Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:17]([C:19]1[N:20]=[C:21]2[CH:27]=[CH:26][N:25]([S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:22]2=[N:23][CH:24]=1)[NH2:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[S:28]([N:25]1[C:22]2=[N:23][CH:24]=[C:19]([NH:17][NH:18][C:14]([C@@H:11]3[CH2:12][CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]3)=[O:16])[N:20]=[C:21]2[CH:27]=[CH:26]1)([C:31]1[CH:32]=[CH:33][C:34]([CH3:35])=[CH:36][CH:37]=1)(=[O:29])=[O:30]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(=O)O)C1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)[C@@H]4CC[C@@H](NC(=O)OC(C)(C)C)C4)cnc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
To (1R,3R)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (2.25 g, 9.81 mmol, Acros) in DCM (98 mL) was added 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.98 g, 9.81 mmol), HATU (3.73 g, 9.81 mmol) and TEA (5.5 mL, 39 mmol). The reaction mixture was stirred at ambient temperature for about 4 h then diluted with DCM (300 mL). The reaction mixture was washed with water (2×80 mL), saturated aqueous NaHCO3 (80 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The residue was purified using silica gel chromatography (220 g) eluting with a gradient of 50-100% EtOAc in DCM give tert-butyl (1R,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate (5.03 g, 100%) as a brown solid: LC/MS (Table 1, Method b) Rt=2.18 min; MS m/z: 513 (M−H)−
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:11]([F:12])=[CH:10][C:9]([N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[C:8]([F:26])[CH:7]=1)=[O:5])[CH3:2].[ClH:27]>O1CCOCC1.C(OCC)C>[ClH:27].[CH2:1]([NH:3][C:4](=[O:5])[C:6]1[CH:7]=[C:8]([F:26])[C:9]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:10][C:11]=1[F:12])[CH3:2]
Reactant: CCNC(=O)c1cc(F)c(N2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCNC(=O)c1cc(F)c(N2CCNCC2)cc1F
Reaction time: 0.5 h
Yield: 98 %

Procedure:
tert-butyl 4-(4-(ethylcarbamoyl)-2,5-difluorophenyl)piperazine-1-carboxylate (0.020 g, 0.054 mmol) was diluted with 4.0M HCl in dioxane (3 mL) and stirred for 30 min. The thick white precipitate that formed was diluted with ethyl ether (10 mL) and stirred until a fine suspension resulted. The precipitate was filtered under nitrogen and dried in vacuum to afford N-ethyl-2,5-difluoro-4-(piperazin-1-yl)benzamide hydrochloride (16.2 mg, 0.053 mmol, 98% yield) as a white solid. ESI-MS: m/z 270 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)[N:23]=2)=[CH:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[N:6][CH:7]=1.Cl.O1CCOCC1>>[Cl:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)[N:23]=2)=[CH:4][C:5]([NH:8][CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1cccc(CNc2cccc(-c3cc(NC4CCNCC4)ncc3Cl)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 141.1 %

Procedure:
