Reactant: OO
Solvent: CC(=O)O
Product: Cc1cc(C)nc(NC(=O)c2cccc(S(N)(=O)=O)c2CS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 0.1 g (0.2 mmol) of [N-(4,6-dimethylpyrimidinyl)aminocarbonyl]-o-methylsulfinylmethylbenzenesulfonamide and 0.3 ml of 30% hydrogen peroxide in 5 ml of acetic acid was stirred at room temperature for 3 days. The resulting white solid precipitate was filtered to afford 30 mg of the desired product: m.p. 222°-225° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([O:47]CC2C=CC=CC=2)[C@@H:15]([N:32](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([O:24]CC3C=CC=CC=3)[CH:18]=2)[CH2:12][O:11][CH:10]([OH:55])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:56][CH2:57][C:58](OS(C(F)(F)F)(=O)=O)([CH2:60][F:61])[CH3:59]>>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:47])[C@@H:15]([NH2:32])[CH2:16][C:17]2[CH:18]=[C:19]([OH:24])[CH:20]=[C:21]([F:23])[CH:22]=2)[CH2:12][O:11][C@H:10]([O:55][C:58]([CH2:60][F:61])([CH3:59])[CH2:57][F:56])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(CF)(CF)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(O)OC[C@@H]1[C@@H](OCc1ccccc1)[C@H](Cc1cc(F)cc(OCc2ccccc2)c1)N(Cc1ccccc1)Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@@H](OC(C)(CF)CF)OC[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(O)cc(F)c1

Procedure:
Beginning with (5R)-5-[(1S,2S)-1-Benzyloxy-3-(3-benzyloxy-5-fluoro-phenyl)-2-dibenzylamino-propyl]-2-hydroxy-morpholine-4-carboxylic acid tert-butyl ester and trifluoromethanesulfonic acid 2-fluoro-1-fluoromethyl-1-methyl-ethyl ester, the desired compound may be prepared essentially as described in Preparation 306.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].CI.[C:14](=O)([O-])O.[K+]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C([O-])O
Reactant: Cc1cccc(Br)c1C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)cccc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-bromo-6-methylbenzoic acid (5.02 g) and methyl iodide (2.9 mL) in N,N′-dimethylformamide (30 mL) was added powdered potassium hydrogen carbonate (4.67 g). The mixture was stirred at ambient temperature for 16 hours and concentrated. The concentrate was partitioned between ethyl acetate and water. The extract was washed with brine and concentrated, and the concentrate was purified by flash chromatography on silica gel with 60% ethyl acetate in hexanes.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:18][CH2:17][C:16]([OH:15])([C:22]4[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: OC1(c2ccc(Br)cc2)CCNCC1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(O)(c2ccc(Br)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-hydroxy-4-(4-bromophenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 80% overall yield. FDMS m/e=444, 446 (M+ of free base). α[D]589 =-7.52 (c=0.45, methanol).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[N:16]=2)=[O:14])[CH:7]=1)C.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[C:28]([Cl:30])[CH:29]=1>>[Cl:23][C:24]1[CH:25]=[C:26]([C:17]2[N:16]=[C:15]([C:13]([NH:12][C:8]3[CH:7]=[C:6]([CH2:5][C:4]([OH:3])=[O:22])[CH:11]=[CH:10][CH:9]=3)=[O:14])[CH:20]=[CH:19][CH:18]=2)[CH:27]=[C:28]([Cl:30])[CH:29]=1
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2cccc(Br)n2)c1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: O=C(O)Cc1cccc(NC(=O)c2cccc(-c3cc(Cl)cc(Cl)c3)n2)c1

Procedure:
The pyridyl bromide (77) (44 mg, 0.12 mmol) was coupled to 3,5-dichloro-phenylboronic acid (20 mg, 0.10 mmol) using Method E. During this reaction, hydrolysis occurred. The residue was extracted using Work-up E1 to give the acid. The solid was further purified by preparative HPLC to give the title compound.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[C:16]([CH2:18][CH3:19])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:20].[C:21]1([CH:27]([CH2:31][CH3:32])[C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[CH2:18]([C:16]1[C:14](=[O:15])[NH:13][C:11](=[O:12])[N:10]([CH:17]=1)[C@@H:8]1[O:9][C@H:5]([CH2:4][NH:3][C:28](=[O:29])[CH:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:31][CH3:32])[C@@H:6]([OH:20])[CH2:7]1)[CH3:19]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)[nH]c1=O
Reactant: CCC(C(=O)Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)C(CC)c3ccccc3)O2)c(=O)[nH]c1=O
Reaction time: 0.17 h
Yield: 69.8 %

