Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1C=CC(C2C=C(C)N=CC=2NC)=C(OC)C=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][C:27]=2[N:32]([CH3:54])[C:33](=[O:53])[C:34]2[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([S:44]([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)(=[O:46])=[O:45])[CH:35]=2)=[C:22]([O:55][CH3:56])[CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[C:30]([CH3:2])[N:29]=[CH:28][C:27]=2[N:32]([CH3:54])[C:33](=[O:53])[C:34]2[CH:39]=[C:38]([C:40]([F:41])([F:43])[F:42])[CH:37]=[C:36]([S:44]([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)(=[O:45])=[O:46])[CH:35]=2)=[C:22]([O:55][CH3:56])[CH:21]=1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCOCC2)c1
Reactant: CNc1cnc(C)cc1-c1ccc(F)cc1OC
Product: COc1cc(F)ccc1-c1cc(C)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCOCC2)c1

Procedure:
The title compound was prepared in analogy to example 90, from 4-(4-fluoro-2-methoxyphenyl)-N,6-dimethylpyridin-3-amine (example 301, intermediate a) and 3-(morpholinosulfonyl)-5-(trifluoromethyl)benzoic acid (example 256, intermediate) after a reaction time of 15.5 hours. The compound was purified by silica gel chromatography on a 20 g column using an MPLC system eluting with EtOAc (isocratic). The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless oil (67%). MS (ESI): m/z=568.15 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[N+:19]([C:22]1[O:26][C:25]([C:27](O)=[O:28])=[CH:24][CH:23]=1)([O-:21])=[O:20]>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:25]3[O:26][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1ccc([N+](=O)[O-])o1
Product: C[C@]1(c2cc(NC(=O)c3ccc([N+](=O)[O-])o3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-nitro-furan-2-carboxylic acid (CAS645-12-5) following procedure I yielded the title compound after purification by preparative HPLC. MS (ISP): m/z=399.3 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([NH:24][O:25]C1CCCCO1)/[CH:3]=[CH:4]/[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C@@H:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]2)=[N:9][CH:10]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CCO>[OH:25][NH:24][C:2](=[O:1])/[CH:3]=[CH:4]/[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C@@H:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13]2)=[N:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc(/C=C/C(=O)NOC3CCCCO3)cn2)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc(/C=C/C(=O)NO)cn2)C1
Yield: 32.6 %

Procedure:
A solution of tert-butyl (3R)-3-[(5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl)amino]-1-pyrrolidinecarboxylate (450 mg) and pyridinium p-toluenesulfonate (261 mg) in EtOH (10 ml) was stirred at 55-60° C. for 9 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of AcOEt and H2O and adjusted to was adjusted to PH10 with aq.K2CO3 solution. The aqueous solution was adjusted to PH6.5 with aq.HCl solution and extracted with AcOEt. The extract was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was washed with IPE to give tert-butyl (3R)-3-({5-[(1E)-3-(hydroxyamino)-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate (118 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:16]2[CH2:15][CH2:14][CH:13]3[CH:9]([CH2:10][NH:11][CH2:12]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1.[CH3:17][O:18][C:19]1[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=1[O:21][CH2:22][C:23](O)=[O:24]>>[CH3:2][O:3][C:4]1[C:16]2[CH2:15][CH2:14][CH:13]3[CH:9]([CH:10]([C:23](=[O:24])[CH2:22][O:21][C:20]4[CH:26]=[CH:27][CH:28]=[CH:29][C:19]=4[O:18][CH3:17])[NH:11][CH2:12]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccccc1OCC(=O)O
Reactant: COc1cccc2c1CCC1CNCC21
Agent: Cl
Product: COc1ccccc1OCC(=O)C1NCC2CCc3c(OC)cccc3C21
Yield: 86 %

