Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1N2CN3CN(C2)CN1C3.C1CCN2C(=NCCC2)CC1.[CH3:22][O:23][C:24]([CH:26]1[CH2:30][O:29][C:28]([CH2:31][CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[N:27]1)=[O:25]>C(Cl)Cl>[CH3:22][O:23][C:24]([C:26]1[N:27]=[C:28]([CH2:31][CH:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[O:29][CH:30]=1)=[O:25]
Reactant: CCOC(=O)CC(CC1=NC(C(=O)OC)CO1)c1ccccc1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCOC(=O)CC(Cc1nc(C(=O)OC)co1)c1ccccc1
Reaction time: 0.08 h
Yield: 63.7 %

Procedure:
To a suspension of CuBr2 (1.17 g, 5.26 mmole) in degassed (3×vacuum/N2) CH2Cl2 (6 mL) was added hexamethylenetetramine (737 mg, 5.26 mmole) then DBU (0.78 mL, 5.26 mmole). After 5 min, a solution of ethyl (±)-4-(4-methoxycarbonyl-1,3-oxazolin-2-yl)-3-phenylbutanoate (420 mg, 1.32 mmole) in CH2Cl2 (2 mL) was added dropwise. After 6 hr, the mixture was filtered through a pad of silica gel (EtOAc) and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel (50% EtOAc/hexanes) to give the title compound (267 mg, 64%) as a white solid: MS (ES) m/e 318 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:44])[CH2:7][N:8]1[C:12](=[O:13])[CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][CH:24]([NH:27][CH2:28][C@H:29]([OH:42])[C:30]4[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:31]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[S:10][C:9]1=[O:43])(C)(C)C.ClCCl.FC(F)(F)C(O)=O>C(OCC)C>[OH:42][C@H:29]([C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([NH:37][S:38]([CH3:41])(=[O:39])=[O:40])[CH:31]=1)[CH2:28][NH:27][CH:24]1[CH2:25][CH2:26][N:21]([C:18]2[CH:17]=[CH:16][C:15]([CH2:14][CH:11]3[S:10][C:9](=[O:43])[N:8]([CH2:7][C:6]([OH:44])=[O:5])[C:12]3=[O:13])=[CH:20][CH:19]=2)[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)CN1C(=O)SC(Cc2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)C1=O
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(CC4SC(=O)N(CC(=O)O)C4=O)cc3)CC2)ccc1O
Temperature: 25 °C
Reaction time: 10 h
Yield: 69.3 %

Procedure:
A mixture of 5-[[4-[4-[[(R)-2-hydroxy-2-[4-hydroxy-3-[(methylsulfonyl)amino]-phenyl]ethyl]amino]-1-piperidinyl]phenyl]methyl]-2,4-dioxo-3-thiazolidineacetic acid tert-butyl-ester (300 mg, 0.46 mmol) (which was obtained in Example 64), dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) was stirred at room temperature for 10 hours. The mixture was then poured into ethyl ether (50 mL), and the precipitated solid was filtered and dried to give an off-white solid (189 mg, 58% yield); mp 158–160° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.58–1.66 (m, 2H), 2.02–2.10 (m, 2H), 2.60–2.64 (m, 2H), 2.85–3.04 (m, 4H), 3.16–3.40 (m, 4H), 3.80 (m, 2H), 4.20 (s, 2H), 4.80 (m, 1H), 5.06 (m, 1H), 6.17 (brs, 1H), 6.87–6.91 (m, 3H), 7.05–7.1 (m, 3H), 7.23 (m, 1H), 8.60 (brs, 1H), 8.80 (s, 1H), 9.94 (s, 1H), 13.3 (brs, 1H); MS (ES) m/z: 649 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:13][CH2:12]1)=[O:10].[CH:14]([Mg]Br)=[CH2:15].[Cl-].[NH4+].C1C[O:23][CH2:22]C1>C(OCC)(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:22](=[O:23])[O:10][C:9]([CH:11]3[CH2:12][CH2:13]3)([CH:14]=[CH2:15])[C:3]=2[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)C1CC1
Reactant: C=C[Mg]Br
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: C=CC1(C2CC2)OC(=O)Nc2ccc(Cl)cc21
Temperature: 0 °C

