Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]=[C:12]([O:37][CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[C:13]2[C:18]([C:19]3[CH:28]=[CH:27][C:22]4[N:23]=[C:24]([CH3:26])[O:25][C:21]=4[CH:20]=3)=[CH:17][N:16](COCC[Si](C)(C)C)[C:14]=2[N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[Cl:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]=[C:12]([O:37][CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[C:13]2[C:18]([C:19]3[CH:28]=[CH:27][C:22]4[N:23]=[C:24]([CH3:26])[O:25][C:21]=4[CH:20]=3)=[CH:17][NH:16][C:14]=2[N:15]=1
Reactant: CCn1ncc(Nc2nc(OC3CCCC3)c3c(-c4ccc5nc(C)oc5c4)cn(COCC[Si](C)(C)C)c3n2)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCn1ncc(Nc2nc(OC3CCCC3)c3c(-c4ccc5nc(C)oc5c4)c[nH]c3n2)c1Cl
Temperature: 80 °C
Reaction time: 12 h
Yield: 19.7 %

Procedure:
N-(5-Chloro-1-ethyl-1H-pyrazol-4 yl)-4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (1 equiv) dissolved in 1 M tetrabutylammonium fluoride in THF (6.3 equiv). The mixture was stirred at 80° C. for 12 h. After cooling to room temperature, the reaction was diluted with THF (0.063 M) and cesium carbonate (5 equiv) was added. The solids were filtered and the filtrate was dried over sodium sulfate and concentrated. The crude product was purified to give the desired compound (19.7% yield). 1H NMR (400 MHz, CHLOROFORM-d1) δ ppm 8.81 (br. s, 1H), 8.13 (s, 1H), 7.81 (s, 1H), 7.62-7.56 (m, 2H), 6.91 (s, 1H), 6.30 (s, 1H), 5.68-5.65 (m, 1H), 4.18 (q, J=7.2 Hz, 2H), 2.66 (s, 3H), 1.95-1.87 (m, 4H), 1.74-1.68 (m, 2H), 1.43 (t, J=7.2 Hz, 3H). MS (ESI) m/z 478.2 [M+H]+.
Reaction SMILES: [C:1]([O-:5])(=O)[CH:2]=[CH2:3].[NH2:6][CH2:7][CH2:8][N:9]([CH2:13][CH2:14][NH2:15])[CH2:10][CH2:11][NH2:12].Cl>O>[CH2:7]([NH2:6])[CH2:8][N:9]([CH2:13][CH2:14][NH2:15])[CH2:10][CH2:11][NH2:12].[C:1]([NH2:6])(=[O:5])[CH:2]=[CH2:3]
Reactant: C=CC(=O)[O-]
Agent: Cl
Agent: NCCN(CCN)CCN
Solvent: O
Product: C=CC(N)=O
Reaction time: 96 h

Procedure:
Poly(NHS-acrylate) (4.4 g) was suspended in a solution containing water (100 mL) and tris(2-aminoethyl)amine (30 mL) which had been adjusted to pH 9 with concentrated HCl. After 4 days of stirring, the solid was filtered off, and the wash repeated. The solid was then rinsed briefly with water twice, isopropanol once, and dried in a vacuum oven to yield 3.4 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH2:9]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12].CC(C)([O-])C.[Na+]>>[CH2:9]([N:13]([CH2:14][CH2:15][CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH3:12]
Reactant: Cc1ccc(Br)cc1
Reactant: CCCCNCCCC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CCCCN(CCCC)c1ccc(C)cc1
Yield: 93 %

Procedure:
According to the general procedure B, 4-bromotoluene (94 mg, 0.55 mmol) reacted with N,N-di-n-butylamine (65 mg, 0.50 mmol) using 1 mol % of catalyst and sodium tert-butoxide (58 mg, 0.60 mmol) at 40° C. for 24 h to give the title compound (102 mg, 93%) as a colorless oil: 1H-NMR (300 MHz, CDCl3): δ 7.07 (d, 2H, J=8.4 Hz), 6.64 (d, 2H, J=8.4 Hz), 3.28 (t, 4H, J=7.2 and 7.8 Hz), 2.30 (s, 3H), 1.60 (m, 4H), 1.40 (m, 4H), 1.00 (t, 6H, J=7.5 and 7.2 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 146.17, 129.67, 124.34, 112.19, 50.99, 29.41, 20.38, 20.12, 14.01. GC/MS(EI): m/z 219 (M+), 176, 134.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][N:12](C)C)=[CH:5][CH:4]=1.O.[NH2:17]N.[OH-].[Na+]>CO>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][NH:12][N:17]=2)=[CH:5][CH:4]=1
Reactant: CN(C)CCC(=O)c1ccc(Cl)cc1
Reactant: NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Clc1ccc(C2=NNCC2)cc1
Temperature: 50 °C

