Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[CH:23][N:22]([CH3:31])[N:21]=3)=[CH:16][CH:15]=2)[CH:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:46](=O)([O-])[O-:47].[Cs+].[Cs+]>CO.[Cu](I)I>[CH3:46][O:47][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[CH:23][N:22]([CH3:31])[N:21]=3)=[CH:16][CH:15]=2)[CH:3]=1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3cc(Cl)c4ccccc4n3)cc2)n1
Reactant: O=C([O-])[O-]
Agent: I[Cu]I
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CO
Product: COc1cc(COc2ccc(-c3nn(C)cc3-c3ccncc3)cc2)nc2ccccc12
Temperature: 165 °C
Yield: 59.8 %

Procedure:
To a solution of 4-Chloro-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (125 mg) in methanol (4 mL) was added phenanthroline (78 mg), cesium carbonate (143 mg) and copper iodide (5 mg). The reaction mixture was heated in a microwave reactor at 165° C. with 50 W of power for 20 min. The reaction mixture was filtered through celite and concentrated. Purification via MPLC biotage chromatography, eluting with 5% methanol/1% ammonium hydroxide/methylene chloride provided the title compound (74 mg). 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=5.4 Hz, 2H), 8.18 (d, J=8.3 Hz, 1H), 7.97 (d, J=8.3 Hz, 1H), 7.68 (m, 1H), 7.55 (s, 1H), 7.49 (t, J=7.1 Hz, 1H), 7.37 (d, J=9.1, Hz, 2H), 7.15 (d, J=6.2 Hz, 2H), 7.01 (m, 3H), 5.32 (s, 2H), 4.02 (s, 3H), 3.95 (s, 3H); MS: (M+H m/z=423.3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[N:13][N:12]2[CH:18]=1)=[O:8])[CH3:2].[Cl:20]N1C(=O)CCC1=O.O1CCCC1>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[N:13][N:12]2[C:18]=1[Cl:20])=[O:8])[CH3:2]
Reactant: CCOC(=O)CNC(=O)c1cn2nc(Cl)ccc2n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)c1nc2ccc(Cl)nn2c1Cl
Yield: 57.2 %

Procedure:
0.86 g of N-(6-chloroimidazo[1,2-b]pyridazine-2-carbonyl)glycine ethyl ester was suspended in 30 ml of ethyl acetate; 1.2 g of N-chlorosuccinimide was added, followed by thermal refluxing for 20 hours. After cooling, 30 ml of tetrahydrofuran was added; the mixture was washed with an aqueous solution of sodium thiosulfate and saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; ethyl ether was added to the residue; the crystal precipitated was collected by filtration, washed with ethyl ether and dried to yield 0.552 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]=1.C=O.Cl.[CH3:15][NH2:16].[C:17](O)(=O)[CH3:18]>>[CH3:15][N:16]1[CH2:5][CH2:6][C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:18][C:17]=3[CH2:4][CH2:3][C:2]=2[CH2:1]1
Reactant: CC(=O)O
Reactant: CN
Reactant: CC1=CCCc2ccccc21
Agent: C=O
Agent: Cl
Product: CN1CCC2=C(CCc3ccccc32)C1
Yield: 44 %

Procedure:
Following the procedure of Example 1, step 3, 10 g (70 mmol) of 1-methyl-3,4-dihydronaphthalene and 22.55 g (278 mmol) of 37% formaldehyde solution in 60 ml of acetic acid were reacted with 10.8 g (0.16 mol) of methylamine hydrochloride. Chromatography on flash silica, eluting with 10% methanol/dichloromethane gave 6.0 g (44%) of the title product as a yellow oil. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent and recrystallisation from ethyl acetate/ethanol, the title product hydrochloride was obtained, m.p. 198°-200° C. NMR δ(D2O) 2.23 (2H, t), 2.74-3.01 (7H, m), 3.35 (1H, m), 3.72 (1H, m), 3.90-3.95 (2H, m), 7.27-7.33 (4H, m). m/z (FAB+) 200 (M+H)+.
Reaction SMILES: [FH:1].[CH3:2][C@:3]12[CH2:20][CH:19]=[C:18]3[C@@H:8]([CH2:9][CH2:10][C:11]4[C@:16]3([CH3:17])[CH2:15][CH2:14][C:13](=[O:21])[CH:12]=4)[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:22].[Cl:23]N1C(=O)CCC1=O.N>CC(C)=O.CCCCCC.CN1CCCC1=O>[Cl:23][C@:18]12[C@@H:19]([F:1])[CH2:20][C@@:3]3([CH3:2])[C@@H:7]([CH2:6][CH2:5][C:4]3=[O:22])[C@@H:8]1[CH2:9][CH2:10][C:11]1[C@:16]2([CH3:17])[CH2:15][CH2:14][C:13](=[O:21])[CH:12]=1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: F
Reactant: O=C1CCC(=O)N1Cl
Agent: N
Solvent: CC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCCCCC
Product: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)C[C@H](F)[C@@]12Cl
Temperature: 0 °C
Reaction time: 48 h

