Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:3].[B-](F)(F)(F)F.CNC.[N+:26]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][C:34]=1[O:35][CH:36]1[CH2:41][CH2:40][CH:39]([C:42]([OH:44])=O)[CH2:38][CH2:37]1)([O-:28])=[O:27].CCN(C(C)C)C(C)C>C1COCC1>[CH3:1][N:2]([CH3:3])[C:42]([CH:39]1[CH2:38][CH2:37][CH:36]([O:35][C:34]2[CH:33]=[CH:32][N:31]=[CH:30][C:29]=2[N+:26]([O-:28])=[O:27])[CH2:41][CH2:40]1)=[O:44]
Reactant: O=C(O)C1CCC(Oc2ccncc2[N+](=O)[O-])CC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)C(=O)C1CCC(Oc2ccncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TBTU (630.0 mg, 1.962 mmol) and dimethylamine (1.784 mL of 2 M, 3.568 mmol) were added to a solution of 4-[(3-nitro-4-pyridyl)oxy]cyclohexanecarboxylic acid (475 mg, 1.784 mmol) and DIPEA (253.6 mg, 341.8 μL, 1.962 mmol) in THF (9.500 mL) and the resulting solution was stirred at RT overnight. The reaction mixture was partitioned between EtOAc and water, and the combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 0-100% EtOAc/petroleum ether using the ISCO column companion system (12 g column) Clean fractions were combined and concentrated in vacuo to yield N,N-dimethyl-4-[(3-nitro-4-pyridyl)oxy]cyclohexanecarboxamide as a pale yellow oil. (180 mg, 34%). MS (ES+) 294.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([N+:18]([O-])=O)[CH:4]=1.[H][H]>CCOC(C)=O.[Pd]>[NH2:18][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COCCOc1cc(C(=O)OC)c([N+](=O)[O-])cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCOc1cc(C(=O)OC)c(N)cc1OC
Yield: 92.6 %

Procedure:
According to the procedure described in Example 6A Step 3, a mixture of methyl 4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzoate (3.67 g, 12.9 mmol) and Pd/C (10%, 0.4 g) in EtOAc (60 mL) was stirred under 1 atmosphere of hydrogen at room temperature overnight, to afford methyl 2-amino-4-methoxy-5-(2-methoxyethoxy)benzoate as a solid (3.05 g, 93%). 1H NMR (300 MHz, DMSO-d6) δ 7.15 (s, 1H), 6.46 (s, 2H), 6.36 (s, 1H), 3.91 (m, 2H), 3.75 (s, 3H), 3.74 (s, 3H), 3.59 (m. 2H), 3.32 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:25][CH3:26])[C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)(=[O:18])=[O:17])[CH:11]=2)=[N:6][CH:7]=1.[C:27]1([SH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:26][O:25][C:4]1[C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)(=[O:18])=[O:17])[CH:11]=2)=[N:6][CH:7]=[C:2]([S:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:3]=1
Reactant: Sc1ccccc1
Reactant: COc1cc(Br)cnc1NC(=O)c1cccc(S(=O)(=O)N2CCCC2)c1
Product: COc1cc(Sc2ccccc2)cnc1NC(=O)c1cccc(S(=O)(=O)N2CCCC2)c1

Procedure:
The entitled compound was produced according to the method of Reference Example 8 (step 1) but using the compound obtained in Example 109 (step 1) and benzenethiol as the starting materials.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:18])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[CH2:29][CH:30]=O>>[CH3:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[CH2:29][CH2:30][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:13](=[O:18])[CH2:14]1
Reactant: Cc1cc([N+](=O)[O-])ccc1CC=O
Reactant: O=C1CNCCN1CCc1ccc([N+](=O)[O-])cc1
Product: Cc1cc([N+](=O)[O-])ccc1CCN1CCN(CCc2ccc([N+](=O)[O-])cc2)C(=O)C1

