Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:20]=[C:19]([C:21]([OH:23])=O)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl.[OH:25][C:26]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][CH2:29][NH:30][CH2:31]2>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:20]=[C:19]([C:21]([N:30]3[CH2:29][CH2:28][C:27]4[C:32](=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:26]=4[OH:25])[CH2:31]3)=[O:23])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1O)CCNC2
Reactant: CC(=O)Nc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(NC(C)=O)cc3)nc3ccccc13)C2
Yield: 9 %

Procedure:
Reaction of 2-(4-acetamidophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 62 (9% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.10 (s, 3H), 2.63 and 2.89 (2t, 2H), 3.47 and 4.03 (2t, 2H), 3.74 and 3.80 (2s, 3H), 4.38 and 4.91 (2s, 2H), 6.32 and 6.77 (2d, 1H), 6.70 and 6.91 (2d, 1H), 7.64-7.93 (m, 4H), 8.03-8.13 (m, 2H), 8.41-8.49 (m, 2H), 8.69 and 8.74 (2s, 1H), 10.23 (s, 1H); MS (ESI) m/z 469 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]([OH:23])=O)[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.[CH:28]1([SH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21](=[O:23])[S:34][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:25])([F:27])[F:26])[CH:3]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Reactant: SC1CCCCC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)SC3CCCCC3)cs2)CC1

Procedure:
A solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-4, 200 mg) is reacted analogously to Example I-227 with cyclohexanethiol (64.0 mg). This gives, after chromatographic purification, S-cyclohexyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbothioate (110 mg, 44%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[N:12]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[N:11]=[CH:10][CH:9]=2)=[CH:6][N:5]2[C:21](=[O:24])[NH:22][N:23]=[C:4]2[C:3]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1.Cl[CH2:36][C:37]([NH:39][CH3:40])=[O:38]>>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([N:12]2[C:8]([C:7]3[C:2]([CH3:1])=[C:3]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)[C:4]4[N:5]([C:21](=[O:24])[N:22]([CH2:36][C:37]([NH:39][CH3:40])=[O:38])[N:23]=4)[CH:6]=3)=[CH:9][CH:10]=[N:11]2)=[CH:14][CH:15]=1)#[N:18]
Reactant: CNC(=O)CCl
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2c(=O)[nH]nc2c1-c1cccc(C(F)(F)F)c1
Product: CNC(=O)Cn1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(-c3ccnn3-c3ccc(C#N)cc3)cn2c1=O

Procedure:
The title compound was prepared from 4-{5-[7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 9, 55 mg. 0.12 mmol) and 2-chloro-N-methylacetamide (19 μL, 0.18 mmol), using a similar method to that used in Example 11 (25 mg).
Reaction SMILES: CC(C)([O-])C.[Na+].[CH3:7][C@H:8]([OH:11])[CH2:9][CH3:10].F[C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[C:15]([NH2:28])[N:14]=1>C(OCC)(=O)C>[CH3:7][C@H:8]([O:11][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[C:15]([NH2:28])[N:14]=1)[CH2:9][CH3:10]
Reactant: CC[C@H](C)O
Reactant: Nc1nc(F)nc2c1ncn2C1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC[C@H](C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 50 °C
Yield: 78.8 %

Procedure:
Sodium tert-butoxide (3.24 g, 33.7 mmol) was added portionwise with stirring to (2S)-2-butanol (10 g, 135 mmol). 2-Fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (2 g, 8.43 mmol) was added to the resulting suspension and the mixture heated to 50° C. for 6 hours when LCMS showed complete reaction. After cooling the mixture was diluted with ethyl acetate (100 ml), and washed with water (50 ml) and the aqueous layer extracted again with ethyl acetate (50 ml). The combined organic extracts were washed with brine, dried using a hydrophobic frit and evaporated in vacuo (at 62° C. to remove the excess alcohol). The residue (2.52 g) was dissolved in dichloromethane and purified on an aminopropyl cartridge (110 g) using a Flashmaster II apparatus and eluting with a 0-100% ethyl acetate in cyclohexane gradient over 60 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (1.935 g).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:22](=[CH:23][CH:24]=1)[C:9]1=[N:10][O:11][C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[CH:15][CH:14]=3)=[C:8]1[CH2:7][CH2:6]2.B(Br)(Br)Br.CCOCC>ClCCl>[CH2:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]2[O:11][N:10]=[C:9]3[C:22]4[C:5]([CH2:6][CH2:7][C:8]=23)=[CH:4][C:3]([OH:2])=[CH:24][CH:23]=4)=[CH:14][CH:15]=1)[CH2:20][CH3:21]
Reactant: CCCc1ccc(-c2onc3c2CCc2cc(OC)ccc2-3)cc1
Agent: BrB(Br)Br
Solvent: CCOCC
Solvent: ClCCl
Product: CCCc1ccc(-c2onc3c2CCc2cc(O)ccc2-3)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.4 %