Procedure:
Under N2 atmosphere, 1-(4-chloro-phenyl)-3-dimethylamino-propan-1-one hydrochloride (37.2 g) was dissolved in warm MeOH (75 mL), and slowly added to a solution of hydrazine hydrate (23 mL) and 50% aqueous NaOH (12 mL) in MeOH (30 mL) stirred at 50° C. The mixture was refluxed for 2 hours, and evaporated under reduced pressure. Water was added to the residue, followed by extraction with DCM. The organic phase was washed twice with water, dried and evaporated under reduced pressure, to give 25.0 g of a yellow solid, m.p. 90-100° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C@H:17]1([C:26]([OH:28])=O)[CH2:22][CH2:21][C@@H:20]([C:23]([OH:25])=O)[CH2:19][CH2:18]1>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:26]([C@H:17]1[CH2:18][CH2:19][C@@H:20]([C:23]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:25])[CH2:21][CH2:22]1)=[O:28])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)[C@H]1CC[C@@H](C(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)CC1

Procedure:
Using General Procedure A with 2.0 g (8.2 mmol) D-Proline benzyl ester hydrochloride and 700 mg (4.1 mmol) cis-cyclohexane-1,4-dicarboxylic acid afforded, after flash chromatography (EtOAc), 2.0 g (91%) of the title compound as a colorless oil. MS m/e (%): 547 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[C:4]([CH2:10][CH2:11]Cl)[CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:8][CH:9]=1)[CH2:6][N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][CH2:10]2
Reactant: Nc1ccccc1
Reactant: ClCCc1cc(Cl)ccc1CCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Clc1ccc2c(c1)CCN(c1ccccc1)C2

Procedure:
4-chloro-2-(2-chloroethyl)benzyl chloride (5 g), aniline (2.1 g) and triethylamine (5.7 g), were dissolved in chloroform (40 ml) and the mixture heated at reflux for 18 hr. The reaction mixture was cooled and washed with 2M sodium hydroxide solution (100 ml), 2M hydrochloric acid (100 ml) and water (100 ml), then dried (sodium sulphate) and evaporated to dryness in vacuo. The residue was chromatographed on silica gel to give the product, 6-chloro-2-phenyl-1,2,3,4-tetrahydroisoquinoline m.pt. 67°-70°.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:27])[C:21]([CH2:25][CH3:26])([CH3:24])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:45])[C@@H:15]2[CH2:28][CH2:29][C@H:30]2[O:35][C:34](=[O:36])[CH2:33][C@H:32]([O:37][Si](C(C)(C)C)(C)C)[CH2:31]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:27])[C:21]([CH2:25][CH3:26])([CH3:24])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:45])[C@@H:15]2[CH2:28][CH2:29][C@H:30]2[O:35][C:34](=[O:36])[CH2:33][C@H:32]([OH:37])[CH2:31]2)=[CH:10]1
Reactant: CCC(C)(CC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCC(C)(CC)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.9 %