Procedure:
The title compound was prepared from 1-[2-(4-Nitrophenyl)ethyl]piperazin-2-one and (2-Methyl-4-nitrophenyl)acetaldehyde following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 413 [M+1]+.
Reaction SMILES: O=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][CH:5]=[CH:4][C:3]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH:6]1[C:7]2[CH:3]([CH2:2][CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1
Reactant: O=C1CCCc2[nH]ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C1=CCC2CCNC2=C1
Temperature: 77.5 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
4-oxo-4,5,6,7-tetrahydroindole 5.15 g (38.1 mmol) was gradually added to a stirred slurry of lithium aluminum hydride 4.0 g in anhydrous THF 0.45 L with cooling on ambient water bath, portion-wise, over 30 min period. The mixture was then placed on oil bath and refluxed under Ar on a 75-80° C. oil bath for 26 hours. The reaction mixture was cooled on ambient water bath, quenched by sequential addition of ethyl acetate 4 mL followed by dropwise water addition, 4 mL (very slowly, gas evolution), followed by 15% wt NaOH solution 12 mL followed by additional water 4 mL. The resulting slurry was stirred vigorously for 30 min, the salts were removed by filtration (the cake was washed thoroughly with THF) and the filtrates were concentrated on a rotovap. The oily residue was distilled on highvac using a short-path distillation apparatus, to provide 3.83 g (84%) of tetrahydroindole as oily liquid that turns yellow on light and air exposure, by 57-60° C./0.7 Torr.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C.O>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 76.4 %

Procedure:
1-(tert-Butoxycarbonyl)-4-hydroxypiperidine (4.81 g) was dissolved in pyridine (48 ml), added with p-toluenesulfonyl chloride (9.0 g) and triethylamine (6.7 ml) and stirred at room temperature for 17 hours. The reaction mixture was added with cold water (500 ml) and stirred for 2 hours, and then the produced crystals were collected by filtration. These crystals were purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=3:1) to obtain 6.49 g of the title compound. Yield: 76%.
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:25]=[C:26]3[CH2:37][CH2:36][NH:35][CH2:34][C:27]3=[N:28][C:29]=2[NH:30][CH:31]([CH3:33])[CH3:32])[CH2:20][CH2:19]1)[C:12]#[N:13].N1C=CC=CC=1.C(OC(=O)C)(=O)C>C(Cl)Cl>[C:2]([N:35]1[CH2:36][CH2:37][C:26]2[C:27](=[N:28][C:29]([NH:30][CH:31]([CH3:33])[CH3:32])=[C:24]([N:21]3[CH2:20][CH2:19][CH:18]([O:17][C:16]4[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=4[F:8])[CH2:23][CH2:22]3)[N:25]=2)[CH2:34]1)(=[O:1])[CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CCNC2
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCc2nc(N3CCC(Oc4ccc(C#N)cc4F)CC3)c(NC(C)C)nc2C1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-fluoro-4-((1-(3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)oxy)benzonitrile TFA salt (33.5 mg, 0.064 mmol) in DCM (639 μL) at 0° C. was added pyridine (15.5 μL, 0.192 mmol), followed by acetic anhydride (12.0 μL, 0.128 mmol). The reaction was allowed to stir for 45 min, gradually warming to room temperature. The reaction was concentrated under reduced pressure and purified directly by HPLC Method B, with the exception that a Waters SunFire™ C18, 5 nm, ID 30×75 mm column was used, using a 40% to 70% ACN gradient to give the title compound, as a TFA salt, as a yellow solid (7.1 mg, 20%). 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.31 (m, 6H), 2.02 (m, 2H), 2.20 (m, 5H), 2.74 (t, J=5.9 Hz, 0.7H), 2.85 (m, 1.3H), 3.14 (m, 2H), 3.43 (m, 2H), 3.83 (t, J=5.9 Hz, 1.3H), 3.87 (t, J=5.9 Hz, 0.7H), 4.14 (m, 1H), 4.60 (s, 0.7H), 4.64 (s, 1.3H), 4.80 (m, 1H), 7.34 (m, 1H), 7.54 (m, 2H); ESI-MS m/z [M+H]+ 453.5.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][NH:6][S:7]([CH3:10])(=[O:9])=[O:8].[OH:14][C:15]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[C:24]([CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[C:16]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[OH:14][C:15]1[C:27]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:25]=[C:24]([CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:13]=[CH:12][CH:11]=[C:4]([CH2:5][NH:6][S:7]([CH3:10])(=[O:9])=[O:8])[CH:3]=3)=[CH:36][CH:35]=2)[C:16]=1[C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18]
Reactant: CS(=O)(=O)NCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)c1c(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)ccc(C(F)(F)F)c1O
Product: CC(C)(C)OC(=O)c1c(COc2ccc(-c3cccc(CNS(C)(=O)=O)c3)cc2)ccc(C(F)(F)F)c1O

