Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].Br[C:12]([CH3:19])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].O>CN(C)C=O>[CH3:18][C:12]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)([CH3:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)n1cnc([N+](=O)[O-])c1
Reaction time: 0.33 h

Procedure:
To a solution of 4-nitro-1H-imidazole (10 g) in N,N-dimethylformamide (150 mL) was added sodium hydride (60% in mineral oil, 4.2 g) in an ice bath, and the mixture was stirred at the same temperature for 20 min. To the reaction mixture was added ethyl 2-bromo-2-methylpropanoate (20 mL) at the same temperature, and the mixture was stirred overnight at 50° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (12 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([N:27]3[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH:35][CH3:36])[CH2:29][CH2:28]3)=[N:23][CH:24]=[CH:25][N:26]=2)=[CH:17][CH:16]=1.N1CCOCC1>ClCCl>[ClH:11].[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:35]([CH2:34][CH2:33][N:30]2[CH2:29][CH2:28][N:27]([C:22]3[C:21]([C:18]4[CH:19]=[CH:20][C:15]([CH2:14][O:13][CH3:12])=[CH:16][CH:17]=4)=[N:26][CH:25]=[CH:24][N:23]=3)[CH2:32][CH2:31]2)[CH3:36])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNCCN1CCN(c2nccnc2-c2ccc(COC)cc2)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: C1COCCN1
Solvent: ClCCl
Product: COCc1ccc(-c2nccnc2N2CCN(CCN(C)S(=O)(=O)c3ccc(F)cc3)CC2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
Dissolve 4-fluoro-benzenesulfonyl chloride (0.095 g, 0.49 mmol, 1.1 eq.) in dichloromethane (4 mL). Add {2-[3′-(4-methoxymethyl-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl]-ethyl}-methyl-amine (0.150 g, 0.440 mmol, 1 eq.). Add morpholine, polymer-bound (0.201 g, 0.490 mmol, 1.1 eq.). Stir at room temperature for 2 hr. Purify by SCX chromatography (column washed with methanol and extracted with 7N NH3/MeOH) to afford the free base of the title compound (0.220 g, 100% yield). MS (loop): m/z=500.0 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([N+:20]([O-])=O)=[CH:12][C:13]=1[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:6]([O:8][CH2:9][CH3:10])=[O:7]>[Pd].C(O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([NH2:20])=[CH:12][C:13]=1[O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1cc(OC)c(OCC(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OC)c(OCC(F)(F)F)cc1N
Reaction time: 18 h
Yield: 92.7 %

Procedure:
A suspension of ethyl 3-methoxy-4-(2,2,2-trifluoroethoxy)-6-nitrobenzoate (24.0 g, 74.3 mmol) and 10% palladium on carbon (3.0 g) in a mixture of ethanol (100 ml) and ethyl acetate (750 ml) was stirred under an atmosphere of hydrogen for 18 hours. Removal of the catalyst by filtration, followed by solvent evaporation in vacuo yielded ethyl 3-methoxy-4-(2,2,2-trifluoroethoxy)-6-aminobenzoate (20.2 g, 93% yield) as a pale brown solid:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:9]=[C:8]2[N:10]=[C:11]([CH2:13][CH3:14])[NH:12][C:7]2=[C:6]([CH3:15])[CH:5]=1.[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27](CCl)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[I-].[Na+].[CH3:34]N(C=O)C>>[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([N:10]2[C:8]3=[N:9][C:4]([CH3:3])=[C:5]([CH3:34])[C:6]([CH3:15])=[C:7]3[N:12]=[C:11]2[CH2:13][CH3:14])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)C=O
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Product: CCc1nc2c(C)c(C)c(C)nc2n1-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 79 %

