Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:28][C:27]3[CH:30]=[CH:31][CH:32]=[C:25]([C:24]([F:23])([F:33])[F:34])[CH:26]=3)[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2n1Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (355 mg) in DMF (5 mL) was added potassium carbonate powder (548 mg) and 3-trifluoromethylbenzyl bromide (947 mg). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes) to yield the title compound as an orange solid.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10]C(C#N)=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+].O.[C:18]([OH:21])(=[O:20])[CH3:19]>>[CH:1]([C:4]1[CH:11]=[CH:10][C:19]([C:18]([OH:21])=[O:20])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C#N)c([N+](=O)[O-])c1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Yield: 73 %

Procedure:
The product of Example 431B (1.746 g, 9.1798 mmol) dissolved in a 2:1:1 v/v/v mixture of water/acetic acid/concentrated sulfuric acid (24 mL) was heated at reflux for 3 days. The reaction was cooled, poured onto ice water (80 mL) and adjusted to pH12 with 6N aqueous sodium hydroxide. The reaction was washed with ethyl ether (3×50 mL). The aqueous phase was acidified to pH 2 with concentrated hydrochloric acid and extracted with ethyl ether (2×75 mL). The ethereal extracts were dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. The residue was co-concentrated with methylene chloride (5 mL)/hexanes (100 mL) three times and dried on high vacuum to afford the title compound as an off-white solid (1.402 g, 6.702 mmol, 73%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.23 (d, J=6.62 Hz, 6 H) 2.88-3.23 (m, 1 H) 7.66 (dd, J=8.09, 1.84 Hz, 1 H) 7.80 (d, J=7.72 Hz, 1 H) 7.83 (d, J=1.47 Hz, 1 H) 13.70 (br s, 1 H).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C@:8]([NH:18][C:19]([C:21]1[N:25]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH2:31][C:32]3[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=3[F:39])[C:24]2=[N:23][C:22]=1[CH3:40])=[O:20])([C:10]1[N:11]=[N:12][N:13]([CH:15]([F:17])[F:16])[N:14]=1)[CH3:9])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O.C(OC(C)C)(C)C>C1COCC1.C(OCC)(=O)C>[F:39][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:32]=1[CH2:31][O:30][C:29]1[C:24]2[N:25]([C:21]([C:19]([NH:18][C@@:8]([C:10]3[N:11]=[N:12][N:13]([CH:15]([F:17])[F:16])[N:14]=3)([CH3:9])[CH2:7][OH:6])=[O:20])=[C:22]([CH3:40])[N:23]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)N[C@@](C)(CO[Si](C)(C)C(C)(C)C)c1nnn(C(F)F)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)N[C@@](C)(CO)c1nnn(C(F)F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
To a solution of 463 mg of N-{(2R)-1-{[tert-butyl (dimethyl)silyl]oxy}-2-[2-(difluoromethyl)-2H-tetrazol-5-yl]propan-2-yl}-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide in 8 ml of THF was added 1 ml of a 1 M tetrabutylammonium fluoride/THF solution, followed by stirring at room temperature for 2 hours. To the reaction mixture was added water, followed by extraction with chloroform. The organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography. To the obtained crude product was added ethyl acetate, and diisopropyl ether was further added thereto. The mixture was stirred for 1 hour in an oil bath at 85° C., left to be cooled to room temperature, and stirred overnight. The insoluble materials were collected by filtration and the solid was washed with diisopropyl ether to obtain 260 mg of 8-[(2,6-difluorobenzyl)oxy]-N-{(2R)-2-[2-(difluoromethyl)-2H-tetrazol-5-yl]-1-hydroxypropan-2-yl}-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:17]N(C=O)C.[H-].