Procedure:
Using the procedure described in example 14, but starting with the product of example 27 and o-methoxyphenoxyacetic acid afforded the desired compound, (86%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:17])([CH3:16])[CH2:8][CH2:7]1.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[CH3:16][C:9]1([CH3:17])[C:10]2[C:15](=[CH:14][C:13]([C:19](=[O:21])[CH3:20])=[CH:12][CH:11]=2)[C:6]([CH3:18])([CH3:5])[CH2:7][CH2:8]1
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 3.45 g (25.9 mmol) aluminum chloride in 15 ml methylene chloride was cooled under argon in an ice/salt bath and treated while stirring with a mixture of 4 g (21.2 mmol) 1,1,4,4-tetramethyl-1,2,3,4-tetrahydro naphthalene (from Example 2) and 1.94 g (24.7 mmol) acetylchloride via a dropping funnel over a period of 0.5 hours. Then the cooling bath was removed, the mixture stirred for 2 hours at room temperature and the reaction quenched with ice. The organic layer was recovered and the aqueous layer extracted with 2×50 ml methylene chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].O=[CH:11][C:12]([Cl:15])([Cl:14])[Cl:13]>C1(C)C=CC=CC=1>[Cl:13][C:12]([Cl:15])([Cl:14])[CH:11]1[NH:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH2:4][O:5]1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: Nc1ccccc1CO
Solvent: Cc1ccccc1
Product: ClC(Cl)(Cl)C1Nc2ccccc2CO1
Reaction time: 0.5 h

Procedure:
A solution of o-aminobenzyl alcohol (2.4 g.) in toluene (5 ml.) was stirred at ambient temperature while anhydrous chloral (2.0 ml.) was added dropwise. The mixture was stirred for 30 minutes, and evaporated to dryness to yield an oil, which was crystallised from aqueous ethanol to give 1,2-dihydro-2-trichloromethyl-4H-benzo[d]-[1,3]-oxazine, m.p. 90°-92° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[C:23]([C:22]1[CH:25]=[C:18]([NH:17][C:14]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[C:12]=2[CH3:13])=[O:16])[CH:19]=[CH:20][C:21]=1[N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)[CH2:28][CH2:27]1)#[N:24]
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Reactant: Cc1ccc(-n2ncc(C(=O)O)c2C)cc1
Product: Cc1ccc(-n2ncc(C(=O)Nc3ccc(N4CCC(N5CCOCC5)CC4)c(C#N)c3)c2C)cc1
Yield: 41.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-methylphenyl)-5-methylpyrazole-4-carboxylic acid (1.0 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (1.4 g), the title compound (0.94 g) was obtained, melting point: 243° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[I:17][CH2:18][C:19](Cl)=[O:20].Cl>O>[I:17][CH2:18][C:19]([NH:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1)=[O:20]
Reactant: O=C(Cl)CI
Reactant: NC(=O)c1cc(N)ccc1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NC(=O)c1cc(NC(=O)CI)ccc1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To an ice-cooled, stirred solution of 5-Aminosalicylamide (10.0 grams, 0.073 mol), in 300 mL of water containing NaHCO3 (42.0 grams, 0.5 mol), iodoacetyl chloride (18.4 grams, 0.09 mol) is added dropwise over 15 min. After stirring at 0°-5° C. for 1 hr., the solution is acidified with cold 6N HCl. The precipitate is collected and dried in vacuo over NaOH pellets, to afford 21.3 grams (96% yield) of crude 5-(iodoacetamido)salicylamide.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:16])[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:16])[CH2:14][CH2:13][CH:12]([N:18]3[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=4)=[O:24])[CH2:19]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C2(O)CCC(=O)CC2)cc1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: CN(C)c1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-(4-dimethylamino-phenyl)-4-hydroxy-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.O=[C:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.[NH4+].[Cl-]>C1COCC1>[CH2:2]=[C:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C1CCC(C(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of MePh3PBr (37.1 g, 104 mmol) in THF (500 mL) at 0° C. was added slowly LDA (1.2 eq) over 1 h. The resulting orange solution was stirred for 30 min before ethyl 4-oxocyclohexanecarboxylate (16.1 g, 94.4 mmol) was added dropwise. The resulting suspension was warmed to rt and stirred overnight. A saturated NH4Cl (aq) was added and THF was removed. The aqueous residue was extracted with EtOAc (100 ml×3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by passing through a short silica gel plug (hexanes/EtOAc 7:1). After being concentrated, ethyl 4-methylenecyclohexanecarboxylate was obtained as a pale yellow oil (12.1 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH2:5]Cl.[C-:11]#[N:12].[Na+]>CN(C)C=O.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:5][C:11]#[N:12])[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: [C-]#N
Reactant: Cc1ccc(CCl)cc1C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(CC#N)cc1C
Yield: 100 %