Procedure:
To a suspension of 0.503 g (12.5 mmol) of a 60% oil dispersion of sodium hydride in 20 mL of DMF was added 2.0 g (11.4 mmol) of the product of Step C and the mixture was stirred at room temperature. After 25 minutes, 2.92 g (12.5 mmol) of 4-benzyloxybenzyl chloride and a catalytic amount of sodium iodide were added and the reaction was stirred for an additional 4 hours. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried (MgSO4), filtered and evaporated. The residual oil was purified on a silica gel flash chromatography column eluted with 30% ethyl acetate/hexane to afford 3.33 g (79% ) of the title compound.
Reaction SMILES: [C:1]([C:9]([NH:11][CH:12]1[C:18](=[O:19])[N:17]2[CH:20]([C:24]([NH:26][CH:27]3[CH2:31][C:30](=[O:32])[O:29][CH:28]3[O:33]CC3C=CC=CC=3)=[O:25])[CH2:21][CH2:22][CH2:23][N:16]2[C:15](=[O:41])[CH2:14][CH2:13]1)=[O:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.CC#N.O>>[C:1]([C:9]([NH:11][CH:12]1[C:18](=[O:19])[N:17]2[CH:20]([C:24]([NH:26][CH:27]([CH:28]=[O:33])[CH2:31][C:30]([OH:32])=[O:29])=[O:25])[CH2:21][CH2:22][CH2:23][N:16]2[C:15](=[O:41])[CH2:14][CH2:13]1)=[O:10])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(NC(=O)C2CCCN3C(=O)CCC(NC(=O)C(=O)c4ccccc4)C(=O)N23)C(OCc2ccccc2)O1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: O=CC(CC(=O)O)NC(=O)C1CCCN2C(=O)CCC(NC(=O)C(=O)c3ccccc3)C(=O)N12
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 99.1 %

Procedure:
Compound 2001 (58.6 mg, 0.10 mmol) was treated with 15 mg of TFA/MeCN/water (1:2:3) and stirred at room temperature for 6.5 h. The reaction was extracted with ether. The aqueous layer was concentrated with azeotropic removal of the water using MeCN. The product was suspended in CH2Cl2, concentrated in vacuo and precipitated with ether to give 46.8 mg (99%) of 2002 as a white solid: 1H NMR (CD3OD) δ9.05 (0.25H, d), 8.15 (1H, d), 7.68 (1H, t), 7.64 (0.25H, d), 7.55 (3H, t), 7.35 (0.5H, m), 5.22 (1H, t), 4.90 (1H, m), 4.58 (1H, dd), 4.50 (1H, m), 4.28 (1H, bm), 3.45 (1H, m), 3.10 (1H, bt), 2.68 (1H, ddd), 2.60-2.45 (2H, m), 2.30 (1H, dd), 2.15-2.05 (2H, m), 1.90 (2H, bm), 1.68 (1H, bm).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.[C:11]([C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1)#[CH:12].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.[OH-].[NH4+].[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([C:12]#[C:11][C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: C#Cc1ccc(C(=O)OCC)cc1
Reactant: N#Cc1ncc(Cl)cc1Cl
Agent: [Cu]I
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C#Cc2cnc(C#N)c(Cl)c2)cc1
Temperature: 25 °C

Procedure:
A solution of 3,5-dichloropicolinonitrile (commercially available) (1.0 eq.), ethyl 4-ethynylbenzoate (commercially available) (1.0 eq.), trans-dichlororbis(triphenylphosphine)palladium (II) (10 mol %), copper (I) iodide (20 mol %), and triethylamine (5.0 eq.) in DMF (0.3 M) was stirred at 50° C. for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and 10% aqueous ammonium hydroxide. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH®, system (ISCO) using 0-20% ethyl acetate in hexane to give ethyl 4-((5-chloro-6-cyanopyridin-3-yl)ethynyl)benzoate as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[CH:13]([OH:16])([CH3:15])[CH3:14].[CH2:17]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:18]1[O:20][CH2:19]1.[ClH:34]>O>[ClH:34].[OH:16][CH:13]([CH2:15][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:14][N:1]([CH2:19][CH:18]([OH:20])[CH2:17][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: CC(C)O
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCCOCC1CO1
Agent: Cl
Solvent: O
Product: CCCCCCCCCCCCOCC(O)CN(CC(O)COCCCCCCCCCCCC)[C@@H](CCCNC(=N)N)C(=O)O
Reaction time: 0.5 h
Yield: 17.2 %