[Na+].CI>O>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[N:6]([CH3:17])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc2c(C(C)=O)c[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COC(=O)c1ccc2c(C(C)=O)cn(C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of methyl 3-acetyl-1H-indole-6-carboxylate (0.92 g) and DMF (18 ml) was added sodium hydride (0.18 g) under ice-cooling, followed by stirring at room temperature for 0.5 hour. Next, methyl iodide (0.29 ml) was added thereto under ice-cooling, followed by stirring at room temperature for 5 hours. Then, water was added thereto under ice-cooling, followed by stirring at room temperature. The solid precipitated was collected by filtration, washed with water, and purified by silica gel column chromatography (hexane/THF=2:1→chloroform /THF=9:1) to obtain methyl 3-acetyl-1-methyl-1H-indole-6-carboxylate (0.98 g).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:18][C:17]3[CH:19]=[C:20]([C:23]4[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=4)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:30][CH3:31])=[CH:7][CH:8]=2)[N:3]=1.Br[C:33]1C=CC(N)=N[CH:38]=1.ClC1C2C(=CC(OC)=CC=2)N=C(C)N=1>>[CH3:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:18][C:17]3[CH:19]=[C:20]([C:23]4[CH:24]=[C:25]5[CH:38]=[CH:33][NH:29][C:26]5=[N:27][CH:28]=4)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:30][CH3:31])=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc2c(N3CCOc4ccc(-c5ccc(N)nc5)cc4C3)nc(C)nc2c1
Reactant: Nc1ccc(Br)cn1
Agent: COc1ccc2c(Cl)nc(C)nc2c1
Product: COc1ccc2c(N3CCOc4ccc(-c5cnc6[nH]ccc6c5)cc4C3)nc(C)nc2c1

Procedure:
(5-{4-[2-methyl-7-(methyloxy)quinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}pyridin-2-amine. Synthesized according to the method of example 3 using 5-bromo-2-aminopyridine in step 1 and 4-chloro-7-methoxy-2-methylquinazoline in step 3. 1H NMR (400 MHz, DMSO-d6): 11.9 (s, 1H, AcOH), 8.21 (d, 1H), 7.87 (d, 1H), 7.67 (dd, 1H), 7.55 (m, 1H), 7.38 (dd, 1H), 7.10 (d, 1H), 7.02 (dd, 1H), 6.96 (d, 1H), 6.52 (d, 1H), 6.03 (s, 2H), 4.96 (s, 2H), 4.38 (m, 2H), 4.13 (m, 2H), 3.87 (s, 3H), 2.42 (s, 3H), 1.90 (s, 3H, AcOH); MS (EI) for C24H23N5O2: 413.9 (MH+).
Reaction SMILES: [C:1]([CH2:4][C@H:5]1[CH2:17][C:16]2[C:15]3[C:14]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH2:20]4)=[N:13][CH:12]=[N:11][C:10]=3[S:9][C:8]=2[CH2:7][CH2:6]1)(=[O:3])[NH2:2].[ClH:33]>ClCCl>[ClH:33].[NH2:25][CH:22]1[CH2:23][CH2:24][CH:19]([O:18][C:14]2[C:15]3[C:16]4[CH2:17][C@H:5]([CH2:4][C:1]([NH2:2])=[O:3])[CH2:6][CH2:7][C:8]=4[S:9][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)C[C@H](CC(N)=O)CC4)CC1
Agent: Cl
Solvent: ClCCl
Product: NC(=O)C[C@@H]1CCc2sc3ncnc(OC4CCC(N)CC4)c3c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl N-(4-[[(12R)-12-(carbamoylmethyl)-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate (72 mg, 0.16 mmol, 1.00 equiv) in 5 mL of dichloromethane (5 mL) was added 6 M aqueous hydrochloric acid (0.5 mL) at 0° C. and the resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum to give 62 mg (crude) of 2-[(12R)-3-[(4-aminocyclohexyl)oxy]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]acetamide hydrochloride as a yellow solid. The crude hydrochloride in 4 mL of MeOH was added HCHO (37%, 1 mL) and 0.5 mL of HOAc at room temperature. Then NaCNBH3 (31 mg, 0.49 mmol, 2.54 equiv) was added and the resulting solution was stirred for 4 h at ambient temperature. The resulting mixture was filtered through a thin silica column and further purified by preparative HPLC under the following conditions (Waters): column: Xbridge Prep C18 5 um, 19*150 mm; mobile phase: water with 0.05% NH4HCO3 and CH3CN (5.0% CH3CN up to 41.0% in 9 min, up to 95.0% in 2 min, down to 5.0% in 2 min); flow rate: 20 mL/min; UV detection at 220/254 nm. The product-containing fractions were collected and evaporated under reduced pressure to give the desired 2-[(12R)-3-[[4-(dimethylamino)cyclohexyl]oxy]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]acetamide (13.8 mg) as a white solid. MS: 389 (M+H)+. 