Procedure:
To 7-methoxy-3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 9B, 0.35 g, 1.096 mmol) in dichloromethane (10 mL) was added boron tribromide (1.425 mL, 1.425 mmol) dropwise over a period of 3 min. at 0° C. Approximately 2 min. after the addition was complete a white solid separated out. The reaction mixture was allowed to come to room temperature over a period of 10 min. and then was stirred at room temperature for 30 min. Additional boron tribromide (2 mL) was added at room temperature and the contents were stirred at room temperature for 1.5 h. Additional boron tribromide (10 mL) was added at room temperature. The heterogeneous solution become homogenous and brown. The contents were stirred at room temperature for an additional 3 h, then cooled to 0° C. and quenched by the very slow addition of MeOH (˜5 mL). The reaction mixture was concentrated under reduced pressure and partitioned between dichloromethane (50 mL) and water (20 mL). The dichloromethane layer was dried over sodium sulfate and concentrated to yield a greenish solid. Trituration with dichloromethane (2 mL) and ether (10 mL) followed by sonication for 3 min. yielded an off-white solid which was collected by filtration and washed with ether (2×5 mL) to afford 3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-ol (0.115 g). The compound had an HPLC retention time=3.80 min (condition C); LC/MS M+1=306. 1H NMR (400 MHz, MeOD) δ ppm 7.72 (dd, J=8.16, 1.38 Hz, 3H) 7.38 (d, J=8.28 Hz, 2H) 6.76-6.84 (m, 2H) 2.93-3.07 (m, 4H) 2.65-2.72 (m, 2H) 1.65-1.78 (m, 2H) 0.99 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@@:8]2([CH:16]([F:18])[F:17])[C@H:14]3[C@H:12]([CH2:13]3)[O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[CH:20]1([CH:24]=O)[CH2:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:20]1([CH2:24][NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]3([CH:16]([F:17])[F:18])[C@@H:14]4[C@@H:12]([CH2:13]4)[O:11][C:10]([NH2:15])=[N:9]3)[CH:7]=2)[CH2:23][CH2:22][CH2:21]1
Reactant: O=CC1CCC1
Reactant: NC1=N[C@](c2cc(N)ccc2F)(C(F)F)[C@@H]2C[C@@H]2O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: NC1=N[C@@](c2cc(NCC3CCC3)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (1R,5S,6R)-5-(5-amino-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine (16g-B, 50 mg, 0.184 mmol) in 1,2-dichloroethane (1.2 mL) was added cyclobutanecarbaldehyde (15.51 mg, 0.184 mmol) and sodium triacetoxyborohydride (0.033 mL, 0.221 mmol). After addition, the mixture was then stirred at room temperature for 3 h. Additional cyclobutanecarbaldehyde (15.51 mg, 0.184 mmol) was added and the mixture was stirred at room temperature for additional 30 min. The mixture was quenched with saturated NaHCO3 and extracted with DCM (1×6 mL). The organic layer was collected, dried over MgSO4, and concentrated. The residue was then dissolved in MeOH and solution mixture was purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give a desired product, which was dissolved in MeOH. The solution was loaded onto a PL-HCO3 MP SPE 200 mg/6 mL column and eluted with MeOH (2×2 mL). The combined eluates were concentrated and dried in vacuo to give 30 mg of the title compound as a light yellow solid. MS m/z=340.1 [M+H]+
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[C:15]([C:16](=O)[CH:17]=[CH:18]N(C)C)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH:30]1([NH:35][C:36]([NH2:38])=[NH:37])[CH2:34][CH2:33][CH2:32][CH2:31]1.CC(C)([O-])C.[K+].O>O1CCCC1>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=4)[C:15]([C:16]4[CH:17]=[CH:18][N:38]=[C:36]([NH:35][CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[N:37]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C=CC(=O)c1c(-c2ccncc2)nn2c(NC3CCCC3)cccc12
Reactant: N=C(N)NC1CCCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: c1cc(NC2CCCC2)n2nc(-c3ccncc3)c(-c3ccnc(NC4CCCC4)n3)c2c1
Temperature: 25 °C
Yield: 75 %