Procedure:
At -78°, a mixture of 15 ml. of hydrogen fluoride and 5 ml. of N-methylpyrrolidone is combined successively with 5.1 g of 4,9(11)-androstadiene-3,17-dione and 10 g. of N-chlorosuccinimide. The reaction solution is allowed to stand for 2 days at +3° and then introduced into a mixture of ice/water and a 25% ammonia solution. The thus-precipitated product is worked up as set forth in Example A. After chromatography of the crude product on silica gel with acetone/hexane, 1.6 g. of 9-chloro-11β-fluoro-4-androstene-3,17-dione is isolated as an oil. UV: ε239 = 16,200 (methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH:67]1[CH2:72][CH2:71][CH:70]([N:73]2[CH2:78][CH2:77][O:76][CH2:75][CH2:74]2)[CH2:69][CH2:68]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:67]3[CH2:72][CH2:71][CH:70]([N:73]4[CH2:78][CH2:77][O:76][CH2:75][CH2:74]4)[CH2:69][CH2:68]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: C1CC(N2CCOCC2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cn(CC(=O)N2CCC(N3CCOCC3)CC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (100 mg) in DMF (2 mL) was added HATU (100 mg, 0.26 mmol), DIEA (85 mg, 0.66 mmol), and 4-(piperidin-4-yl)morpholine hydrochloride (67 mg, 0.32 mmol). The resulting solution was stirred at room temperature overnight. The crude product (60 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with 10 mM NH4CO3 and MeCN (20.0% MeCN up to 35.0% in 8 min); Detector, 254/220. This resulted in 28.3 mg (21%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(morpholin-4-yl)piperidin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a yellow solid. LCMS (Method 20) [M+H]+=615.2, RT=1.84 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.5, 6.9 Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz), 7.02 (t, 1H, J=73.2 Hz), 5.24-5.21 (m, 2H), 4.42-4.31 (m, 1H), 4.02-3.95 (m, 1H), 3.55 (t, 4H, J=4.5 Hz), 3.16-3.02 (m, 1H), 2.78-2.64 (m, 1H), 2.49-2.45 (m, 5H), 1.90-1.76 (m, 2H), 1.54-1.21 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=1)[O:9][CH:8]([C:22]([F:25])([F:24])[F:23])[C:7]([C:26]([O:28]CC)=[O:27])=[CH:6]2)[CH3:2].[OH-].[Li+].C(O)C>O1CCCC1.O>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=1)[O:9][CH:8]([C:22]([F:25])([F:24])[F:23])[C:7]([C:26]([OH:28])=[O:27])=[CH:6]2)[CH3:2]
Reactant: CCOC(=O)C1=Cc2cc(CC)c(Oc3ccnc(SC)n3)cc2OC1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc2c(cc1Oc1ccnc(SC)n1)OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 25 °C
Yield: 52.7 %