1H NMR (300 MHz, CDCl3): δ 8.51 (s, 1H), 5.46-5.40 (m, 1H), 5.24-5.21 (m, 1H), 3.30-3.24 (m, 1H), 2.91 (m, 2H), 2.62-2.59 (m, 1H), 2.56-2.32 (m, 11H), 2.15-2.11 (m, 1H), 2.02-2.00 (m, 3H), 1.74-1.49 (m, 6H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>ClCCl>[CH3:1][N:2]([CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:32](=[O:34])[CH3:33]
Reactant: CNCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(C)CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reaction time: 8 h
Yield: 38.3 %

Procedure:
To a stirred solution of methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}amine (200 mg, 0.60 mmol) and triethylamine (102 μL, 0.72 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere was added dropwise a solution of acetyl chloride (52 μL, 0.72 mmol) in anhydrous dichloromethane (2 mL). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with water then dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with DCM:MeOH (95:5 to 90:10) to give the title compound (86 mg, 36%). 1H NMR (400 MHz, CDCl3) δ Shows rotomers 7.19-7.13 (2d, 2H), 6.91-6.88 (d, 2H), 4.05-4.02 (m, 2H), 3.85-3.80 (m, 2H), 3.56-3.45 (m, 4H), 2.67-2.65 (m, 2H), 2.60-2.56 (m, 4H), 2.32-1.96 (several multiplets, 12H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].C([Li])CCC.[CH2:16]([Mg]Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]#[N:10]
Reactant: Br[Mg]Cc1ccccc1
Reactant: N#CCc1ccccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#CC(Cc1ccccc1)c1ccccc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
A solution of 2-(2-fluorophenyl)acetonitrile (2.1 g, 15.5 mol) in tetrahydrofuran (50 ml) and hexane (20 ml) was treated with n-butyl lithium (6.2 ml, 15.5 mol) at −78° C. The mixture was stirred at −78° C. for one hour. A solution of benzyl magnesium bromide (2.02 ml, 17.05 mmol) in hexane (10 ml) was added at −78° C. The mixture was stirred at −78° C. for two hours, then warmed to room temperature and stirred at room temperature overnight. The mixture was quenched with water and extracted in ether. The combined organic layers were washed with brine, dried with magnesium sulfate then filtered and evaporated. Purification by MPLC with 3 to 5% MeOH:CH2Cl2 afforded 2-(2-fluorophenyl)-3-phenylpropanenitrile, (Intermediate 11), (3.4 g).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:24]([NH:32][NH2:33])[N:23]=[C:22]([S:34][CH3:35])[N:21]=2)=[CH:16][CH:15]=1>C1COCC1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:34][CH3:35])[N:23]3[C:2](=[O:4])[NH:33][N:32]=[C:24]3[C:25]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:16][CH:15]=1
Reactant: CSc1nc(NN)c(-c2ccccc2)c(-c2ccc(Cl)cc2)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CSc1nc(-c2ccc(Cl)cc2)c(-c2ccccc2)c2n[nH]c(=O)n12
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a stirred solution of triphosgene (2.08 g, 7.04 mmol) in THF (10 mL) at room temperature under argon was added a suspension of 4-(4-chlorophenyl)-6-hydrazinyl-2-(methylthio)-5-phenylpyrimidine (3.52 mmol) in THF (5 mL). The reaction mixture was stirred overnight. Analysis by HPLC/MS indicated that no starting material remained. The reaction mixture was cooled to 0° C. in an ice bath and ice water (50 mL) was added. After stirring for 30 min, the solid precipitate was collected and further washed with water (50 mL). After drying, the title compound (1.25 g) was obtained as an off-white solid. HPLC/MS: retention time=3.51 min, [M+H]30 =369.