A mixture of tert-butyl 4-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)piperidine-1-carboxylate (220 mg, 0.430 mmol), HCl 4M in Dioxane (7 mL, 28.0 mmol) was stirred at ambient temperature for 1 hr. The solvent was evaporated under reduced pressure to yield a solid which was furthe dried under high vacuum to yield 250 mg of the title compound as a HCl salt. A portion of the title compound was purified by prep LC, and then lyophilized to yield 19.0 mg of the title compound as a TFA salt. LCMS (m/z): 412.2 (MH+), retention time=0.60 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.66-1.83 (m, 2 H) 2.25 (dd, J=14.21, 3.08 Hz, 2 H) 3.08-3.21 (m, 2 H) 3.36-3.51 (m, 2 H) 3.96-4.12 (m, 1 H) 4.65 (s, 2 H) 6.74 (s, 1 H) 6.91 (s, 1 H) 6.94 (s, 1 H) 6.98-7.06 (m, 1 H) 7.12 (d, J=9.96 Hz, 1 H) 7.19 (d, J=7.62 Hz, 1 H) 7.31-7.43 (m, 1 H) 7.77-7.85 (m, 1 H) 8.09 (s, 1 H)
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:8][NH:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]1[C:15]1([C:18]([OH:20])=O)[CH2:17][CH2:16]1.[NH2:21][C:22]1[CH:23]=[C:24]2[CH2:40][C:29]3([O:34][C:33]4[CH:35]=[CH:36][CH:37]=[N:38][C:32]=4[NH:31][C:30]3=[S:39])[CH2:28][C:25]2=[N:26][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[O:2]=[C:3]1[CH2:8][NH:7][CH:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][N:4]1[C:15]1([C:18]([NH:21][C:22]2[CH:23]=[C:24]3[CH2:40][C:29]4([O:34][C:33]5[CH:35]=[CH:36][CH:37]=[N:38][C:32]=5[NH:31][C:30]4=[S:39])[CH2:28][C:25]3=[N:26][CH:27]=2)=[O:20])[CH2:16][CH2:17]1
Reactant: O=C1CNC(c2ccccc2)CN1C1(C(=O)O)CC1
Reactant: Nc1cnc2c(c1)CC1(C2)Oc2cccnc2NC1=S
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C1CNC(c2ccccc2)CN1C1(C(=O)Nc2cnc3c(c2)CC2(C3)Oc3cccnc3NC2=S)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1-(2-oxo-5-phenylpiperazin-1-yl)cyclopropanecarboxylic acid hydrochloride (57 mg, 0.22 mmol) [Wood et al. US 2007/0265225], 3-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,2′-pyrido[3,2-b][1,4]oxazine]-3′(4′H)-thione (Intermediate 1, 57 mg, 0.20 mmol) and HATU (84 mg, 0.22 mmol) in DMF (2 mL) is treated with N-methylmorpholine (0.096 mL, 0.88 mmol). The mixture is stirred at rt for 18 h and is then purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and lyophilized to afford the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[N:21]=[C:20]([N:31]4[CH2:35][CH2:34][CH2:33][C@H:32]4[CH3:36])[N:19]=3)[C@H:14]([CH3:37])[CH2:13]2)[N:6]=1)=[O:4].O.O[Li].O>C1COCC1>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C:22]2[N:21]=[C:20]([N:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[CH3:36])[N:19]=[C:18]([N:15]3[CH2:16][CH2:17][N:12]([C:7]4[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[CH:9][C:8]=4[CH3:11])[CH2:13][C@H:14]3[CH3:37])[CH:23]=2)=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(C)c(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCC[C@H]4C)n3)[C@H](C)C2)n1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)nc1N1CCN(c2cc(-c3ccc(F)cc3)nc(N3CCC[C@H]3C)n2)[C@H](C)C1
Temperature: 50 °C

Procedure:
To a solution of 6-{4-[6-(4-fluoro-phenyl)-2-(2-(R)-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-3-(R)-methyl-piperazin-1-yl}-5-methyl-pyridine-2-carboxylic acid methyl ester (300 mg, 0.595 mmol) in THF, add water dropwise until the cloudiness almost persists. To this mixture add LiOH.H2O (50 mg, 1.2 mmol). Heat the mixture at 50° C. for 2 h, and then concentrate under reduced pressure. Add a small amount of water to the residue. Adjust the final pH to 6 and collect the off-white solid via filtration. Wash the solid with water and dry to afford the title compound.