Procedure:
A mixture solution of 3,4-dimethylbenzyl chloride 10 g (64.7 mmol) in dimethyl formamide (15 ml) was treated with sodium cyanide (15.85 g, 323.8 mmol) for 16 hrs at 100° C. The mixture was diluted with H2O and extracted with CH2Cl2 several times. The combined organic layers were washed with H2O, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with EtOAc/hexanes (1:10) as an eluant to give compound 2.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:10]
Reactant: Cc1ccccc1B(O)O
Reactant: Cc1cccc(C)c1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1c(C)cccc1C
Yield: 85.8 %

Procedure:
2-Bromo-m-xylene (186 mg, 1.01 mmol) reacted with 2-methylphenylboronic acid (164 mg, 1.21 mmol) using 2/4 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and K3PO4 (640 mg, 3.00 mmol) in toluene at 100° C. to give the title compound (170 mg, 87%) as a colorless oil: 1H-NMR (400 MHz, CDCl3): δ 7.31-7.25 (m, 3H), 7.20-7.11 (m, 3H), 7.03 (m, 1H), 1.98 (s, 3H), 1.96 (s, 6H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][C@@H:21]([OH:23])[CH2:20][N:19]3[C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O:57][CH2:58][CH3:59])=O.CC(O)=O>C1COCC1>[C:58]([O:23][C@@H:21]1[CH2:20][N:19]([C:24]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25])[C@@H:18]([C:9]2[O:10][C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH2:22]1)(=[O:57])[CH3:59]
Reactant: O=C(OCc1ccccc1)N1C[C@H](O)C[C@@H]1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1C[C@H](c2nc(-c3ccccc3)c(-c3ccccc3)o2)N(C(=O)OCc2ccccc2)C1
Reaction time: 0.5 h

Procedure:
To a mixture of benzyl (2R, 4R)-2-(4,5-diphenyloxazol-2-yl)-4-hydroxypyrrolidine-1-carboxylate (1.50 g) and triphenylphosphine (1.43 g) in THF (15 mL) was added diethyl azodicarboxylate (0.86 mL) at 5° C., and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added AcOH (0.29 mL) at 5° C., and the mixture was stirred at room temperature for 3 hours. The reaction mixture was evaporated, and the residue was dissolved in EtOAc, washed with saturated sodium hydrogen carbonate solution, water and brine, dried (MgSO4), and evaporated in vacuo. The residue was purified by silica gal column chromatography (hexane-EtOAc, 2:1 elution) to give benzyl (2R, 4S)-4-acetoxy-2-(4,5-diphenyloxazol-2-yl)pyrrolidine-1-carboxylate (1.88 g).
Reaction SMILES: N1C(C)=CC=CC=1C.[CH2:9]([C:11]([C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][C:38]2([OH:44])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[C:32]([CH3:45])[CH:31]=1)([C:14]1[CH:19]=[CH:18][C:17]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)=[C:16]([CH3:29])[CH:15]=1)[CH2:12][CH3:13])[CH3:10].O([Si:54]([CH3:57])([CH3:56])[CH3:55])S(C(F)(F)F)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:9]([C:11]([C:14]1[CH:19]=[CH:18][C:17]([B:20]2[O:24][C:23]([CH3:25])([CH3:26])[C:22]([CH3:27])([CH3:28])[O:21]2)=[C:16]([CH3:29])[CH:15]=1)([C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][C:38]2([O:44][Si:54]([CH3:57])([CH3:56])[CH3:55])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[C:32]([CH3:45])[CH:31]=1)[CH2:12][CH3:13])[CH3:10]
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reaction time: 1 h
Yield: 96.3 %