Procedure:
L-arginine (17.4 g, 0.1 mmols) was dissolved in 100 ml of water in a three-necked round flask, and 100 ml of i-propanol were added thereto. Dodecyl glycidyl ether (48.4 g, 0.2 mols) was added thereto dropwise over a period of 30 minutes while being heat-stirred under reflux, and the mixture was stirred as such under reflux for 3 hours. After it was identified through TLC and gas chromatography that dodecyl glycidyl ether disappeared, the residue was neutralized with 10.1 g (0.1 mols) of 36-% hydrochloric acid. The reaction solution was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (Kieselgel 60, eluent--mixture of chloroform, methanol and acetic acid at a ratio of 3:1:0.5) to give 11.4 g of N,N-bis (2-hydroxy-3-dodecyloxypropyl)-L-arginine hydrochloride in a yield of 17.2%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9](/[C:11](/[S:18][CH3:19])=[N:12]/[CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[S:20]1[CH2:23][CH:22]([NH2:24])[CH2:21]1.CCN(C(C)C)C(C)C.F[B-](F)(F)F.BrC1C=CC=C[N+]=1CC>ClCCl.O>[CH3:19][S:18][C:11](=[N:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:9]1[CH:8]=[CH:7][C:3]([C:4](=[O:6])[NH:24][CH:22]2[CH2:23][S:20][CH2:21]2)=[C:2]([CH3:1])[CH:10]=1
Reactant: NC1CSC1
Reactant: CS/C(=N\C[Si](C)(C)C)c1ccc(C(=O)O)c(C)c1
Agent: CC[n+]1ccccc1Br
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CSC(=NC[Si](C)(C)C)c1ccc(C(=O)NC2CSC2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.1 %

Procedure:
To a solution of 2-methyl-4-{methylsulfanyl-[(Z)-trimethylsilanyl methylimino]methyl}-benzoic acid (Example I18) (107 mg) in dichloromethane (6 ml) was added thietan-3-ylamine (88 mg), Hünigs base (0.248 ml) and 2-bromo-1-ethyl-pyridinium tetrafluoroborate (169 mg). The reaction mixture was stirred at ambient temperature for 2 hours. Water was added and the mixture was extracted twice with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: ethyl acetate/heptanes 1:3) to give 3-methyl-4-(thietan-3-ylcarbamoyl)-N-trimethylsilanylmethyl-thiobenzimidic acid methyl ester (16 mg). 1H-NMR (400 MHz, CDCl3): 7.40-7.20 (m, 3H), 6.20 (d, 1H); 5.30 (m, 1H), 3.55 (s, 2H), 3.35 (m, 2H), 3.25 (m, 2H), 2.35 (s, 3H), 1.95 (s, 3H), 0.00 (s, 9H) ppm.
Reaction SMILES: [CH3:1][CH2:2][O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=1.[F:16][C:17]([Si](C)(C)C)([F:19])[F:18].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:14]([O:13][CH:4]([O:3][CH2:2][CH3:1])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:12])[C:17]([F:19])([F:18])[F:16])=[CH:7][CH:6]=1)[CH3:15]
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(OCC)c1ccc(C(O)C(F)(F)F)cc1
Yield: 77.9 %