Reaction SMILES: [CH:1]12[CH2:24][CH2:23][CH:4]([C:5]([C:7]3[N:12]=[C:11]4[N:13]([CH3:22])[C:14](=[O:21])[N:15]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:10]4=[CH:9][CH:8]=3)=[CH:6]1)[CH2:3][NH:2]2.CCN(C(C)C)C(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:18][C:17]([CH3:19])([CH3:20])[CH2:16][N:15]1[C:10]2[C:11](=[N:12][C:7]([C:5]3[CH:4]4[CH2:23][CH2:24][CH:1]([CH:6]=3)[N:2]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:3]4)=[CH:8][CH:9]=2)[N:13]([CH3:22])[C:14]1=[O:21]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CCC3CN4)nc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CCC3CN4S(C)(=O)=O)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-(2-Azabicyclo[2.2.2]oct-5-en-5-yl)-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2-5, 25 mg, 0.08 mmol, 1.0 equiv) was added to anhydrous DCM (0.80 mL). To this solution was added DIPEA (40 μL, 0.23 mmol, 3.0 equiv) and methanesulfonyl chloride (12 μL, 0.15 mmol, 2.0 equiv) and the resulting mixture was allowed to stir at room temperature for 10 min. Following this duration, LCMS showed consumption of starting material. Saturated NaHCO3 (3 mL) and ethyl acetate (3 mL) were then added and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (3×3 mL) and the combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give a yellow oil. Purification by reverse-phase HPLC (10-100% CH3CN:0.1% TFA in H2O) afforded 4-1 as a white solid. MS m/z (M+H): calculated=405.1955; observed=405.1952.
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(=O)C2C(C3C(C=2)=CC=CC=3)=CC=C1.[NH2:29][C:30]1[N:31]=[C:32]([NH2:41])[C:33]2[CH:39]=[C:38](N)[CH:37]=[N:36][C:34]=2[N:35]=1.CCN(CC)CC>>[NH2:29][C:30]1[N:31]=[C:32]([NH2:41])[C:33]2[CH:39]=[C:38]([NH:14][CH:1]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:7]4[C:2]3=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:37]=[N:36][C:34]=2[N:35]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: Nc1cnc2nc(N)nc(N)c2c1
Agent: O=C1C=CC=C2C1=Cc1ccccc12
Solvent: CCN(CC)CC
Product: Nc1nc(N)c2cc(NC3c4ccccc4-c4ccccc43)cnc2n1

Procedure:
9-[N-(2,4-Diaminopyrido[2,3-d]pyrimidin-6-yl)amino]fluorene (Formula I: Ar=2,4-diaminopyrido[2,3-d]pyrimidin-6-yl; W=NH; X=CH; Z=chemical bond; m=n=0) is prepared similarly to N-(2,4-diaminopyrido[2,3-d]pyrimidin-6-yl)amino]benzhydrylamine as disclosed above by using fluorenone (360 mg, 2.0 mmol), 2,4,6-triaminopyrido[2,3-d]pyrimidine (350 mmol), mg, 2.0 mmol), and BH3.Et3N (75 mg, 6.6 mmol). The product can be purified by chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]2([CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14]2)[C:12](=[O:20])[N:11]([CH2:21][C:22]([OH:24])=O)[C@H:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:55][C:56]1[CH:57]=[C:58]2[C:71](=[CH:72][CH:73]=1)[CH2:70][C@@:60]1([C:68]3[C:63](=[N:64][CH:65]=[CH:66][CH:67]=3)[NH:62][C:61]1=[O:69])[CH2:59]2>CN(C=O)C>[O:20]=[C:12]1[C:13]2([CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14]2)[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][C@@H:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:11]1[CH2:21][C:22](=[O:24])[NH:55][C:56]1[CH:57]=[C:58]2[C:71](=[CH:72][CH:73]=1)[CH2:70][C@:60]1([C:68]3[C:63](=[N:64][CH:65]=[CH:66][CH:67]=3)[NH:62][C:61]1=[O:69])[CH2:59]2