Procedure:
To the solution of 100 mg (0.23 mmol) intermediate isolated from step 2 in 1.5 mL of tetrahydrofuran was added a solution of 48 mg (1.2 mmol) lithium hydroxide in 2.5 mL of water, followed by addition of 2.5 mL of ethanol. The reaction was then heated to reflux for one h. After cooling to room temperature, the volatiles were removed, the residue was diluted with water, then acidified at 0° C. with dilute hydrochloric acid to pH=1.0. The product was extracted with ethyl ether. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate and concd in vacuo to afford 50 mg (53%) of a yellow solid: 1H NMR (CDCl3/400 MHz) 8.40(d, J=6 Hz, 1H), 7.85(s, 1H), 7.17(s, 1H), 6.78(s, 1H, 6.58(d, J=5.6 Hz, 1H), 5.66(q, J=7.2 Hz, 1H), 2.48(q, J=7.2 Hz, 2H), 2.29(s, 3H), 1.l4(t, J=7.6 Hz, 3H); MS (ES+) 413 (M+l, 100), HRMS (EI) m/z calcd for (C18H16F3N2O4S) 413.0777, found 413.0768.
Reaction SMILES: [C:1](=[S:3])=[S:2].C([O:6][CH2:7][CH3:8])C.[CH2:9]([CH2:11][NH2:12])[OH:10]>C(O)C>[OH:10][CH2:9][CH2:11][N:12]1[C:7](=[O:6])[CH2:8][S:2][C:1]1=[S:3]
Reactant: CCOCC
Reactant: NCCO
Reactant: S=C=S
Solvent: CCO
Product: O=C1CSC(=S)N1CCO
Temperature: -5 °C
Reaction time: 1.25 h

Procedure:
Sixty milliliters of carbon disulfide were added to 200 ml of diethyl ether. The solution was chilled to -5° C. and slowly added to a solution of 138 ml of ethanolamine in 250 ml of ethanol. After holding the mixture at ambient temperature for 16 hours, the resulting top layer was decanted and the residual oil washed twice with 50 ml of diethyl ether. To the oil was added a solution of 71 g of chloroacetic acid in 150 ml of 5N sodium hydroxide at 0° C. The cooling bath was removed and the reaction was allowed to stand for 75 minutes. The mixture was poured into 400 ml of 6N hydrochloric acid and the resulting mixture heated to 91° C. for 20 minutes. The heat was removed, and the solution allowed to stand for 5 hours at ambient temperature. An oily organic layer was separated from the aqueous layer and the aqueous layer extracted twice with 250 ml of ethyl acetate. The organic layers were combined, washed twice with a saturated sodium chloride solution, dried and concentrated in vacuo to provide 113.4 g of the desired subtitled intermediate, which was used without further purification.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16].C(N(CC)C(C)C)(C)C>O1CCCC1>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:13][CH2:14][C:15]([OH:17])([CH3:18])[CH3:16])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CC(C)(O)CN
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)CNS(=O)(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(Bromomethyl)benzenesulfonyl chloride (2.0 g, 7.3 mmol) was dissolved in tetrahydrofuran. 3-Amino-2-methyl-2-propanol (1.0 g, 8 mmol) and and N,N-diisopropylethylamine (1.5 mL, 8.8 mmol) were added, and the reaction was allowed to stir at ambient temperature for 30 minutes. The reaction was concentrated to an oil that was partitioned between water and ethyl acetate and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over Na2SO4, and filtered. The resulting filtrate was concentrated to an oil that was a mixture of the title compound and 4-chloromethyl-N-(2-hydroxy-2-methylpropyl) benzenesulfonamide. The resulting oil was dried in vacuo (1.9 g, 81%).
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH3:11]>C(O)C>[CH3:8][CH2:9][CH2:2][CH:3]([CH3:6])[CH3:4].[NH2:11][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cccc(F)c1F
Reactant: N
Solvent: CCO
Product: CCCC(C)C
Product: N#Cc1cccc(F)c1N
Temperature: 140 °C
Yield: 50 %