Procedure:
(2-Amino-5-chlorophenyl)(cyclopropyl)methanone (450 mg, 2.30 mmol) was dissolved in THF (5 mL), and while stirring the reaction solution at 0° C., vinyl magnesium bromide (1.0 M THF solution, 5.7 mL) was added dropwise thereto. The reaction solution was stirred overnight at room temperature, and then, a saturated aqueous ammonium chloride solution was added to the solution. After the solution was diluted with ethyl acetate, the organic layer was separated and washed with saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The resulting residue was dissolved in THF (5 mL), and 1,1-carbonyldiimidazole (CDI) (745 mg) was added thereto at room temperature. The reaction solution was stirred at room temperature for 2 hours, followed by ice-cooling, and water was added to the reaction solution. The solution was diluted with ethyl acetate and a saturated aqueous ammonium chloride solution was added thereto. The organic layer was separated and washed with saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2), whereby 6-chloro-4-cyclopropyl-4-vinyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (610 mg) was quantitatively obtained as a pale white solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][OH:7])[C@H:3]([CH3:5])[OH:4].N1C=CN=C1.[Si:13](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C@@H:2]([CH2:6][O:7][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@@H:3]([OH:4])[CH3:5]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C[C@H](O)[C@@H](N)CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](O)[C@@H](N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49.1 %

Procedure:
D-threoninol (2 g, 19.02 mmol) was dissolved in DMF (15 ml), treated with imidazole (3.89 g, 57.1 mmol) and stirred at RT for 5 min. Then, TBDPS-Cl (5.13 ml, 19.97 mmol) was added dropwise to the reaction solution under argon. The reaction solution was stirred for 16H at RT. Then it was diluted in EtOAc and washed twice with saturated NaHCO3 solution and once with brine. Organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (heptane/EtOAc: 100%→0% heptane.) to give the title compound (3.21 g, 47%). tR: 0.98 min (LC-MS 1); ESI-MS: 344.3 [M+H]+ (LC-MS 1).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[CH:21]1([CH:24]([C:30]2[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=2)[CH2:25][C:26]([O:28]C)=[O:27])[CH2:23][CH2:22]1>>[CH:21]1([CH:24]([C:30]2[CH:31]=[CH:32][C:33]([O:14][CH2:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5]/[C:4](=[N:3]\[O:2][CH3:1])/[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:8][CH:9]=3)=[CH:34][CH:35]=2)[CH2:25][C:26]([OH:28])=[O:27])[CH2:23][CH2:22]1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Reactant: COC(=O)CC(c1ccc(O)cc1)C1CC1
Product: CO/N=C(\COc1ccc(COc2ccc(C(CC(=O)O)C3CC3)cc2)cc1)c1ccccc1
Yield: 22.9 %

Procedure:
Compound 87 was synthesized from (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl)methanol (0.22 g, 0.8146 mmol) and methyl 3-cyclopropyl-3-(4-hydroxyphenyl)propanoate (0.2 g, 0.9082 mmol) by following the procedure described in scheme 30 (0.04 g, yield: 22.90%); Purity: 98.07%.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].O=C1CCC(=O)N1[O:41][C:42]([NH:44][C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1)=O>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:42]([NH:44][C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)=[O:41])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C(Nc1cccnc1)ON1C(=O)CCC1=O
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)Nc4cccnc4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 30.5 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.9 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in acetonitrile (50 mL). After stirring for 20 min, (2,5-dioxopyrrolidinyloxy)-N-(3-pyridyl)carboxamide (0.44 g, 1.85 mmol) was added. The mixture was stirred at room temperature for 17 hours. The mixture was filtered and the solid was recrystallized from methanol (25 mL) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(3-pyridylamino)carboxamide (0.23 g, 30%). 2N HCl/ether was added to a stirred solution of N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(3-pyridylamino)carboxamide (0.23 g) in methanol (5 mL) and ethyl acetate (10 mL). The mixture was stirred for 2 hours and filtered to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(3-pyridylamino)carboxamide hydrochloride (0.2 g) as a white solid: mp 263–265° C.; 1H NMR (DMSO-d6) δ 11.17 (s, 1H), 10.43 (s, 1H), 9.08 (d, J=1.7 Hz, 1H), 8.44 (d, J=5.4 Hz, 1H), 8.33–8.29 (dd, J=1.2 and 8.5 Hz, 1H), 7.93–7.78 (m, 4H), 7.55 (t, J=6.0 Hz, 1H), 5.21–5.14 (dd, J=5.a and 12.5 Hz, 1H), 4.80 (d, J=5.9 Hz, 2H), 2.97–2.84 (m, 1H), 2.65–2.50 (m, 2H), 2.10–2.06 (m, 1H); 13C NMR (DMSO-d6) δ 172.78, 169.83, 167.54, 166.96, 154.78, 139.97, 139.51, 134.80, 134.37, 133.35, 132.34, 131.60, 130.43, 127.17, 127.10, 121.99, 48.88, 38.68, 30.94, 21.99; Anal. Calcd. For C20H18N5O5Cl: C, 54.12; H. 4.09; N, 15.78; Cl, 7.99. Found: C, 54.11; H, 4.10; N, 15.44; Cl, 7.81.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]C(C)(C)C.[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[O:24])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1.CCOC(C)=O>[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[OH:24])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=CCCCCCCc1ccccc1
Reactant: c1cscn1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(CCCCCCc1ccccc1)c1nccs1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
Thiazole (21 μL, 0.29 mmol) in anhydrous THF (1.9 mL) was cooled to −78° C. and treated dropwise with 1.4 M t-BuLi (273 μL, 0.38 mmol). The reaction mixture was stirred at −78° C. for 0.5 h before a solution of 7-phenylheptanal (73 mg, 0.38 mmol) in THF (1.3 mL) was added. The reaction mixture was stirred at −78° C. for 0.5 h before being warmed to room temperature. The reaction mixture was diluted with EtOAc, and washed with H2O, saturated aqueous NaHCO3 and saturated aqueous NaCl before the organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. Flash chromatography (SiO2, 1.5×6.5 cm, 15-25% EtOAc-hexanes) afforded the title compound (50 mg, 62%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.68 (d, 1H, J=3.2 Hz), 7.24 (m, 3H), 7.14 (m, 3H), 4.96 (dd, 1H, J=4.8, 7.6 Hz), 3.09 (br s, 1H), 2.56 (t, 2H, J=7.8 Hz), 1.87 (m, 2H), 1.58 (m, 2H), 1.44 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)C#N.[C:10]([O-:13])([O-])=O.[Na+].[Na+].[CH2:16]1COCC1>CCOCC>[CH3:1][C:2]1[CH:9]=[C:6]([C:10](=[O:13])[CH3:16])[CH:5]=[N:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: C1CCOC1
Reactant: Cc1cncc(C#N)c1
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)c1cncc(C)c1
Yield: 30 %