Procedure:
A solution of 600 mg (0.9 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-(2-ethyl-2-methylbutyryloxy)-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 5, above] in 2 ml of tetrahydrofuran was added to a mixture of 12.7 ml of a 1M tetrahydrofuran solution of tetrabutylammonium fluoride and 1.27 ml of acetic acid, and the resulting mixture was stirred at room temperature for 15 hours. At the end of this time, the tetrahydrofuran was removed from the reaction mixture by distillation under reduced pressure. The residue was then diluted with 50 ml of ethyl acetate and the diluted solution was washed twice with 50 ml each time of water, three times with 30 ml each time of a saturated aqueous solution of sodium hydrogencarbonate and once with a saturated aqueous solution of sodium chloride, in that order. The organic layer was then dried over anhydrous magnesium sulfate and removed from the mixture by filtration, after which the solvent was removed by distillation under reduced pressure. The residue was purified by flash column chromatography through silica gel, using ethyl acetate as the eluent, to give 387 mg (98% yield) of the title compound as a colorless solid. This compound was recrystallized from a mixture of hexane and ethyl acetate to produce the title compound as colorless prisms, melting at between 152° and 154° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([CH:9](O)[C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=1[F:18])[C:5]([O:7][CH3:8])=[O:6].CCN(CC)CC.CS(Cl)(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[C:4](=[CH:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=1[F:18])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(C(=O)OC)C(O)c1c(F)ccc(F)c1F
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(=Cc1c(F)ccc(F)c1F)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-[Hydroxy-(2,3,6-trifluoro-phenyl)-methyl]-malonic acid dimethyl ester (13 g, 44.5 mmol) and NEt3 (99, 89 mmol) were dissolved in 300 mL CH2Cl2. MsCl (10.3 g, 89 mmol) was then added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture washed with 1N HCl solution (200 mL×2), brine (100 mL), dried over Na2SO4 and concentrated. The product was purified by column chromatography using EtOAc/Hexane as eluent (gradient from 0/100 to 25/75 in 40 min, 6.5 g, 53%). 1H NMR (CDCl3 400 MHz) δ 7.71 (s, 1H), 7.20 (m, 1H), 6.89 (m, 1H), 3.87 (s, 3H), 3.80 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:28])([O:7][C:8]1[CH:27]=[CH:26][C:11]([O:12][CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].[ClH:29]>O1CCOCC1>[ClH:29].[F:28][C:2]([F:1])([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:26][CH:27]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OC(F)(F)C(F)(F)F)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)(F)C(F)(F)Oc1ccc(OC2CCNCC2)cc1

Procedure:
tert-butyl 4-[4-(pentafluoroethoxy)phenoxy]piperidine-1-carboxylate (3.8 g) was stirred in 4.0M HCl in 1,4-dioxane (50 mL) for 1 hour. The solvent was removed the resulting solid triturated with diethyl ether (50 mL), filtered and washed with diethyl ether (2×50 mL) to yield 4-[4-(pentafluoroethoxy)phenoxy]piperidine hydrochloride as a white solid (2.9 g) NMR Spectrum: (CDCl3) 2.1 (m, 2H), 2.3 (m, 2H), 3.3 (m, 4H), 4.6.(s, 1H), 6.9 (m, 2H), 7.2 (m, 2H), 9.8 (broad, 1H); Mass Spectrum: M−H− 312
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14]S(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][O:34][C:35]3[CH:48]=[CH:47][C:38]4[C@H:39]([CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH2:40][O:41][C:37]=4[CH:36]=3)[CH:28]=2)=[C:22]([CH3:49])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:20]2[CH:21]=[C:22]([CH3:49])[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][O:34][C:35]4[CH:48]=[CH:47][C:38]5[C@H:39]([CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH2:40][O:41][C:37]=5[CH:36]=4)[CH:28]=3)=[C:24]([CH3:26])[CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O)cc4C)c3)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCN(C(=O)OC(C)(C)C)CC5)cc4C)c3)ccc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
4-[(Methylsulfonyl)oxy]piperidine-1-carboxylic acid tert-butyl ester (134 mg, 0.48 mmol), (S)-methyl 2-(6-((4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 3 h (200 mg, 0.48 mmol) and cesium carbonate (470 mg, 1.43 mmol) were dissolved in 10 mL of N,N-dimethylformamide. The reaction mixture was heated to 80° C. and stirred for 12 hours. The resulting solution was mixed with 30 mL of ethyl acetate. The organic phase was washed with water (20 mL×2) and saturated sodium chloride solution (20 mL) successively, dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by elution system B to obtain the title compound methyl (S)-2-(6-((4′-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 3j (101 mg, yield 35.0%) as a colorless slime.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:13]2[CH:12]=[N:11][N:10]([CH3:9])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1ccc(Cl)nn1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccc(Cl)nn2)cn1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 59.9 %