Procedure:
A mixture of 2,3-difluorobenzonitrile (19.0 g, 137 mmol) and ethanol (200 ml) pre-saturated with ammonia gas was heated at 140° C. in an autoclave for 8 h (terminal pressure 200 psi). The mixture was allowed to cool to ambient temperature and evaporated to dryness. The residue was dissolved in water (400 ml) and extracted with diethyl ether (2×300 ml). The combined organics were washed with water (300 ml) and brine (250 ml), dried over anhydrous magnesium sulfate, filtered and evaporated. Trituration with isohexane (150 ml) afforded 2-amino-3-fluorobenzonitrile (9.8 g, 50%) as an off-white solid: 1H NMR (360 MHz, CDCl3) δ 4.47 (2H, s), 6.65-6.71 (1H, m), 7.14-7.20 (2H, m).
Reaction SMILES: [OH-:1].[Na+].S(O)(O)(=O)=O.[NH2:8]O.[Cl:10][C:11]1[CH:12]=[C:13]([C:21]([C:39]([F:42])([F:41])[F:40])=[CH:22][C:23]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([C:35]([O:37][CH3:38])=[O:36])=[CH:27][CH:26]=2)=O)[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1>O.O1CCCC1>[Cl:10][C:11]1[CH:12]=[C:13]([C:21]2([C:39]([F:41])([F:40])[F:42])[O:1][N:8]=[C:23]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]([C:35]([O:37][CH3:38])=[O:36])=[CH:27][CH:26]=3)[CH2:22]2)[CH:14]=[C:15]([C:17]([F:18])([F:20])[F:19])[CH:16]=1
Reactant: [OH-]
Reactant: NO
Reactant: COC(=O)c1ccc(C(=O)C=C(c2cc(Cl)cc(C(F)(F)F)c2)C(F)(F)F)c2ccccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 119.5 %

Procedure:
Aqueous sodium hydroxide (50%, 2.08 g, 25.5 mmol) was added dropwise to a stirred solution of hydroxylamine sulfate (1.07 g, 6.52 mmol) in water (20 mL) at 25° C. After this addition was complete the product of Example 8, Step A (5 g, 10.27 mmol) in tetrahydrofuran (20 mL) was added dropwise over 40 min. After the addition was complete the mixture was stirred further for 30 min. The organic phase was separated and added to hydrochloric acid (100 mL). The mixture was extracted with ethyl acetate (2×20 mL). The organic solvent was evaporated under reduced pressure. The residue was redissolved in acetic acid (16 mL) and then warmed to 100° C. Water (2 mL) was added dropwise, and the mixture was cooled to 50° C. The mixture was seeded with a small amount of previously prepared methyl 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1-naphthalenecarboxylate and then cooled to 25° C. Water (2 mL) was added and the mixture was cooled to 0° C. The mixture was filtered, and the solid was washed with acetic acid:water (8 mL:2 mL). The solid was dried in a vacuum oven to give the title product as a white solid (3.91 g, 76% yield) melting at 111.5-112° C. (after recrystallisation from acetonitrile).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:36](=[O:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38].C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:36](=[O:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
7-[[4-[(1-t-Butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile obtained in Reference Example 2 (200 mg) was dissolved in 2 ml of dichloromethane, 299 mg of ethyl chloroglyoxylate and 266 mg of triethylamine were added to the solution, and the mixture was stirred at room temperature for 15 hours. Ethyl acetate was added to the reaction solution. The mixture was washed with 10% citric acid aqueous solution and saturated sodium bicarbonate aqueous solution in that order, dried over anhydrous sodium sulfate, and then evaporated. The resulting residue was purified by silica gel column chromatography using hexane:ethyl acetate (8:2) as the eluent to give 241 mg of ethyl N-[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]oxamate.
Reaction SMILES: Cl.C[O:3][C:4]([C:6]1[C:7]2[CH2:8][NH:9][CH2:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:5].[OH-].[Li+].Cl>CO.C1COCC1.O>[CH2:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:6]([C:4]([OH:5])=[O:3])[C:7]=2[CH2:8][NH:9]1
Reactant: COC(=O)c1cccc2c1CNC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc2c1CNC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 4.4 %