Procedure:
According to a method similar to Example (31), from N-(3-bromobenzyl)methanesulfonamide (119 mg, 0.45 mmol) and tert-butyl 2-hydroxy-6-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}-3-(trifluoromethyl)benzoate (250 mg, 0.51 mmol) obtained in Example (22-4), the title compound was obtained as a pale brown powder (49 mg, yield: 20%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:9]#[N:10])[CH2:8][CH2:7]1.B.[ClH:12]>O1CCCC1>[ClH:12].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([CH2:9][NH2:10])[CH2:8][CH2:7]1
Reactant: N#CC1(c2cccs2)CC1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: NCC1(c2cccs2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(thiophen-2-yl)cyclopropanecarbonitrile (14.9 g) in tetrahydrofuran (100 mL) was added 1.1M borane.tetrahydrofuran complex (100 mL) at room temperature, and the mixture was stirred at 60° C. overnight. 6M Aqueous hydrochloric acid solution (20 mL) was carefully added to the reaction mixture, and the mixture was stirred at 60° C. for 0.5 hr. The reaction mixture was allowed to cool to room temperature, and tetrahydrofuran was evaporated under reduced pressure. The obtained residue was diluted with water, and washed with ethyl acetate. The aqueous layer was basified with 8M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethyl acetate, 4M hydrochloric acid/ethyl acetate solution (30 mL) was added, and the solvent was evaporated under reduced pressure. The obtained solid was recrystallized from ethanol-ethyl acetate to give the title compound (10.5 g) as white needle crystals.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=1.[Li+].[CH3:11][Si]([N-][Si](C)(C)C)(C)C.CI.O>CN(C=O)C>[CH3:11][N:8]1[C:7](=[O:9])[CH:6]=[CH:5][N:4]=[C:3]1[S:2][CH3:1]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CSc1nccc(=O)[nH]1
Agent: [Li+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nccc(=O)n1C
Temperature: 0 °C

Procedure:
2-Methylthio-3H-pyrimidin-4-one (Step 1, 6.29 g, 44.2 mmol) was suspended in DMF (100 mL), cooled to 0° C., and additional DMF (50 mL) was added. Solid LiHMDS (9.58 g, 57.3 mmol) was added in one portion, and the reaction was stirred at 0° C. MeI (3.6 mL, 57.8 mmol) was added via syringe, and the reaction was warmed to RT and stirred for 20.75 h. At this time, the mixture was poured into 300 mL H2O and extracted exhaustively with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered, concentrated, and purified on silica gel (3:1→3:2→1:1 hexanes/EtOAc) to give the title compound. MS (ESI pos. ion) m/z: 157. Calc'd for C6H8N2OS: 156.04.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]1([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[N:12]1([C:6]2[CH:11]=[CH:10][C:9]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:8][CH:7]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc(-n2ccnc2)cc1
Product: O=S(=O)(Cl)c1ccc(-n2ccnc2)cc1