Procedure:
According to Step 2 of Reference Example 8-17, by use of terephthalaldehyde mono(diethyl acetal) (796 μL, 4.00 mol), (trifluoromethyl)trimethylsilane (709 μL, 4.80 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 4.40 mL, 4.40 mmol) and tetrahydrofuran (10 mL), the mixture was stirred and reacted at room temperature for 2.5 hours. Then, purification by silica gel column chromatography (hexane/ethyl acetate=4/1) was performed to give 1-diethoxymethyl-4-(2,2,2-trifluoro-1-hydroxyethyl)benzene (Compound CR) (1.04 g, yield: 93%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9](F)[C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.ClC=C(Cl)Cl.Cl>O>[CH2:23]([NH:30][C:9]1[C:10]([F:15])=[C:11]([F:14])[CH:12]=[C:13]2[C:8]=1[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][N:4]2[CH:1]1[CH2:3][CH2:2]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)c(F)c2c1=O
Agent: Cl
Solvent: ClC=C(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)c(NCc3ccccc3)c2c1=O

Procedure:
A mixture of 2.57 g of ethyl 1-cyclopropyl-5,6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, 1.8 ml of benzylamine and 180 ml of trichloroethylene was heated under reflux for 3 hours and 40 minutes. Water and 10% hydrochloric acid were added to the reaction mixture to render the aqueous layer acidic. The trichloroethylene layer was separated and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to give 2.78 g of ethyl 5-benzylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxlate. m.p. 144°-145° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:17])[CH:14]=3)[CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][N:26]1[NH:35][C:36](Cl)=[O:37].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][N:26]1[NH:35][C:36](=[O:37])[O:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([NH:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[CH2:16]2
Reactant: Oc1ccc2c(c1)CN(Nc1ccncc1)C2
Reactant: O=C(Cl)NN1CCc2ccccc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NN1CCc2ccccc2C1)Oc1ccc2c(c1)CN(Nc1ccncc1)C2
Temperature: 25 °C
Yield: 30.2 %

Procedure:
To a mixture of 2,3-dihydro-2-(4-pyridinylamino)-1H-isoindol-5-ol (1.50 g), triethylamine (1.47 g), and chloroform (15 ml), 1,2,3,4-tetrahydroisoquinolin-2-ylcarbamyl chloride (1.55 g) in chloroform (10 ml) was added dropwise with stirring, under nitrogen, at ambient temperature. The reaction mixture was stirred under reflux for 3 hrs, at ambient temperature overnight and poured into dilute sodium bicarbonate solution. The layers were separated. The aqueous phase was extracted with chloroform, and the combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated in vacuo. The residue was chromatographed on silica, eluting with 7% methanol-dichloromethane followed by 185:14:1 dichloromethane-methanol-ammonium hydroxide. The appropriate fractions were collected and evaporated. The residue was recrystallized from ethanol-toluene to give 800 mg (31%) of product, mp 162-163° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([C@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[CH:14]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:28](O)(=[O:32])[C:29]#[C:30][CH3:31]>>[NH2:22][C:20]1[C:21]2[C:13]([C:12]#[C:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)=[CH:14][N:15]([C@H:23]3[CH2:27][CH2:26][N:25]([C:28](=[O:32])[C:29]#[C:30][CH3:31])[CH2:24]3)[C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: COc1cc(C#Cc2cn([C@H]3CCNC3)c3ncnc(N)c23)cc(OC)c1
Reactant: CC#CC(=O)O
Product: CC#CC(=O)N1CC[C@H](n2cc(C#Cc3cc(OC)cc(OC)c3)c3c(N)ncnc32)C1

Procedure:
In accordance with Example 4 (Step 1), except that (S)-5-((3,5-dimethoxyphenyl)ethynyl)-7-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (i.e., the intermediate obtained in Example 38 (Step 4)) and 2-butynoic acid were used, the title compound was obtained as a colorless, amorphous substance. Table 1 shows the physical properties thereof.
Reaction SMILES: [Na].[CH2:2](O)[CH3:3].[NH2:5][C:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[N:12]=2)[N:7]=1.COC(CC)CC#N>O.ClCCl>[NH2:5][C:6]1[CH2:10][CH:9]([CH2:2][CH3:3])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[N:12]=2)[N:7]=1
Reactant: CCO
Reactant: NC1=NN(c2cccc(Cl)n2)CC1
Agent: CCC(CC#N)OC
Agent: [Na]
Solvent: O
Solvent: ClCCl
Product: CCC1CC(N)=NN1c1cccc(Cl)n1