Procedure:
5-Methyl-nicotinonitrile (2.08 g, 17.6 mmol) is heated at reflux in dry THF (20 mL) with MgMeBr (3 M solution in Et2O, 10 mL, 30 mmol) for 2 h. After cooling down, aq. Na2CO3 is added slowly to quench the reaction. Extractions with DCM affords the crude mixture which is purified by silica gel chromatography to yield 1-(5-methyl-pyridin-3-yl)-ethanone 18 (0.7 g, 30%). LC/MS (m/z) (M+1)+: 136.1.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N+:12]([O-])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(OC(=O)C)(=[O:22])C>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:22])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: [O-][n+]1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Product: O=c1cc(OCc2ccc(C(F)(F)F)cc2)cc[nH]1
Temperature: 80 °C
Yield: 91 %

Procedure:
4-(4-(Trifluoromethyl)benzyloxy)pyridine 1-oxide (600 mg, 2.22 mmol) was heated to 140° C. in acetic anhydride (20 mL) for 2 h. The mixture was concentrated and then heated at 80° C. for 1 h in a mixture of MeOH (10 mL) and aqueous 1 N NaOH (10 mL). The resultant black solution was concentrated to a volume of 10 mL and extracted with CHCl3/EtOH (3:1). The organic layer was removed and concentrated to provide the title compound (550 mg, 91%) as a tan solid: 1H NMR (300 MHz, CD3OD) δ 7.70-7.60 (m, 4H), 7.41 (d, J=7.0 Hz, 1H), 6.17 (dd, J=7.0, 2.5 Hz, 1H), 5.96 (d, J=2.4 Hz, 1H), 5.18 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C([Li])(C)(C)C.[B:17](OC)([O:20]C)[O:18]C>C1COCC1>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([B:17]([OH:20])[OH:18])[CH:3]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: OB(O)c1cnc2ccccc2c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
3-Bromoquinoline (0.4 mL, 3 mmol) was dissolved in THF, and the solution was cooled to -78° C. To this solution was added t-butyllithium (4.1 mL, 7 mmol), and the reaction mixture was stirred for 20 minutes. Trimethyl borate (0.81 mL, 7.1 mmol) was added at -78° C., and the mixture was stirred and allowed to warm to room temperature. The reaction was quenched with water, and the solvents were removed under vacuum. The residue 180 mg was taken directly to the next step.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([Cl:10])[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:13]>O>[Cl:1][C:2]1[N:9]=[C:8]([Cl:10])[C:7]([F:11])=[CH:6][C:3]=1[C:4]([NH2:5])=[O:13]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Solvent: O
Product: NC(=O)c1cc(F)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 82 %