Reactant: Nc1ccc2c(c1)C[C@]1(C2)C(=O)Nc2ncccc21
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2ccccc2)N(CC(=O)O)C(=O)C12COCCOC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](c2ccccc2)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C(=O)C12COCCOC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.21 g (0.5 mmol) (R)-2-(1-(tert-butoxycarbonyl)-5-oxo-3-phenyl-8,11-dioxa-1,4-diaza-spiro[5.6]dodecan-4-yl)ethanoic acid in 3 ml DMF were combined with 0.38 g (1 mmol) HATU and 0.18 ml (1.3 mmol) TEA and stirred for 10 min at RT. Then 0.13 mg (0.5 mmol) (S)-5-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one were added and the mixture was stirred overnight at RT. The reaction mixture was poured onto ice water. The precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: [S:1]([N:11]1[CH2:17][CH2:16][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][C:13]2[CH:26]=[CH:27][CH:28]=[CH:29][C:12]1=2)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[H][H]>CO.[Pd]>[S:1]([N:11]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:14][C:13]2[CH:26]=[CH:27][CH:28]=[CH:29][C:12]1=2)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)=Cc3ccccc32)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)Cc3ccccc32)cc1
Yield: 840.3 %

Procedure:
To a solution of tert-butyl 1-tosyl-2,3-dihydro-1H-benzo[b]azepin-4-ylcarbamate (4.5 g, 0.001 mol) in methanol (120 mL), 10% palladium on carbon (0.5 g) was added. The reaction mixture was stirred under 1 atmosphere of hydrogen for 4 days. The reaction mixture was filtered and concentrated to dryness to give a residue which was purified by silica gel column chromatography eluting with (0-10% ethyl actetae in hexane) to afford tert-butyl 1-tosyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-4-ylcarbamate (3.5 g). 1H NMR: (400 MHz, CDCl3) δ: 7.54 (d, 1H), 7.40 (d, 2H), 7.18-7.08 (m, 4H), 7.06 (d, 1H), 6.38 (s, 1H), 5.65 (s, 1H), 3.86-3.82 (m, 2H), 2.78-2.74 (m, 2H), 2.18 (bs, 3H), 1.44 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[CH:13]2[CH2:16][CH2:17][CH2:18][C:12]2=[N:11][C:10]2[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)C>[CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[NH:11][C:10]2[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C2CCCC2=Nc2ccc(F)cc2N1Cc1ccccc1
Solvent: CCOCC
Product: O=C1[C@H]2CCC[C@H]2Nc2ccc(F)cc2N1Cc1ccccc1
Yield: 94 %

Procedure:
Employing 9-benzyl-7-fluoro-2,3,9,10a-tetrahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one, the titled compound was synthesized by substantially the same procedure as in Reference Example 15. Yield 94%. m.p.124°-126° C. (diethyl ether).