Procedure:
A mixture of 3,6-dichloropyridazine (5.37 g, 33.5 mmol), 1-methyl-4-pyrazoleboronic acid pinacol ester (5 g, 24.0 mmol) and cesium carbonate (23.44 g, 72 mmol) in 1,4-dioxane (150 mL) and water (750 mL) under nitrogen was degassed by bubbling in nitrogen for 15 min. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (1 g, 1.37 mmol) was than added and nitrogen was bubbled in the mixture for another 10 min. The reaction mixture was stirred at 80° C. for 2.5 h, then cooled to room temperature and concentrated in vacuo. The residue was partitioned between 1 N aqueous potassium carbonate and ethyl acetate. The organic layer was washed with 1 N aqueous potassium carbonate and brine, dried over sodium sulfate, filtered and adsorbed on silica gel for purification. Purification by flash chromatography on silica gel using a gradient of 0-50% ethyl acetate/hexane afforded 2.8 g of the title compound as a white solid (60% yield); MS (m/z) 195 [M+H+]+.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].C(O[C:8](=[O:24])[CH2:9][NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)C.C(O)(=O)C>O>[O:1]=[C:2]1[NH:3][C:8](=[O:24])[CH2:9][N:10]1[CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:15][CH2:16]1
Reactant: CCOC(=O)CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CC(=O)NC2=O)CC1
Temperature: 40 °C
Reaction time: 16 h
Yield: 30.3 %

Procedure:
Potassium cyanate (31 mg, 0.384 mmol) was added to a solution of tert-butyl 4-[(2-ethoxy-2-oxoethyl)amino]piperidine-1-carboxylate (100 mg, 0.384 mmol) in water (2 mL). Acetic acid was then added to adjust pH of reaction to 4-5 and the mixture was heated at 40° C. After 16 h, the reaction was cooled to ambient temperature and purified by reverse phase HPLC(C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) to give the title compound (33 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=2)[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][C:28]=2[NH2:29])[CH2:23][CH2:22]1.Cl.O1CCOCC1>CO>[N:24]1([C:27]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][C:28]=2[NH:29][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=3)[N:5]=[C:4]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=3)[C:3]=2[CH3:20])[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1
Reactant: Cc1c(-c2cncc(F)c2)nc2ccc(F)cc2c1Cl
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(-c2cncc(F)c2)nc2ccc(F)cc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-6-fluoro-2-(5-fluoropyridin-3-yl)-3-methylquinoline (110 mg, 0.38 mmol), 2,5-dimorpholinoaniline (120 mg, 0.38 mmol) and a 4.0M solution of HCl in dioxane (0.09 mL, 0.38 mmol) in MeOH (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification N-(2,5-di-4-morpholinylphenyl)-6-fluoro-2-(5-fluoro-3-pyridinyl)-3-methyl-4-quinolinamine was obtained. 1H NMR (500 MHz, chloroform-d) δ ppm 8.70 (1H, t, J=1.7 Hz), 8.60 (1H, d, J=2.7 Hz), 8.13-8.22 (1H, m), 7.77 (1H, dt, J=8.8, 2.3 Hz), 7.44-7.55 (2H, m), 7.25 (1H, s), 7.15 (1H, d, J=8.6 Hz), 6.51 (1H, dd, J=8.8, 2.7 Hz), 6.01 (1H, dd, J=2.4, 0.5 Hz), 3.91 (4H, t, J=4.6 Hz), 3.69-3.79 (4H, m), 3.06 (4H, t, J=4.6 Hz), 2.90-2.99 (4H, m), 2.34 (3H, s). Mass Spectrum (ESI) m/e=518.1 (M+1).
Reaction SMILES: [CH:1]([O:14][C:15]1[C:16]2[C:35](=[O:36])[N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:33][C:17]=2[C:18](OS(C(F)(F)F)(=O)=O)=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)([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.C([O-])([O-])=O.[K+].[K+].[CH3:51][C:52]1[C:56](B(O)O)=[C:55]([CH3:60])[O:54][N:53]=1>C1(C)C=CC=CC=1.C(O)C.O.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]([O:14][C:15]1[C:16]2[C:35](=[O:36])[N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:33][C:17]=2[C:18]([C:56]2[C:52]([CH3:51])=[N:53][O:54][C:55]=2[CH3:60])=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: O=C1c2c(c(OS(=O)(=O)C(F)(F)F)c3cccnc3c2OC(c2ccccc2)c2ccccc2)CN1Cc1ccc(F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1noc(C)c1-c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Temperature: 120 °C