Procedure:
To chlorosulfonic acid cooled to 0° C. in an ice bath is added portionwise 1-phenyl-1H-imidazole. Monitor the progress of the reaction by thin-layer chromatography. When the reaction is complete, quench the mixture on ice. Saturated aqueous NaHCO3 is added until the solution is no longer acidic. Extract the mixture with CH2Cl2. Dry the organic layer over anhydrous Na2SO4 and remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15][CH3:16])[C:9]=3[C:8]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH3:30]>CN(C=O)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15][CH3:16])[C:9]=3[C:8]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH:26][CH3:30])(=[O:24])=[O:25])=[CH:19][CH:18]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CI
Reactant: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccc(-c2nn(C3CCCC3)c3ccnc(OC)c23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (50.0 mg) obtained in Step A of Example 92 in DMF (3 ml) was added sodium hydride (60% dispersion in mineral oil, 5.91 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added iodomethane (0.0126 ml), and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (10.9 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CCO.C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:21]2[CH2:22][C:23]([CH3:30])([CH3:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH2:26]2)[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(CCC(=O)O)cc2)CC(C)(C)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 3-{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}propanoate (169) (0.20 g, 0.49 mmol) in a mixture of EtOH (6 mL) and THF (6 mL) was added an aqueous solution of 1 N NaOH (7 mL). The mixture was stirred at 60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 1 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract was washed with brine and dried over Na2SO4. Upon concentration and trituration with hot hexanes (contained 1% methanol), the title compound 170 was obtained as white solid (0.177 g, 92%). mp 243-244° C. 1H NMR (400 MHz, CD3OD): δ 0.91 (s, 6H), 0.92 (s, 6H), 1.29 (s, 2H), 1.95 (s, 2H), 1.98 (s, 2H), 2.58 (t, J=7.7 Hz, 2H), 2.87 (t, J=7.7 Hz, 2H), 6.67 (d, J=8.5 Hz, 2H), 6.94 (d, J=8.5 Hz, 2H), 7.05 (d, J=8.1 Hz, 2H), 7.12 (d, J=8.1 Hz, 2H). LCMS (ESI): m/z 393 (M+H)+, m/z 391 (M−H)−.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[C:14]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][C:37]([O:39][CH2:40][CH:41]=[CH2:42])=[O:38])=[C:32]([F:43])[CH:31]=3)=[CH:26][CH:25]=2)[C:6]=1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:2]=[CH2:3].C(O[CH:49](OC(C)(C)C)[N:50]([CH3:52])[CH3:51])(C)(C)C.O>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]1[C:17]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:15]=[C:14]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([C:37]([O:39][CH2:40][CH:41]=[CH2:42])=[O:38])=[CH:49][N:50]([CH3:52])[CH3:51])=[C:32]([F:43])[CH:31]=3)=[CH:26][CH:25]=2)[C:6]=1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OCC=C)c3C(=O)OC(C)(C)C)cc2)cc1F
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCOC(=O)C(=CN(C)C)c1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OCC=C)c3C(=O)OC(C)(C)C)cc2)cc1F
Yield: 65.2 %

Procedure:
tert-Butyl 2-(allyloxy)-6-{[(4′-{[(allyloxy)carbonyl]methyl}-3′-fluoro-1,1′-biphenyl-4-yl)oxy]methyl}-3-(trifluoromethyl)benzoate (200 mg, 0.33 mmol) obtained in Example (11-6) was dissolved in toluene (3 ml) and N,N-dimethylformamide di-tert-butyl acetal (0.4 ml, 1.7 mmol) was added thereto, and the mixture was heated under reflux for 3 hours. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate (three times), the organic layer was successively washed with water (twice) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=10/1-1/1) to give tert-butyl 2-(allyloxy)-6-{[(4′-{1-[(allyloxy)carbonyl]-2-(dimethylamino)vinyl}-3′-fluoro-1,1′-biphenyl-4-yl)oxy]methyl}-3-(trifluoromethyl)benzoate (141 mg, yield: 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[NH:16][C:17]1[N:22]=[CH:21][C:20]2=[CH:23][CH:24]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[N:19]2[N:18]=1.[CH2:38]1[O:41][C@H:39]1[CH3:40]>CO>[OH:41][C@@H:39]([CH3:40])[CH2:38][N:13]1[CH2:14][CH2:15][N:10]([CH2:9][C:7]2[CH:6]=[CH:5][C:4]([NH:16][C:17]3[N:22]=[CH:21][C:20]4=[CH:23][CH:24]=[C:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[N:19]4[N:18]=3)=[C:3]([O:2][CH3:1])[CH:8]=2)[CH2:11][CH2:12]1
Reactant: C[C@H]1CO1
Reactant: COc1cc(CN2CCNCC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Solvent: CO
Product: COc1cc(CN2CCN(C[C@H](C)O)CC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 25 °C
Yield: 17.2 %