Procedure:
A solution of 1-[7-(cyclopentylamino)-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (0.3 g, 0.94 mmol) in N,N-dimethylformamide dimethyl acetal (10 mL) was heated at reflux for 3 days. The mixture was allowed to cool to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate. The ethyl acetate phase was dried (magnesium sulfate), filtered and concentrated. The resulting residue was purified by flash chromatography (7:3 ethyl acetate-acetone) to give 1-[7-(cyclopentylamino)-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (0.23 g, 65%) as a colored syrup which was used in the next step without further purification. To a solution of 1-[7-(cyclopentylamino)-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (0.10 g, 0.27 mmol) in tetrahydrofuran (10 mL) was added cyclopentyl guanidine hydrochloride (0.06 g, 0.38 mmol) followed by potassium tert-butoxide (0.085 g, 0.76 mmol). The resulting mixture was heated at reflux for 12 hours. Upon cooling to room temperature, water was added. The mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (1:9 methanol-dichloromethane) to give the title compound (89 mg, 75%) as a white solid. 1H NMR (CDCl3): δ 8.64 (d, 2H), 8.04 (d, 1H), 7.58 (m, 3H), 7.28 (t, 1H), 6.32 (d, 1H), 6.02 (d, 1H), 5.95 (d, 1H), 5.03 (d, 1H), 4.22 (m, 1H), 3.97 (m, 1H), 1.2–2.2 (m, 16H); MS m/z 440 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.C(O[Na])(C)(C)C.C(=[NH:69])(C1C=CC=CC=1)C1C=CC=CC=1.O.NO.C([O-])(=O)C.[Na+].C(=O)([O-])O.[Na+].C(OC(N1CC=C(C2C=CC(N)=CN=2)CC1)=O)(C)(C)C.C(OC(N1CC=C(C2C=CC(N(C3C=CC=CC=3)C3C=CC=CC=3)=CN=2)CC1)=O)(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:69])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(Br)cn2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)OC(=O)N1CC=C(c2ccc(N(c3ccccc3)c3ccccc3)cn2)CC1
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cn2)CC1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-(5-bromopyridin-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (6.45 g), palladium(II) acetate (533 mg), (±)-2-(di-tert-butylphosphino)-1,1′-binaphthyl (1.48 g), and tert-butoxysodium (2.74 g) in toluene (47 ml) was added benzophenone imine (3.35 ml), stirred at 120° C. for 3 hours, then ethanol (50 ml), water (50 ml), hydroxylamine monohydrate (5.28 g), and sodium acetate (9.35 g) were added thereto at room temperature, and stirred at room temperature for 2.5 hours. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The obtained residue was purified with basic silica gel chromatography (n-hexane/ethyl acetate) to give a mixture of 4-(5-aminopyridin-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester and 4-(5-diphenylaminopyridin-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester. To the obtained mixture were added ethanol (100 ml), water (50 ml), hydroxylamine monohydrate (2.64 g), and sodium acetate (4.67 g), and stirred at room temperature for 6.5 hours. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The obtained residue was purified with basic silica gel chromatography (n-hexane/ethyl acetate). To the obtained oil were added 1,4-dioxane (15 ml) and 10% palladium carbon (containing about 50% water, 1.7 g), stirred at room temperature for 3.5 hours under hydrogen atmosphere, and then stirred at 40° C. for 12 hours. The reaction solution was filtered through Celite, then the solvent was evaporated in vacuo, and the obtained residue was purified with basic silica gel chromatography (chloroform/methanol) to give 4-(5-aminopyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (2.8 g) as a yellow oil.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[C:11]([Si:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Cl)=[C:25]([O:31][CH3:32])[CH:24]=1)([CH3:17])[CH3:16])([CH3:14])([CH3:13])[CH3:12].[I-].[K+]>CN(C=O)C.O>[Si:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH3:8])=[O:6])=[C:25]([O:31][CH3:32])[CH:24]=1)([C:11]([CH3:13])([CH3:12])[CH3:14])([CH3:16])[CH3:17]
Reactant: COc1cc(OCCCO[Si](C)(C)C(C)(C)C)ccc1CCl
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Cc1ccc(OCCCO[Si](C)(C)C(C)(C)C)cc1OC)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl acetoacetate (4.18 mL) was added to a suspension of NaH (55% oil dispersion, 1.70 g) in DMF (60 mL) at 0° C. and stirred at r.t. for 0.5 h. The product from step (iii) (10.0 g) in DMF (60 mL) and potassium iodide (4.73 g) were added to the mixture and stirred at 80° C. for 6 h. The mixture was cooled to RT and diluted with water and extracted with EtOAc. And the combined organic solutions were washed with water and brine, dried and concentrated. The residue was purified by silica gel chromatography to give 9.98 g of the subtitle compound as a yellow oil; 1H NMR: 6.99 (1H, d), 6.42 (1H, d), 6.37 (1H, dd), 4.02 (2H, t), 3.89 (1H, t), 3.80 (3H, s), 3.79 (2H, t), 3.67 (3H, s), 2.99-3.14 (2H, m), 2.17 (3H, s), 1.92-2.00 (2H, m), 0.88 (9H, s), 0.04 (6H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2([C:14]([NH2:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5]([F:17])=[CH:4][C:3]=1[C:18]#[N:19].[NH2:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2.O.O.O.[O-]C1C=CC=CC=1.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:18]([C:3]1[CH:4]=[C:5]([F:17])[C:6]([NH:8][C:9]2([C:14]([NH2:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:7][C:2]=1[NH:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)#[N:19]
Reactant: Nc1cnc2ccccc2c1
Reactant: N#Cc1cc(F)c(NC2(C(N)=O)CCCC2)nc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc(F)c(NC2(C(N)=O)CCCC2)nc1Nc1cnc2ccccc2c1
Reaction time: 4 h