Procedure:
To a solution of trifluoro-methanesulfonic acid 9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester 46 (23.6 mg, 0.038 mmol) dissolved in toluene (3 mL)/ethanol (0.6 mL)/water (0.4 mL) was added K2CO3 (16 mg, 0.11 mmol), 3,5-dimethylisoxazole-4-boronic acid (11 mg, 0.076 mmol) and tetrakis-(triphenylphosphine)-palladium(0) (9 mg, 0.007 mmol). The reaction mixture in the flask was flashed with argon three times. It was then heated to 120° C. under argon 3 hours. The reaction was monitored by LC/MS. After cooling to room temperature, the mixture was diluted with EtOAc (20 mL) and washed with 1N HCl, saturated NaHCO3 and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo to afford crude 9-benzhydryloxy-5-(3,5-dimethyl-isoxazol-4-yl)-7-(4-fluoro-benzyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 279.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](N1C=CN=C1)([N:19]1C=CN=[CH:20]1)=O.C(N(CC)CC)C.Cl.CNC>CN(C)C=O>[CH3:17][N:19]([CH3:20])[C:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)=[O:16]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 8.1 %

Procedure:
To a solution of (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (10 g, 43.6 mmol) in N,N-dimethylformamide (150 mL) was added 1,1′-carbonyldiimidazole (14.13 g, 87.23 mmol). The reaction mixture was stirred at room temperature for 10 min. Triethylamine (18.3 mL, 130.2 mmol) and dimethylamine hydrochloride (7.1 g, 87.2 mmol) were then added sequentially. The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated and the residue was treated with cold water and was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified via flash chromatography to afford (R)-tert-butyl 3-(dimethylcarbamoyl)piperidine-1-carboxylate (0.9 g, 80%). MS (ES+APCI) (M+H) 257.1; LCMS retention time: 2.829 min (Method D1)
Reaction SMILES: [CH2:1]([Sn:5](Cl)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].O.[CH2:16]1[CH2:20]O[CH2:18][CH2:17]1>>[CH2:1]([Sn:5]([C:2]#[C:1][Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:18][CH2:17][CH2:16][CH3:20])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: C1CCOC1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Solvent: O
Product: CCCC[Sn](C#C[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC
Yield: 88 %

Procedure:
A mixture of 48.8 g (0.150 Mol) of tri-n-butyl-tin chloride and 20.7 g (0.225 Mol) of lithium acetylide ethylenediamine complex in 300 mL of anhydrous THF was heated at reflux under argon for 24 hr, cooled and treated with 200 mL of water. The layers were separated and the THF phase was suction-filtered through Celite with a 150 mL THF wash to afford a clear solution. This solution was washed with water (3×200 mL), saturated aqueous sodium bicarbonate (2×100 mL), 5% HCl (2×100 mL), and dried over anhydrous sodium sulfate. Removal of the solvent gave 40.2 g (88%) of the bis(tri-n-butylstannyl)ethyne as a colorless liquid.
Reaction SMILES: C(O[C:4](=[O:18])[CH:5]=[C:6]([NH:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[O:16][CH3:17])[CH3:7])C>C1(OC2C=CC=CC=2)C=CC=CC=1.CCCCCC>[F:15][C:13]1[CH:12]=[CH:11][C:10]([O:16][CH3:17])=[C:9]2[C:14]=1[C:4]([OH:18])=[CH:5][C:6]([CH3:7])=[N:8]2
Reactant: CCOC(=O)C=C(C)Nc1cc(F)ccc1OC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: COc1ccc(F)c2c(O)cc(C)nc12
Temperature: 25 °C

Procedure:
A solution of 3-(5-fluoro-2-methoxy-phenylamino)-but-2-enoic acid ethyl ester (1.8 g, 6.7 mmol) in diphenyl ether (10.7 mL) was heated to 250° C. for 25 min. The reaction mixture was cooled to room temperature, diluted with hexane, and filtered to give the title compound. MS (m/z): 208.1 [M+H+].