Procedure:
Into a 8-dram vial, N-{2-[2-(2-Methoxy-4-piperazin-1-ylmethyl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methanesulfonamide (70 mg, 0.1 mmol), Methanol (5 mL) and (S)-(−)-Propylene Oxide (0.00818 g, 0.141 mmol) were added. The reaction was stirred at room temperature over the weekend. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give N-[2-(2-{4-[4-((S)-2-Hydroxy-propyl)-piperazin-1-ylmethyl]-2-methoxy-phenylamino}-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide as a yellow solid (10 mg, 11%). LCMS (E/I+) 580.13 (M+H). NMR 1H (DMSO-d6)-8.99 (s, 1H), 8.05 (d, 1H, J=7.67 Hz), 7.96-8.01 (m, 1H), 7.80 (s, 1H), 7.64-7.69 (m, 1H), 7.52-7.58 (m, 2H), 7.80 (bs, 1H), 7.03 (d, 1H, J=4.69 Hz), 7.00 (d, 1H, J=4.69 Hz), 6.87 (bd, 1H, J=7.39 Hz), 4.00 (bs, 2H), 3.88 (s, 3H), 2.50-3.70 (bm, 17H), 1.05 (bs, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1.Br[CH2:31][CH2:32][CH3:33]>>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH2:31][CH2:32][CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH:16]=3)=[CH:13][CH:14]=2)[S:3]1
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Reactant: CCCBr
Product: CCCN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)OC(C)(C)C
Yield: 78 %

Procedure:
In a manner similar to that of Example 17(d), starting with 700 mg (1.7 mmol) of tert-butyl [4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-ylmethyl]carbamate and 350 μl (3.8 mmol) of 1-bromopropane, 600 mg (78%) of the desired product are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:8][C:9]([CH:11]2[CH2:16][CH2:15][N:14](C(OCC3C=CC=CC=3)=O)[CH2:13][CH2:12]2)=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[C:3]([NH:8][C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1NC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cccnc1NC(=O)C1CCNCC1

Procedure:
Benzyl 4-{[(3-methyl-2-pyridinyl)amino]carbonyl}-1-piperidinecarboxylate from Step 1 above (5.45 g, 15.42 mmol) was suspended in absolute ethanol (250 mL) and was treated with 10% palladium on carbon (1.50 g) and stirred vigorously for 18 h under 1 atm of hydrogen. The catalyst was filtered off and the filtrate was concentrated under reduced pressure giving the piperidine-4-carboxylic acid (3-methyl-pyridin-2-yl)-amide as yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:10]=1)=[N:7][O:8][N:9]=2.C(OC(=O)[N:17]([C:21]1[CH:26]=[CH:25][C:24](Br)=[C:23]([O:28][CH3:29])[CH:22]=1)[CH2:18][CH2:19][F:20])(C)(C)C>>[N:9]1[O:8][N:7]=[C:6]2[CH:10]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([NH:17][CH2:18][CH2:19][F:20])=[CH:22][C:23]=3[O:28][CH3:29])[CH:3]=[CH:4][C:5]=12
Reactant: Brc1ccc2nonc2c1
Reactant: COc1cc(N(CCF)C(=O)OC(C)(C)C)ccc1Br
Product: COc1cc(NCCF)ccc1-c1ccc2nonc2c1

Procedure:
The starting compound is obtained according to the procedure described in Example 7 from 5-bromo-benzo[1,2,5]oxadiazole and (4-bromo-3-methoxy-phenyl)-(2-fluoro-ethyl)-carbamic acid tert-butyl ester, as a yellow glass. MS(ES+): 410 (M+23).
Reaction SMILES: Br.Br[CH2:3][CH2:4][NH:5][CH:6]([CH3:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1C2C(CCCC2)CCC1>[CH3:13][CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:3][CH2:4][NH:5]1
Reactant: CC(NCCBr)c1ccccc1
Agent: Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCC2CCCCC2C1
Product: CC1NCCc2ccccc21
Temperature: 150 °C
Reaction time: 0.67 h
Yield: 82.8 %

Procedure:
200 g (647.17 mmole) of N-(2-bromoethyl)-α-methylbenzylamine hydrobromide produced in Example 5(2) or Example 6(1) above was suspended in 700 ml of decalin and then heated to 150° C. 261.5 g (1961 mmole) of anhydrous aluminum chloride was added thereto over 40 minutes. The reaction solution was stirred for s further 30 minutes at constant temperature and then cooled to room temperature. The supernatant was removed and the lower layer was poured onto 3500 g of ice-water with stirring. 210 ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 2500 ml of ethyl acetate, and then the aqueous layer was separated, adjusted to pH 12 with sodium hydroxide, and then extracted three times, each time with 3000 ml of ethyl acetate. The extracts were combined, washed with 550 ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 78.9 g of the title compound.