Reaction SMILES: C([N:9]=[C:10]=[S:11])(=O)C1C=CC=CC=1.[F:12][C:13]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:14]=1[NH2:15].[OH-].[Na+].Cl>CC(C)=O.O>[F:12][C:13]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:14]=1[NH:15][C:10]([NH2:9])=[S:11]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1ccc(F)c(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(F)c(NC(N)=S)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of benzoyl isothiocyanate (20.20 g, 123.9 mmol) in acetone (350 mL) at 60° C. was added a solution of 2-fluoro-5-methoxyaniline (15.90 g, 112.6 mmol) in acetone (60 mL). The reaction mixture was refluxed for 2 hours and cooled to room temperature. The solution was concentrated to a volume of approximately 100 mL and then poured into ice water (900 mL). The resulting precipitate was collected, washed with water and hexanes, and dried at 40° C. under vacuum. It was then added into a solution of sodium hydroxide (15.00 g, 375.0 mmol) in water (300 mL) at 80° C. Heating was continued for 2 hours. After the reaction had cooled to room temperature, the pH was adjusted to 10 with concentrated hydrochloric acid. The precipitate was collected by filtration and washed with saturated aqueous sodium bicarbonate solution (2×250 mL), water (2×250 mL) and hexanes (2×250 mL) to afford the title compound as a white solid. Yield: 17.40 g, 86.9 mmol, 77%. 1H NMR (300 MHz, CDCl3) δ 3.86 (s, 3H), 6.13 (br s, 1H), 6.82 (m, 1H), 6.90 (m, 1H), 7.13 (m, 1H), 7.63 (br s, 1H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Li+].[H-].C(O)(C)C.[CH2:17]([CH:20]1[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[CH2:21]1)[CH:18]=[CH2:19]>CCCCCC.C(OCC)C>[CH2:17]([C@@H:20]1[CH2:25][CH2:24][CH2:23][C@H:22]([OH:26])[CH2:21]1)[CH:18]=[CH2:19]
Reactant: C=CCC1CCCC(=O)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CC(C)O
Product: C=CC[C@@H]1CCC[C@H](O)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
87 ml of a 1 molar solution of lithium diisobutylaluminum hydride in n-hexane are dissolved in 100 ml of diethyl ether, and 7 ml of isopropanol are added at 0° C. After the evolution of gas has ended, 12.4 g of 3-allylcylohexanone, dissolved in 50 ml of diethyl ether, are added. The mixture is stirred at room temperature for 48 hours. The reaction mixture is quenched by addition of 1M hydrochloric acid and the aqueous phase is saturated with sodium chloride and extracted five times with in each case 200 ml of ethyl acetate. The combined organic phases are washed with 2N sodium hydroxide solution and dried over magnesium sulfate, and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate=15:1=>5:1. This gives 6.8 g of cis-3-allylcyclohexanol as an oil. C9H16O (140.23), MS(ESI): 141 (M+H+), Rf(n-heptane:ethyl acetate=2:1)=0.22.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[Br:12][CH2:13][CH2:14][CH2:15]Br>C(#N)C>[Br:12][CH2:13][CH2:14][CH2:15][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C#N)ccc1O
Reactant: BrCCCBr
Solvent: CC#N
Product: COc1cc(C#N)ccc1OCCCBr
Reaction time: 8 h

Procedure:
A mixture of 4-hydroxy-3-methoxybenzonitrile (7.5 g, 50 mmol), K2 CO3 (12.5 g), and 1,3-dibromopropane (15 g, 75 mmol) in acetonitrile (100 ml) was heated at reflux for 3 hours and left standing at room temperature overnight. The solvent of the reaction was removed on a rotary evaporator, and the crude solid was extracted into methylene chloride (500 ml). The insolubles were filtered off. The dichloromethane solution was concentrated and the material was purified on a flash chromatography column (SiO2, 105 g; eluted with 2:3 dichloromethane:hexane, and then with dichloromethane). The desired product thus purified weighed 7.74 g (52%). Recrystallization twice from ethanol gave analytically pure 4(3-bromopropoxy)-3-methoxybenzonitrile, m.p.=99°-101° C.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[NH:11][C:10]3=[O:17])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22](=[O:25])[CH2:23]Br.C([O-])([O-])=O.[K+].[K+]>>[CH3:20][O:21][C:22](=[O:25])[CH2:23][N:11]1[C:10](=[O:17])[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([O:6][C:5]3[CH:18]=[CH:19][C:2]([F:1])=[CH:3][CH:4]=3)[CH:8]=2)[C:12]1=[O:16]