Procedure:
A mixture of 1-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)cyclopentanecarboxamide (90 mg, 0.318 mmol), 3-aminoquinoline (58 mg, 0.402 mmol), sodium phenoxide trihydrate (85 mg, 0.500 mmol), xantphos (30 mg, 0.051 mmol) and Pd2 dba3 (20 mg, 0.021 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 4 h. Water and EtOAc were added. The organic phase was washed with aq. 1N NaOH, dried over Na2SO4, concentrated in vacuo to give crude 1-(5-cyano-3-fluoro-6-(quinolin-3-ylamino)pyridin-2-ylamino)cyclopentanecarboxamide.
Reaction SMILES: COC1C=CC(C2CCC3C(=CC=C(OC)C=3)C2(C)C)=C(N)C=1.Cl.[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[C:29](O)=O.FC1C=[C:47](C=CC=1OCCN1CCCCC1)[CH2:48][NH:49][C:50]1[CH:55]=[C:54]([O:56][CH3:57])[CH:53]=[CH:52][C:51]=1[CH:58]1[CH2:67][CH2:66][C:65]2[C:60](=[CH:61][CH:62]=[C:63]([O:68][CH3:69])[CH:64]=2)[C:59]1([CH3:71])[CH3:70]>>[CH2:48]([N:49]([CH2:29][C:28]1[CH:32]=[CH:33][C:34]([O:35][CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[C:26]([F:25])[CH:27]=1)[C:50]1[CH:55]=[C:54]([O:56][CH3:57])[CH:53]=[CH:52][C:51]=1[CH:58]1[CH2:67][CH2:66][C:65]2[C:60](=[CH:61][CH:62]=[C:63]([O:68][CH3:69])[CH:64]=2)[C:59]1([CH3:70])[CH3:71])[CH3:47]
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2(C)C
Agent: COc1ccc(C2CCc3cc(OC)ccc3C2(C)C)c(N)c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1(C)C