Reaction SMILES: [C:1]([NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([NH:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=O>O>[CH2:14]1[CH2:13][CH2:12][CH:11]([N:10]=[C:1]=[N:3][CH:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:16][CH2:15]1
Reactant: O=C(NC1CCCCC1)NC1CCCCC1
Solvent: O
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
The reaction is conducted at a temperature between -20° C. and 30° C. for 30 minutes to 5 hours. If necessary, it is further continued for 2 hours-20 hours at room temperature. If it is difficult to add the gaseous or liquid amine in an accurately equimolar amount based on the compound (II), the compound (II) and DCC are, in advance, reacted with each other in the aforesaid solvent, followed by adding thereto the amine to obtain the desired compound (I) in good yield. When the reactants are carried out in this order, an aqueous amine solution can be used and, when the used solvent is water-immiscible, it is desirable to stir the mixture as vigorously as possible. After completion of the reaction, dicyclohexylurea (hereinafter referred to as DCU) produced from DCC as by-product can be removed by filtration owing to its poor solubility in the aforesaid solvent. When DCU is not safficiently recovered, the solvent used is once distilled off from the reaction solution to replace it by another poorer solvent for DCU such as methylene chloride or ethyl acetate. Then the remaining DCU is more sufficiently recovered by filtration. And, in the case of using carbonyldiimidazole (hereinafter referred to as CDI) as a coupling agent in place of DCC, the reaction can be conducted in the almost same manner as described above. The solvent for the reaction is required to be anhydrous, but only carbon dioxide and imidazole are formed as by-products during the reaction; the former can be allowed to escape because it is a gas, and the latter can be easily removed out of the reaction system by washing with an acidic water.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@@H:10]([N:15]2[C:24]3[C:19](=[CH:20][N:21]=[C:22]4[NH:27][CH:26]=[CH:25][C:23]4=3)[C:18](=[O:28])[CH:17]=[CH:16]2)[CH2:9]1)C1C=CC=CC=1.[ClH:29].CO>CO.[C].[Pd]>[ClH:29].[CH3:14][C@@H:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]1[N:15]1[C:24]2[C:19](=[CH:20][N:21]=[C:22]3[NH:27][CH:26]=[CH:25][C:23]3=2)[C:18](=[O:28])[CH:17]=[CH:16]1
Reactant: C[C@@H]1CCN(Cc2ccccc2)C[C@@H]1n1ccc(=O)c2cnc3[nH]ccc3c21
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: C[C@@H]1CCNC[C@@H]1n1ccc(=O)c2cnc3[nH]ccc3c21

Procedure:
rac-1-[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one (16 mg, 0.043 mmol) and 5% palladium-carbon (15 mg) in methanol (2 mL) was stirred with hydrogen chloride-methanol solution (10 wt %, 20 μL) at 40° C. for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow solid (15 mg, quantitative yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].CC(C)([O-])C.[K+].[Br:18][C:19]1[N:23]2[N:24]=[C:25](Cl)[CH:26]=[CH:27][C:22]2=[N:21][CH:20]=1>C1COCC1>[Br:18][C:19]1[N:23]2[N:24]=[C:25]([NH:6][C:5]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:26]=[CH:27][C:22]2=[N:21][CH:20]=1
Reactant: COc1ccc(N)cc1OC
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(Nc2ccc3ncc(Br)n3n2)cc1OC
Temperature: 60 °C
Reaction time: 15 h
Yield: 50.2 %

Procedure:
To a solution of 3,4-dimethoxyaniline (178 mg, 1.16 mmol, 2.0 equiv) in THF (5 mL) was added potassium tert-butoxide (131 mg, 1.16 mmol, 2.0 equiv) and heated to 60° C. for 30 min. The reaction mixture was cooled to room temperature then 3-bromo-6-chloroimidazo[1,2-b]pyridazine (135 mg, 0.582 mmol, 1.0 equiv) was added and stirred at room temperature for 15 h. Purification by column chromatography using 2% methanol in dichloromethane elution gave 102 mg of the dark brown solid, 50%.