Reactant: COC(=O)CBr
Reactant: O=C1NC(=O)c2cc(Oc3ccc(F)cc3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)CN1C(=O)c2ccc(Oc3ccc(F)cc3)cc2C1=O
Reaction time: 16 h
Yield: 90.4 %

Procedure:
A mixture of 5-(4-fluoro-phenoxy)-isoindole-1,3-dione (42.9 g, 167 mmol), Bromo-acetic acid methyl ester (21.1 ml, 223 mmol), K2CO3 (62.3 g, 446 mmol) and Et2CO (700 ml) was refluxed with stirring for 16 h before the mixture was concentrated in vacuo. To the residue was added water (150 ml) and the resulting slurry was extracted with EtOAc (1×750 ml, 1×250 ml). The combined organic phases were dried over MgSO4 and concentrated in vacuo to give the title compound as a tan solid (49.7 g); 1H NMR (CDCl3) δ=7.80 (d, 1H), 7.01 to 7.30 (m, 6H), 4.41 (s, 2H), 3.76 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([C@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][N:25]3C(OC(C)(C)C)=O)=[O:23])[CH2:18][CH2:17]2)=[CH:12][C:11]=1[NH:37][C@@H:38]([C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=1[Cl:47])[CH3:39])#[N:9]>ClCCl>[Cl:47][C:41]1[CH:42]=[C:43]([Cl:46])[CH:44]=[CH:45][C:40]=1[C@H:38]([NH:37][C:11]1[CH:12]=[C:13]([N:16]2[CH2:17][CH2:18][N:19]([C:22]([C@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]3)=[O:23])[CH2:20][CH2:21]2)[CH:14]=[CH:15][C:10]=1[C:8]#[N:9])[CH3:39]
Reactant: C[C@@H](Nc1cc(N2CCN(C(=O)[C@H]3CCCCN3C(=O)OC(C)(C)C)CC2)ccc1C#N)c1ccc(Cl)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](Nc1cc(N2CCN(C(=O)[C@H]3CCCCN3)CC2)ccc1C#N)c1ccc(Cl)cc1Cl
Reaction time: 1 h
Yield: 75 %

Procedure:
Trifluoroacetic acid (0.3 mL) was added to a solution of (R)-t-butyl 2-(4-(4-cyano-3-((R)-1-(2,4-dichlorophenyl)ethylamino)phenyl)piperazine-1-carbonyl)piperidine-1-carboxylate (0.095 g, 0.16 mmol) in dichloromethane (1 mL) at room temperature, and the solution was stirred for 1 h. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane. The organic layer was neutralized with aqueous saturated sodium bicarbonate solution, and the aqueous layer was further extracted with dichloromethane. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound as a white solid (0.060 g, 0.12 mmol, 75%). 1H NMR (400 MHz, DMSO-d6) δ 9.0 (br, 1H), 8.62-8.52 (m, 1H), 7.62-7.50 (m, 2H), 7.37 (dd, J=2.2, 8.4 Hz, 1H), 7.05 (d, J=8.8 Hz, 1H), 6.19 (dd, J=2.5, 8.8 Hz, 1H), 5.82 (d, J=2.6 Hz, 1H), 5.68 (br, 1H), 4.86 (br, 1H), 3.70-2.80 (m, 9H), 1.98-1.92 (m, 1H), 1.78-1.58 (m, 4H), 1.50-1.40 (m, 5H); MS: (ES) m/z calculated for C25H30Cl2N5O [M+H]+ 486.2. found 486.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:11]([O:13][C@H:14]([CH3:20])[CH2:15][O:16][C:17](=[O:19])[CH3:18])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31].C(N(CC)CC)C.[C:42]([O:45][CH2:46][CH3:47])(=[O:44])C>ClCCl.CCCCCC>[CH2:33]([O:32][C:30]([O:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:21][C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:11]([O:13][C@H:14]([CH3:20])[CH2:15][O:16][C:17](=[O:19])[CH3:18])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][C:42]([O:45][CH2:46][CH3:47])=[O:44])=[O:31])[CH3:34]
Reactant: CCOC(=O)Cl