Procedure:
1.25 of 1M sodium hydroxide solution were added to 0.255 g of 5'-amino-2',5'-dideoxy-5-ethyluridine in 5 ml of water and then 0.2 g of 2-phenylbutyryl chloride was added to the mixture. The resulting mixture was shaken for 10 minutes, whereby a white solid was deposited. This solid was collected by filtration, washed three times with 5 ml of water each time, dried at 50° C. in vacuo over phosphorus pentoxide and recrystallized from ethanol to give 0.28 g of 2',5'-dideoxy-5-ethyl-5'-(2-phenylbutyramido)uridine of melting point 235°-236° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:20]([C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])(=[O:22])=[O:21])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.CI.[C:31](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:20]([C:23]([F:28])([F:27])[CH:24]([F:25])[F:26])(=[O:21])=[O:22])[N:11]([CH3:31])[C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1)C(F)(F)C(F)F
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(S(=O)(=O)C(F)(F)C(F)F)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 50 h
Yield: 94 %

Procedure:
A mixture of 4,5-bis(4-fluorophenyl)-2-(1,1,2,2-tetrafluoroethylsulfonyl)imidazole (3.0 g, 0.0071 mole), methyl iodide (1.5 g, 0.011 mole), potassium carbonate (1.5 g, 0.011 mole), and dimethylformamide (30 ml) was stirred for 50 hours at room temperature in a stoppered flask. The mixture was then poured into water, and after the oil crystallized, the solid was collected and washed with water. There was obtained 2.9 g of colorless crystals, mp 122°-124°. Recrystallization from heptane (125 ml) gave 2.5 g (81%) of colorless prisms, mp 125°-126.5°.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]=[C:17]([CH3:47])[N:18]([C:37]2[CH:38]=[CH:39][C:40]3[O:44][CH:43]([CH3:45])[CH2:42][C:41]=3[CH:46]=2)[C:19](=[O:36])[C:20]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1)[CH3:14]>C(OCC)(=O)C>[CH2:13]([C:15]1[N:16]=[C:17]([CH3:47])[N:18]([C:37]2[CH:38]=[CH:39][C:40]3[O:44][CH:43]([CH3:45])[CH2:42][C:41]=3[CH:46]=2)[C:19](=[O:36])[C:20]=1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[NH:3][C:4](=[O:7])[O:5][N:35]=2)=[CH:26][CH:27]=1)[CH3:14]
Reactant: CCc1nc(C)n(-c2ccc3c(c2)CC(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCc1nc(C)n(-c2ccc3c(c2)CC(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
A mixture of hydroxylammonium chloride (1.38 g), sodium hydrogen carbonate (1.97 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-ethyl-2-methyl-1-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.08 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (40 mL), N,N′-carbonyldiimidazole (0.65 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.60 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.82 g, 67%).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[CH2:7].[CH:12]([Cl:15])(Cl)[Cl:13]>>[Br:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]1[CH2:7][C:12]1([Cl:15])[Cl:13]
Reactant: ClC(Cl)Cl
Reactant: C=Cc1ccccc1Br
Agent: [Na+]
Agent: [OH-]
Product: ClC1(Cl)CC1c1ccccc1Br
Temperature: 45 °C

Procedure:
A 20 ml solution of 50% sodium hyroxide was added dropwise to 2-bromostyrene (10.0 g, 54.9 mmol) in 100 ml of chloroform. The reaction mixture was warmed to 45° C. for 1 hour. After cooling the solutionwas separated and the organic layer was dried over magnesium sulfate and concentrated. The resulting liquid was flash chromatographed, affording 11.6 g of the desired compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:12][CH3:13])=[N:7]2.Cl[CH2:15][CH:16]([OH:37])[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH:24]([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)[CH2:20][CH2:19]1>>[C:31]1([CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH:16]([OH:37])[CH2:15][O:1][C:2]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:3]=3[CH:4]=[CH:5][C:6]([O:12][CH3:13])=[N:7]4)[CH2:23][CH2:22]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: OC(CCl)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: COc1ccc2c(O)cccc2n1
Product: COc1ccc2c(OCC(O)CN3CCN(C(c4ccccc4)c4ccccc4)CC3)cccc2n1
Yield: 72.4 %

Procedure:
Following the same procedure as in Example 23-(c), reaction and treatment were carried out using 0.6 g of 5-hydroxy-2-methoxyquinoline and 1.93 g of 4-(3-chloro-2-hydroxypropyl)-1-diphenylmethylpiperazine synthesized in Example 23-(b), in order to obtain 1.2 g of 5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]-2-methoxyquinoline.