Procedure:
A 12-L 3-neck round bottom flask equipped with overhead stirrer, refluxing condenser, and N2 inlet/outlet was charged with 2,6-dichloro-5-fluoronicotinonitrile (2.0 kg, 1.0 eq). Concentrated sulfuric acid (4.93 L) was added and the mixture was stirred at RT until most of the brown solids had dissolved. Next, the reaction mixture was stirred at 65° C. for 1 h. The dark-brown solution was cooled to a temperature<10° C. using an ice bath. The reaction mixture was added to a 50-L round bottom flask, which contained de-ionized water (24.7 L) that had been cooled to a temperature<10° C., using a peristaltic pump. The reaction mixture was added to the water quench over a 2.3 h period, which kept the internal temperature of the mixture below 21° C. The resulting slurry was filtered through a Buchner funnel fitted with a Sharkskin filter paper. The 50-L RBF was rinsed with water (3×4 L) and the rinses were used to wash the filter cake. The filter cake was conditioned for 50 min, transferred to a drying tray, and was dried under high vacuum at 40-50° C. for 24 h and then at 20-25° C. for 18 h to give the title compound as a beige solid (896.4 g, 82%). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.94 (s, 1 H), 8.10 (s, 1 H), 8.24 (d, 1 H). [M+H] calc'd for C6H3Cl2FN2O, 209; found, 209.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5])[CH3:2].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[NH:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C1CCCC1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1CCCC1NCc1ccccc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 44.2 %

Procedure:
A solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (3.00 g, 19.2 mmol) in ethanol (20 mL) was treated with benzylamine (2.10 mL, 19.2 mmol), sodium cyanoborohydride (2.42 g, 38.4 mmol), glacial acetic acid (10 drops) and stirred for 16 h at 50° C. After cooling to 25° C. the solvent was removed in vacuo, the crude material was redissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was discarded and the organic layer was washed with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was discarded, 1.0 M aqueous sodium hydroxide solution (75 mL) was added and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo to afford the desired product, 2-benzylamino-cyclopentanecarboxylic acid ethyl ester (2.10 g, 8.49 mmol, 44.2%), as a light yellow oil. LC-MS (ESI) calcd for C15H21NO2 247.16, found 248.2 [M+H+].
Reaction SMILES: [CH3:1][C:2]1([CH3:42])[C:6]2=[N:7][CH:8]=[C:9](B3OC(C)(C)C(C)(C)O3)[CH:10]=[C:5]2[N:4]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=3)[N:23]=[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:37]([CH3:40])(=[O:39])=[O:38])[C:21]=2[CH3:41])[CH2:3]1.[NH2:43][C:44]1[N:49]=[C:48](Cl)[CH:47]=[CH:46][N:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:30][C:26]1[CH:25]=[C:24]2[C:29]([C:20]([N:4]3[C:5]4[C:6](=[N:7][CH:8]=[C:9]([C:46]5[CH:47]=[CH:48][N:49]=[C:44]([NH2:43])[N:45]=5)[CH:10]=4)[C:2]([CH3:1])([CH3:42])[CH2:3]3)=[C:21]([CH3:41])[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:37]([CH3:40])(=[O:38])=[O:39])=[N:23]2)=[CH:28][CH:27]=1
Reactant: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: Nc1nccc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(-c3ccnc(N)n3)cc21
Temperature: 120 °C

Procedure:
Prepared according to procedure P using 4-(3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline (131 mg, 0.22 mmol) (described herein), 2-amino-4-chloropyrimidine (28.9 mg, 0.22 mmol), bis(triphenylphosphine)palladium(ii) chloride (15.7 mg, 0.022 mmol), and sodium carbonate (70.9 mg, 0.67 mmol) in 1,4-dioxane (4.8 mL) and water (1.2 mL). The reaction mixture was heated in a microwave at 120° C. for 60 min. Purification afforded 4-(1-(7-fluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)-4-quinolinyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-2-pyrimidinamine as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.55 (1H, m), 8.11-8.35 (2H, m), 8.04 (1H, m), 7.64-7.91 (3H, m), 7.44-7.57 (1H, m), 7.20-7.44 (2H, m), 6.70-7.05 (1H, m), 4.9-5.35 (2H, m), 3.35-3.96 (2H, m), 2.97-3.22 (3H, m), 1.87-2.05 (3H, m), 1.44-1.73 (6H, m). Mass Spectrum (ESI) m/e=555 (M+1).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:23][N:22]([C:24](=O)[CH2:25][CH3:26])[CH2:21]3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].B.C1COCC1.C(OCC)(=O)C>C1COCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:21][N:22]([CH2:24][CH2:25][CH3:26])[CH2:23]3)=[CH:16][CH:15]=2)(=[O:11])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCC(=O)N1CC(c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cc2)C1
Agent: B
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cc2)C1
Yield: 67.1 %