Procedure:
2,6-Lutidine (0.16 g, 1.49 mmol) was added to a solution of 1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenylethynyl)-cyclohexanol (Example 35-(3); 0.15 g, 0.29 mmol) in dichloromethane (1.5 mL). Trimethylsilyl triflate (0.13 mL, 0.71 mmol) was added at 0° C., and the mixture was stirred at the same temperature for one hour. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (3% ethyl acetate/hexane) to give the title compound (0.16 g, 93%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[CH2:29])=[CH:24][N:23]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:29][CH2:28][C:25]3[CH:24]=[N:23][C:22]([CH3:21])=[CH:27][CH:26]=3)[C:6]3[CH2:11][CH2:12][N:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(c1ccccc1)CC3
Reactant: C=Cc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(c2ccccc2)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-8-methyl-2-phenyl-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH:1]1([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([C@:18]2([CH3:24])[CH2:22][O:21]C(=O)[NH:19]2)[CH:12]=[CH:11]3)[CH2:3][CH2:2]1.C(O)C.O.[OH-].[Li+].O>>[NH2:19][C@@:18]([C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[CH:16][CH:17]=[C:8]([O:7][CH:4]3[CH2:5][CH2:6][CH:1]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[CH2:2][CH2:3]3)[CH:9]=2)[CH:14]=1)([CH3:24])[CH2:22][OH:21]
Reactant: C[C@@]1(c2ccc3cc(OC4CCC(C5CCCCC5)CC4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@](N)(CO)c1ccc2cc(OC3CCC(C4CCCCC4)CC3)ccc2c1
Yield: 24.1 %

Procedure:
The compound was prepared in a manner similar as to that described above using (R)-4-[6-(Bicyclohexyl-4-yloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (200 mg, 0.0005 mol), ethanol (2.2 g, 0.049 mol), and 4.2 M lithium hydroxide, monohydrate in water (2.1 mL, 0.0090 mol) to give 46 mg of the desired product as a white solid (46%). ESI-MS: 365 (M-16)+. 1H NMR (400 MHz, CDCl3) δ=7.99-7.55 (m, 3 H), 7.29-7.12 (m, 1 H), 7.08 (s, 2 H), 4.70 (s, 1 H), 4.32-4.17 (m, 1 H), 3.27-2.99 (m, 2 H), 2.32-0.81 (m, 25 H).
Reaction SMILES: [Na].[F:2][CH2:3][CH2:4][OH:5].Br[CH2:7][C:8]1[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:12][CH:13]=1>O1CCCC1.O>[N+:14]([C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH2:7][O:5][CH2:4][CH2:3][F:2])([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: OCCF
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cccc(COCCF)c1
Yield: 17.5 %