Procedure:
To a suspension of the 2,3-dihydro-1H-isoindole-4-carboxylic acid methyl ester hydrochloride salt (0.18 g, 0.83 mmol) in 25% MeOH/THF (4 ml) was added dropwise lithium hydroxide (0.08 g, 3.32 mmol) in water (1 ml), followed by addition of water (2 ml) and the clear solution stirred at room temperature under nitrogen for 5 h. The solution was acidified with aq. HCl. and purified by ion-exchange (DOWEX™ 50WX2-100) resin eluting with a solvent gradient of ammonia:water (5:95) to give the title compound (0.0059 g, 4%) as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][C@@H:12]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[O:11]=[C:12]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]#[N:34])=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)[CH2:13]1
Reactant: N#Cc1ccc(-c2ccc(OCCCN3CC[C@@H](O)C3)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(-c2ccc(OCCCN3CCC(=O)C3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
Oxalyl chloride (0.195 mmol) in dry CH2Cl2 (5 mL) under an atmosphere of nitrogen at −78° C. was treated with DMSO (0.39 mmol). After 15 minutes of stirring, the product from Example 153 was added and the mixture was stirred for another 15 minutes. Triethylamine (0.45 mmol) was added and the mixture was gradually allowed to warm to 0° C. The solution was partitioned between water (50 mL) and dichloromethane (50 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the residue purified by chromatography (CHCl3:MeOH:NH4OH, 9:1:0.1) to provide the title compound (60% yield).
Reaction SMILES: [N:1]1([NH:14][CH:15]([CH3:17])[CH3:16])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:30].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.O>[CH:15]([NH:14][N:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]([NH2:30])[C:4]=2[N:3]=[CH:2]1)([CH3:17])[CH3:16]
Reactant: CC(C)Nn1cnc2cnc3ccccc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)Nn1cnc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-(1H-imidazo[4,5-c]quinolin-1-yl)isopropylamine (1.36 g, 5.66 mmol) in 50 mL of chloroform was cooled in a cold water bath. The solution was treated with MCPBA (2.03 g, 7.07 mmol) over 5 min and then allowed to warm to ambient temperature. After 1 h, TLC showed complete conversion to the intermediate 5-N-oxide. The reaction mixture was again cooled with a cold water bath. The solution was treated with concentrated ammonium hydroxide solution (25 mL, 30%) and stirred rapidly to homogenize. The reaction mixture was treated with p-toluenesulfonyl chloride (1.13 g, 5.94 g) over 5 min and allowed to warm to ambient temperature. After 30 min, the reaction mixture was diluted with 50 mL of CHCl3 and 25 mL of water. An undissolved solid between the phases was filtered off, saved, and the phases were separated. The organic portion was washed with saturated NaHCO3 solution (30 mL), water (30 mL) and brine (30 mL). The organic portion was then dried over Na2SO4, filtered and concentrated under reduced pressure to yield a tan/orange solid. A high-performance liquid chromatography (HPLC) analysis of the filtered solid matched that of the solid from the concentrated organic extracts. The combined solid was recrystallized twice from MeOH to give 1.18 g of N1-isopropyl-1H-imidazo[4,5-c]quinoline-1,4-diamine as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=4)=[O:28])=[C:22]([F:40])[CH:21]=3)[C:9]([CH2:18]O)=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:6]2[N:5]=[CH:4][N:3]=1.NC1C2=C(C3C=CC(NC(NC4C=C(C(F)(F)[F:77])C=CN=4)=O)=CC=3)C(C=O)=C(CN3CCOCC3)N2N=CN=1>>[NH2:1][C:2]1[C:7]2=[C:8]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[C:34]([C:36]([F:37])([F:39])[F:38])[CH:33]=[CH:32][N:31]=4)=[O:28])=[C:22]([F:40])[CH:21]=3)[C:9]([CH2:18][F:77])=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(CN3CCOCC3)c(CO)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)c(F)c3)c12
Reactant: Nc1ncnn2c(CN3CCOCC3)c(C=O)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)cc3)c12
Product: Nc1ncnn2c(CN3CCOCC3)c(CF)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)c(F)c3)c12
Yield: 23 %

Procedure:
The title compound was prepared in a manner similar to the procedure described for the preparation of Example 87, using N-{4-[4-amino-6-(hydroxymethyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f]-[1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoro-methyl)-pyridin-2-yl]urea (which can be prepared using the procedure used for the preparation of Example 62 substituting Intermediate AJ for Intermediate Y) in place of Example 85 (N-{4-[4-amino-6-formyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f]-[1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoro-methyl)pyridin-2-yl]urea), 45 mg (23%) of the desired product was isolated. 1H-NMR (DMSO-d6) δ 10.16-10.10 (m, 2H), 8.54 (d, J=5.1 Hz, 1H), 8.31 (t, J=8.4 Hz, 1H), 8.01 (s, 1H), 7.95 (s, 1H), 7.39-7.19 (m, 3H), 5.35 (d, J=49.8 Hz, 2H), 3.92 (s, 2H), 3.53-3.52 (m, 4H), 2.48-2.43 (m, 4H); MS [M+H]+=562.7; LCMS RT=2.50.