Procedure:
A 0.26 g. amount of sodium metal is dissolved in 100 ml. of absolute ethanol, then 8.1 g. of 2-chloro-6-hydrazinopyridine (Example 2) is added followed by 6.4 g. of 3-methoxyvaleronitrile. The reaction mixture is refluxed for 16 hours, then is evaporated in vacuo to give a solid. The solid is dissolved in water/dichloromethane. The organic layer is separated, dried over magnesium sulfate, filtered through anhydrous magnesium silicate and concentrated while adding hexane to yield 7.0 g. of pale yellow crystals. A 200 mg. amount of the crude product is recrystallized from dichloromethanehexane to give 171 mg. of the product of the Example, as pale yellow crystals, m.p. 131°-133° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=[O:17].C1[CH2:25][O:24][CH2:23][CH2:22]1>CN(C=O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12](=[O:14])[CH2:22][C:23]([O:24][CH3:25])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCOCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)CCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a solution of 4-(benzyloxy)butanoic acid (25.2 g) and DMF (5 drops) in THF (200 ml) was added dropwise oxalyl chloride (25 ml) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hr, and the solvent and volatile component were evaporated. A solution of the residue in dichloromethane (50 ml) was added dropwise to a solution of Meldrum's acid (15.6 g) and pyridine (18 ml) in dichloromethane (100 ml) under ice-cooling. The reaction mixture was stirred at room temperature for 11 hr, washed with 0.5M hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. A solution of the residue in methanol (500 ml) was stirred with heating under reflux for 9 hr. After cooling to room temperature, the solvent was evaporated. The residue was purified by silica gel column (hexane/ethyl acetate=5/1) to give the title compound as a pale-yellow liquid (14.37 g, 55%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]3[NH:13][CH2:14][C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:10]3=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.CN(C=O)C.[H-].[Na+].Cl[C:29]1[C:38]2[C:33](=[CH:34][C:35]([Cl:39])=[CH:36][CH:37]=2)[N:32]=[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[F:46])[C:30]=1[CH3:47]>CCOC(C)=O>[Cl:39][C:35]1[CH:34]=[C:33]2[C:38]([C:29]([N:13]3[C:11]4[C:10](=[CH:9][CH:8]=[C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[CH:12]=4)[C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH2:14]3)=[C:30]([CH3:47])[C:31]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[F:46])=[N:32]2)=[CH:37][CH:36]=1
Reactant: Cc1c(-c2ccccc2F)nc2cc(Cl)ccc2c1Cl
Reactant: c1cc2c(cc1N1CCOCC1)NCC21CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccc2F)nc2cc(Cl)ccc2c1N1CC2(CCOCC2)c2ccc(N3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under a N2 atmosphere, 6-morpholino-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] (0.18 g, 0.65 mmol) was dissolved in DMF (2.00 mL, 26 mmol) and sodium hydride (0.017 g, 0.72 mmol) was added. The reaction was allowed to stir for 15 minutes at rt. 4,7-Dichloro-2-(2-fluorophenyl)-3-methylquinoline (0.100 g, 0.33 mmol) was added and the reaction was heated to 140° C. for 5 h. The reaction was diluted with EtOAc and washed with 2% sodium bicarbonate then brine. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude solid was purified by flash column chromatography eluting with 40% to 60% EtOAc in hexane, followed by further purification by preparative reverse phase HPLC to afford 1-(7-chloro-2-(2-fluorophenyl)-3-methyl-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran]. Mass Spectrum (ESI) m/e=544.3 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (1H, d, J=2.3 Hz), 7.90 (1H, d, J=9.0 Hz), 7.54-7.65 (3H, m), 7.35-7.42 (2H, m), 7.11 (1H, d, J=8.2 Hz), 6.30 (1H, dd, J=8.2, 2.3 Hz), 5.57 (1H, d, J=2.3 Hz), 4.06 (1H, d, J=9.4 Hz), 3.80-3.92 (3H, m), 3.56-3.63 (4H, m), 3.40-3.54 (2H, m), 2.83-2.89 (4H, m), 2.06 (3H, d, J=1.6 Hz), 1.88-2.03 (2H, m), 1.81-1.87 (1H, m), 1.66 (1H, dt, J=13.4, 1.1 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([N:18]4[CH2:21][C:20](=O)[CH2:19]4)[CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:23])=[CH:5][CH:4]=1.[CH:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([CH3:28])[CH3:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([N:18]4[CH2:21][CH:20]([N:32]5[CH2:33][CH2:34][N:29]([CH:26]([CH3:28])[CH3:27])[CH2:30][CH2:31]5)[CH2:19]4)[CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:23])=[CH:5][CH:4]=1
Reactant: CC(C)N1CCNCC1
Reactant: COc1ccc(Cn2c(=O)ccc3ncc(N4CC(=O)C4)cc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Cn2c(=O)ccc3ncc(N4CC(N5CCN(C(C)C)CC5)C4)cc32)cc1
Yield: 72.3 %