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 114, [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][5-methoxy-2-(6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (306 mg) was used according to an analogous synthetic method to Example 36 to provide ethyl [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][5-methoxy-2-(6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (253 mg). This compound (251 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (228 mg).
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:17][OH:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C>ClCCl.CS(C)=O>[CH2:10]([C@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:6])([CH3:5])[CH3:7])[CH:17]=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 111.9 %

Procedure:
(S)—N-Bocphenylalaninol (5 g, 0.019 mol) was dissolved in dichloromethane (150 mL) and triethylamine (8.3 mL, 3 equivalents) at 0° C. and treated with a solution of pyridine-sulfur trioxide complex (9.5 g, 3 equivalents) in DMSO (30 mL) over several minutes. After 1 h at 0° C., the mixture was added to ice water (200 mL). The dichloromethane was evaporated and the mixture was extracted with ether (100 mL, 4×). The organic layer was washed with 10% citric acid, water, saturated sodium bicarbonate, brine, dried over sodium sulfate, and the solvents were evaporated to give 5.3 g of the title compound.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23](OCC[Si](C)(C)C)=[O:24])[CH:21]=4)[CH:16]=[N:15][CH:14]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+].C([N:36](CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.CN(C)C=O>[C:1]1([N:7]2[CH2:8][CH2:9][N:10]([C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]([NH2:36])=[O:24])[CH:21]=4)[CH:16]=[N:15][CH:14]=3)[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOC(=O)c1ccc2cncc(N3CCN(c4ccccc4)CC3)c2c1
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2cncc(N3CCN(c4ccccc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.1 %

Procedure:
2-(Trimethylsilyl)ethyl 4-(4-phenylpiperazin-1-yl)isoquinoline-6-carboxylate (2.37 g, 5.47 mmol) produced in Example 3 (3d) was dissolved in tetrahydrofuran (27 mL), to which a 1.0M n-tetrabutylammonium fluoride/tetrahydrofuran solution (16.4 mL, 16.4 mmol) was then added, followed by stirring at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure. The residue thus obtained was dissolved in N,N-dimethylformamide (47 mL) under a nitrogen atmosphere, to which ammonium chloride (2.92 g, 54.7 mol), triethylamine (9.14 mL, 65.6 mmol), 1-hydroxybenzotriazole (251 mg, 1.64 mmol), and N-[3-dimethylaminopropyl]-N′-ethylcarbodiimide hydrochloride (5.24 g, 27.3 mmol) were added, followed by stirring at room temperature for 13 hours. The resulting reaction liquid was filtered and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography (hexane:ethyl acetate, 50:50-0:100, V/V) and recrystallized from a mixed solvent of ethanol-dichloromethane to give the desired title compound (1.13 g, yield 62%).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[CH:20]3[CH2:21][C:7]4([CH2:11][N:10]([CH2:12][CH:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)[CH2:9][CH:8]4[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=43)[C:6]=2[CH:26]=1.N([O-])=[O:28].[Na+].[ClH:31]>O>[ClH:31].[OH:28][C:2]1[CH:3]=[CH:4][C:5]2[CH:20]3[CH2:21][C:7]4([CH2:11][N:10]([CH2:12][CH:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)[CH2:9][CH:8]4[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=43)[C:6]=2[CH:26]=1
Reactant: Nc1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Oc1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5.0 g (14.5 mmoles) of 5-amino-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole, the product of Example 64, in 50 ml of 1N aqueous hydrochloric acid, cooled to 0°, was added dropwise a solution of 1.0 g (14.5 mmoles) of sodium nitrite in 5 ml of water. The reaction mixture was stirred overnight at room temperature, filtered and then heated to 90°. A precipitate of 5-hydroxy-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole hydrochloride was collected by filtration, m.p. 218-229°; nmr spectrum of free base: δ 1.0-4.0 (m, 19); 6.3-6.7 (m, 2); 6.7-7.2 (m, 5); 8.7 (s, 1).