Reactant: CC(=O)OC[C@@H](C)OC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H](C)COC(C)=O)cc1OC(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a mixture of (1R)-2-acetyloxy-1-methylethyl(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate (19) (8.9 g, 22.4 mmol) and ethyl chloroformate (5.30 mL, 55.3 mmol) in anhydrous dichloromethane, triethylamine (7.7 mL, 55.3 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. The solution was partitioned between dichloromethane and 10% citric acid and washed with water. The organic layer was dried over MgSO4, and concentrated to dryness. Chromatography (30% ethyl acetate in hexane) provided the title compound (20) (11.5 g, 95% yield) as a white, foamy solid. 1H NMR (400 MHz, CDCl3): δ 1.17 (d, J=6.8 Hz, 3H), 1.37 (t, J=7.2 Hz, 3H), 1.37 (t, J=7.2 Hz, 3H), 1.43 (s, 9H), 2.05 (s, 3H), 3.04 (m, 2H), 4.00 (dd, J=12.0, 6.8 Hz, 1H), 4.14 (dd, J=12.0, 3.2 Hz, 1H), 4.32 (q, J=7.2 Hz, 4H), 4.54 (dd, J=12.8, 6.4 Hz, 1H), 5.02 (d, J=8.0 Hz, 1H, NH), 5.12 (m, 1H), 7.05 (dd, J=8.0, 2.0 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H). MS (ESI) m/z 564.1 (M+Na)+ and 540.1 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[OH:9])=[C:4]([Cl:16])[CH:3]=1.Cl.[Cl:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1>>[ClH:16].[ClH:18].[Cl:16][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[CH:8]([OH:9])[C:10]1[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=1)[NH:1][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1
Reactant: Nc1ccc(C(O)c2ccncc2)c(Cl)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(C(O)c4ccncc4)c(Cl)c3)c2cc1OC
Yield: 12 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-amino-2-chlorophenyl)-1-(4-pyridyl)methanol was reacted with 4-chloro-6,7-dimethoxyquinazoline hydrochloride to give 4-{3-chloro-4-[1-hydroxy-1-(4-pyridyl)methyl]anilino}-6,7-dimethoxyquinazoline dihydrochloride salt in 12% yield;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=[C:10]2[N:9]=[C:8]1[NH:22]C(=O)OCC.[OH-].[K+]>C(O)CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:15]=[C:10]2[N:9]=[C:8]1[NH2:22]
Reactant: CCOC(=O)Nc1nc2cc(-c3ccccc3)cnc2n1Cc1ccc(OCc2ccc(OC)nc2)c(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: COc1ccc(COc2ccc(Cn3c(N)nc4cc(-c5ccccc5)cnc43)cc2OC)cn1
Temperature: 100 °C
Reaction time: 48 h
Yield: 34 %

Procedure:
To a stirred solution of ethyl (3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (0.090 g, 0.17 mmol) in ethylene glycol (10 mL) and water (10 mL) was added potassium hydroxide (1.00 g, 17.82 mmol). The mixture was heated to 100° C. After 48 h, the mixture was allowed to cool to room temperature and was diluted with water (30 mL). The mixture was extracted with dichloromethane (3×10 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC to afford 0.027 g (34%) of the product as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.36 (s, 1H), 8.21 (s, 1H), 7.87 (s, 1H), 7.70-7.68 (m, 3H), 7.50 (s, 2H), 7.40 (s, 1H), 6.90-6.77 (m, 4H), 5.31 (s, 2H), 5.05 (s, 2H), 4.77 (s, 2H), 3.95 (s, 3H), 3.81 (s, 3H) ppm; (M+1)=468.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[CH:15]=[C:14]([C:23](=[O:31])[NH:24][C:25]3[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=3)[CH:13]=2)=[CH:7][N:6]=1)=[O:4].[OH-].[Na+]>C1COCC1>[CH3:21][C:19]1([CH3:22])[CH2:18][C:17]2[C:12]([O:11][C:8]3[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=3)=[CH:13][C:14]([C:23](=[O:31])[NH:24][C:25]3[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=3)=[CH:15][C:16]=2[O:20]1
Reactant: COC(=O)c1ccc(Oc2cc(C(=O)Nc3ccn(C)n3)cc3c2CC(C)(C)O3)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=O)O)nc3)c3c(c2)OC(C)(C)C3)n1
Temperature: 60 °C
Yield: 79 %

Procedure:
To a solution of 5-[2,2-dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-pyridine-2-carboxylic acid methyl ester (179) (524 mg, 1.24 mmol) in 10 mL THF was added 2 mL 1 N aqueous NaOH. The mixture was heated at 60° C. for 1 hr, and concentrated in vacuo. The residue was acidified to pH˜1 with 1N aqueous HCl, filtered, washed with water, and dried under vacuum at 60° C. overnight to give an off-white solid (400 mg, 79% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.74 (br. s., 1 H) 8.51 (br. s., 2 H) 7.97-8.17 (m, 1 H) 7.46-7.64 (m, 2 H) 7.23 (br. s., 2 H) 6.54 (br, s, 1 H) 3.76 (s, 3 H) 2.91 (s, 2 H) 1.44 (s, 6 H); LCMS for C21H20N4O5 m/z 409.20 (M+H+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.FC(F)(F)S(O[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Si](C)(C)C)(=O)=O.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]2[O:18][CH:2]3[CH:3]=[CH:4][C:5]4[C:10]([N:1]3[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]2=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:15][CH:14]=1
Reactant: c1ccc2ncccc2c1
Reactant: COc1ccc(C=O)cc1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C2OC3C=Cc4ccccc4N3c3ccccc32)cc1
Yield: 66 %

Procedure:
Following the general procedure, treatment of quinoline (0.064g, 59 μL, 0.50 mmol) and 4-methoxybenzaldehyde (0.136 g, 91 μL, 0.75 mmol) with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.179 g, 146 μL, 0.60 mmol) in the presence of KF (0.070 g, 1.2 mmol) and 18-crown-6 (0.317 g, 1.2 mmol) in THF (2.0 mL) at −10° C. to rt for 12 h followed by flash column chromatography (Pet. ether/EtOAc=75/25) of the crude reaction mixture afforded 5-(4-methoxyphenyl)-5H,6aH-benzo[4,5][1,3]oxazino[3,2-a]quinoline as a yellow solid (0.112 g, 66% yield, dr determined by 1H NMR analysis of crude reaction mixture is >20:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[F:8].[Mg].[CH2:11]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]2[C:23](=O)[CH2:24][CH2:25][CH2:26][CH:27]=2)[CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][CH3:15].Cl.C([O:32]CC)C>>[CH2:11]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]2[CH2:23][CH2:24][C:25]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)([OH:32])[CH2:26][CH:27]=2)[CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCOCC
Reactant: Fc1ccc(Br)cc1F
Reactant: CCCCC[C@H]1CC[C@H](C2=CCCCC2=O)CC1
Agent: Cl
Agent: [Mg]
Product: CCCCC[C@H]1CC[C@H](C2=CCC(O)(c3ccc(F)c(F)c3)CC2)CC1

Procedure:
A solution of 6.0 g of 3,4-difluorobromobenzene in 25 ml. of anhydrous diethyl ether was added dropwise under stirring at 10°-15° C. to 0.66 g of magnesium metal powder, followed by reaction at room temperature for 1 hour so that a Grignard reagent was formed. After 5 g of trans-4-pentylcyclohexylcyclohexenone were added under stirring at -10° to 0° C. to the thus-formed Grignard reagent, they were reacted at room temperature for additional 1 hour. After the completion of the reaction, diluted hydrochloric acid was added dropwise to the reaction mixture, followed by the extraction of the reaction mixture with diethyl ether. After the extract was washed with saturated NaCl, anhydrous sodium sulfate was added to dry the extract. The diethyl ether was distilled off under reduced pressure, whereby 1-(trans-4-pentylcyclohexyl)-4-(3,4-difluorophenyl)-4-hydroxy-cyclohexene was obtained as a crude reaction product.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:28]([S:30]([NH2:33])(=[O:32])=[O:31])[CH3:29]>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:33][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: CCS(N)(=O)=O
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)CC)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and ethanesulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method B described hereinabove. Yield (25%); 1H NMR (d6-DMSO) δ 11.67 (br s, 1H), 7.47 (d, J=15.7 Hz, 1H), 7.40-7.09 (m, 12H), 6.86 (d, J=8.4 Hz, 2H), 6.47 (d, J=15.7 Hz, 1H), 3.37 (q, J=7.4 Hz, 2H), 2.36 (q, J=7.3 Hz, 2H), 1.16 (t, J=7.3 Hz, 3H), 0.83 (t, J=7.3 Hz, 3H); APcI m/z: 444 (M−H−)