Procedure:
A mixture of 1-(4-methoxybenzyl)-7-(3-oxoazetidin-1-yl)-1,5-naphthyridin-2(1H)-one (C-7) (5.796 g, 17.3 mmol, 1.0 eq) and 1-isopropylpiperazine (4.432 g, 34.6 mmol, 2.0 eq) in DCM (150 mL) and acetic acid (0.5 mL) was heated at reflux temperature for 3 h, then NaBH(OAc)3 (7.33 g, 34.6 mmol, 2.0 eq) was added in portions and the resulting mixture was kept reflux overnight. The reactant mixture was cooled and diluted with H2O (300 mL) and extracted with DCM (4×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (2-5% MeOH-DCM) to afford the desired product 1-(4-methoxybenzyl)-7-(3-(4-isopropylpiperazin-1-yl)azetidin-1-yl)-1,5-naphthyridin-2(1H)-one (C-8) (5.6 g, 72.3% yield) as a pale solid. 1H NMR (300 MHz, CDCl3-d6) δ: 7.83 (d, J=7.5 Hz, 1H), 7.78 (s, 1H), 7.15 (d, J=6.9 Hz, 2H), 6.85 (d, J=6.6 Hz, 2H), 6.72 (d, J=7.2 Hz, 1H), 6.37 (s, 1H), 5.40 (s, 2H), 4.02 (m, 2H), 3.78 (m, 5H), 3.67 (m, 1H), 3.51 (m, 1H), 3.42 (m, 1H), 2.97 (m, 1H), 2.80 (m, 4H), 2.55 (m, 2H), 1.17 (d, J=4.8 Hz, 6H); ESI-MS m/z: 448.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19]Br)[CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:28]=[N+:29]=[N-:30].[Na+]>CS(C)=O.O>[C:1]([O:5][C:6]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][N:28]=[N+:29]=[N-:30])[CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2ccc(CBr)cc12
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2ccc(CN=[N+]=[N-])cc12
Temperature: 85 °C
Yield: 78.2 %

Procedure:
A mixture of bis-tert-butoxycarbonyl-(7-bromomethyl-isoquinolin-1-yl)amine (280 mg, 0.64 mmol) and NaN3 (300 mg, 4.6 mmol) in 3 mL of DMSO was heated at 85° C. for 1 h. Then the solution was cooled down to rt, diluted with water and extracted with 50% EtOAc in hexane. The combined organic layers were washed with water. Removal of solvents furnished the crude product as a yellow oil (200 mg).