Procedure:
Following the same procedure as described in Example 46.6, 4-isopropyl-N-[4-(1-propionyl-azetidin-3-yl)-phenyl]-benzenesulfonamide (140 mg, 0.36 mmol) in THF (18 ml) was then treated with 1M BH3.THF (3.6 ml). The crude material was chromatographied (ethyl acetate) to afford the title compound (90 mg, 67%) as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][CH:6]=2.[N+:18]([C:21]1[CH:22]=[C:23]([CH:32]=[CH:33][CH:34]=1)[CH:24]=[C:25]([C:30]#[N:31])[CH:26](O)C#N)([O-:20])=[O:19].[NH:35]1CCCCC1>C(O)C.CCOCC>[NH2:31][C:30]1[O:12][C:9]2[C:10]3[C:5]([CH:6]=[CH:7][C:8]=2[CH:24]([C:23]2[CH:32]=[CH:33][CH:34]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=2)[C:25]=1[C:26]#[N:35])=[CH:4][C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:2]([OH:1])[CH:11]=3
Reactant: N#CC(=Cc1cccc([N+](=O)[O-])c1)C(O)C#N
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1cc2cccc(O)c2cc1O
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1cc2ccc3c(c2cc1O)OC(N)=C(C#N)C3c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To a solution of ethyl 3,5-dihydroxynaphthalene-2-carboxylate (4.5 g) in ethanol (40 ml) was added 3-nitrobenzylidenemalonitrile (3.9 g) and piperidine (1.95 ml). The mixture was heated under reflux for 15 minutes whereupon a yellow precipitate was observed to form. The mixture was allowed to cool to room temperature, diluted with ether (100 ml) and the solid filtered off to yield ethyl 2-amino-3-cyano-9-hydroxy-4-(3-nitrophenyl)-4H-naphtho[1,2-b]pyran-8-carboxylate as a yellow powder, m.p. 260°-261° C. (dec.)
Reaction SMILES: Cl.[N:2]1([C:7]([NH2:9])=[NH:8])[CH:6]=[CH:5][CH:4]=N1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:19]([C:20]3[N:25]=[C:24]([NH:26][C@H:27]4CCCN[CH2:28]4)[C:23]([F:33])=[CH:22][N:21]=3)=[CH:18][N:17]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[C:14]2=[N:15][CH:16]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[C:13]2[C:19]([C:20]3[N:25]=[C:24]([NH:26][CH:27]4[CH2:28][CH2:4][CH2:5][CH2:6][N:2]4[C:7](=[NH:8])[NH2:9])[C:23]([F:33])=[CH:22][N:21]=3)=[CH:18][N:17]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[C:14]2=[N:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCNC4)n3)c3cc(Cl)cnc32)cc1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CCCCN4C(=N)N)n3)c3cc(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.7 %

Procedure:
To a solution of pyrazole-1-carboxamidine hydrochloride (0.12 g, 0.80 mmol) and 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2, 3-13]pyridin-3-yl]-5-fluoro-N-[(3S)-3-piperidyl]pyrimidin-4-amine, 1c, (0.40 g, 0.80 mmol) in DMF (0.9 mL) was added iPr2NEt (0.14 mL, 0.80 mmol). The reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted into water, filtered, washed with additional water, then ether. The filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography using 5-20% MeOH/CH2Cl2 gradient (product elutes with 20% MeOH) to afford 190 mg of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[C:11]([C:12]#[N:13])=[CH:10][S:9][CH:8]=2)=[C:4]([N+:16]([O-])=O)[CH:3]=1.C(OCC)(=O)C>C(O)C.[Pd]>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[C:11]([C:12]#[N:13])=[CH:10][S:9][CH:8]=2)=[C:4]([NH2:16])[CH:3]=1
Reactant: N#Cc1cscc1Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1cscc1Nc1ccc(Cl)cc1N

Procedure:
3-(4-Chloro-2-nitroanilino)-thiophene-4-nitrile (17.18 g, 0.06 mol) was hydrogenated in ethanol (300 ml) and ethyl acetate (100 ml) using a palladium/charcoal catalyst (3.5 g, 10%) in a Parr hydrogenator to give 3-(4-Chloro-2-aminoanilino)-thiophene-4-nitrile. After two hours, the reaction was complete, the catalyst was filtered off and the solution was evaporated to dryness under vacuum.