Procedure:
Under a dry nitrogen atmosphere 1.1 gram (0.047 mole) of sodium metal was added to a stirred, cold (0° C.) solution of 3.0 grams (0.046 mole) of 2-fluoroethanol in 50 ml of dry tetrahydrofuran. After the sodium had dissolved, the solution was heated at reflux, and a solution of 5.0 grams (0.023 mole) of 3-bromomethylnitrobenzene in 10 ml of dry tetrahydrofuran was added dropwise. This mixture was heated at reflux for 24 hours and then was cooled. The reaction mixture was diluted with water, then was extracted with diethyl ether. The organic extract was washed with an aqueous, saturated, sodium chloride solution. The washed extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure leaving a residue. This residue was purified by column chromatography on silica gel, eluting with n-hexane:diethyl ether (4:1), to yield 0.8 gram of 2-fluoroethyl 3-nitrobenzyl ether as an oil.
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][NH:19][CH2:20][C:21]3[CH:32]=[CH:31][C:24]([O:25][CH2:26][C:27]([O:29]C)=[O:28])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].CCN(C(C)C)C(C)C.[CH:44]1([N:50]=[C:51]=[O:52])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1.C(O)C(N)(CO)CO>C(Cl)Cl>[CH2:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:18][N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:31][CH:32]=3)[C:51]([NH:50][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)=[O:52])=[CH:33][CH:34]=2)=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: O=C=NC1CCCCC1
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)O)cc3)C(=O)NC3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 41.1 %

Procedure:
To a suspension of methyl {4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]-phenoxy}acetate hydrochloride (500 mg, 1.05 mol) in anhydrous DCM (10 ml) was added DIEA (0.2 mL, 1.18 mmol) and cyclohexyl isocyanate (Aldrich, 0.28 mL, 2.20 mmol). The reaction mixture was stirred at rt for 15 hrs. Then PS-trisamine resin (670 mg, Novabiochem, 3.5 mmol/g) was added and the resulting mixture was stirred at rt for 5 additional hrs. The resin was removed by filtration, washed with DCM and the solvent was evaporated off under reduced pressure. Purification by flash chromatography on silicagel (c-Hex/EtOAc (2/1)) gave 500 mg (84%) of the title compound as a pale yellow oil. HPLC, Rt: 5.9 min (purity: 100%). LC/MS, M+(ESI): 567.4. 1H NMR (DMSO-d6) δ: 7.48 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.24 (d, J=8.3 Hz, 2H), 7.20 (d, J=8.3 Hz, 2H), 7.11 (d, J=8.6 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 6.18 (d, J=7.6 Hz, 1H), 4.76 (s, 2H), 4.37 (s, 2H), 4.31 (s, 2H), 3.68 (s, 3H), 3.48 (m, 1H), 2.60 (t, J=7.5 Hz, 2H), 1.75-1.01 (m, 14H), 0.89 (t, J=7.4 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[CH3:24].[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:27]3[CH2:28][CH2:29][O:25][C:26]3=[O:30])=[C:3]([CH3:24])[CH:4]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)c(C)c3)CC2)c(C)c1
Reactant: O=C1NCCO1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)c(C)c3)CC2)c(C)c1
Yield: 33.8 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-3-methylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (775 mg) described in Preparation Example 10 and oxazolidin-2-one (174 mg), the title compound (266 mg) was obtained.
Reaction SMILES: CN(C)C=O.[Br:6][C:7]1[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:10]2[CH:11]=[N:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:14](=[O:15])[C:9]=2[C:8]=1[CH2:33]Br.[CH3:35][C:36]([CH3:39])([O-:38])[CH3:37].[Na+]>O>[Br:6][C:7]1[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:30])[CH3:32])[C:10]2[CH:11]=[N:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:23])[CH3:21])[C:14](=[O:15])[C:9]=2[C:8]=1[CH2:33][O:38][C:36]([CH3:39])([CH3:37])[CH3:35]
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CBr)c(Br)n2COCC[Si](C)(C)C)c1=O
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OCc1c(Br)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Reaction time: 3 h
Yield: 24.5 %

Procedure:
To 50 ml of N,N-dimethylformamide solution containing 2.52 g (4.44 mmol) of 2-bromo-3-bromomethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 25-(a) was added 0.43 g (4.44 mmol) of sodium tert-butoxide at −10° C., and the mixture was stirred at the same temperature for 3 hours. The mixture was further stirred at 0° C. for 10 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with toluene. The organic layer after separation was washed successively with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=98:2→65:35 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 0.61 g of the title compound as a pale yellowish solid. (Yield: 25%)