Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CC[CH2:3][CH2:2]1.[C:6]([O:10][C:11](=[O:47])[N:12]([CH2:36][C:37]1[CH:46]=[CH:45][C:40]2[O:41][CH2:42][CH2:43][O:44][C:39]=2[CH:38]=1)[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]2[C:30]3[C:25](=[C:26]([CH:33]=[O:34])[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=3)[CH:24]=[CH:23][C:22]2=[O:35])[CH2:15][CH2:14]1)([CH3:9])([CH3:8])[CH3:7].C([Mg]Br)C.O1CCCC1.[Cl-].[NH4+]>C(Cl)(Cl)Cl.O>[C:6]([O:10][C:11](=[O:47])[N:12]([CH2:36][C:37]1[CH:46]=[CH:45][C:40]2[O:41][CH2:42][CH2:43][O:44][C:39]=2[CH:38]=1)[CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][N:21]2[C:30]3[C:25](=[C:26]([CH:33]([OH:34])[CH2:2][CH3:3])[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=3)[CH:24]=[CH:23][C:22]2=[O:35])[CH2:17][CH2:18]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: C1CCOC1
Reactant: COc1cc(C=O)c2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC(O)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Reaction time: 1.5 h

Procedure:
To 20 mL of a tetrahydrofuran solution containing 0.65 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-formyl-7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 8.8 mL of 1 mol/L ethylmagnesium bromide/tetrahydrofuran was added at −78° C. and stirred for 1.5 hours. To the reaction mixture, aqueous saturated ammonium chloride solution, water and chloroform were added. The organic layer was separated, washed sequentially with aqueous saturated sodium hydrogen carbonate solution and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=20:1], to give 200 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-(1-hydroxypropyl)-7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow oil.
Reaction SMILES: CC(O)=O.[NH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH3:16])[C:10]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:9]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[CH2:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][C:31]1=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH:31]1[NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH3:16])[C:10]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])=[C:9]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1Cc2ccccc2C1
Reactant: Cc1nc2ccc(N)cc2c(-c2ccccc2)c1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1nc2ccc(NC3Cc4ccccc4C3)cc2c(-c2ccccc2)c1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
A method of Abdel-Magid et al (J. Org. Chem., 61, 3849, 1996) was used: Glacial AcOH (0.25 ml) was added to a solution of the product of Step 2 (1.46 g, 4.4 mmol), 1H-inden-2(3H)-one (0.46 g, 4.5 mmol) and NaBH(OAc)3 (1.4 g, 6.55 mmol) in anhydrous 1,2-dichloroethane (17 ml). The resulting mixture was stirred overnight at room temperature under N2 and to it more of NaBH(OAc)3 (0.4 g, 1.9 mmol) was added. After 2 h of stirring at room temperature, the mixture was quenched by addition of 1N NaOH aq (5 ml). This was diluted to 60 ml with Et2O and washed with H2O and brine. The organic phase was dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (SiO2, CH2Cl2) to give pure product as a creamy solid (1.4 g, 71%). 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=9.0 Hz, 1H), 7.34-7.5(m, 5H), 7.12-7.21(m, 4H), 7.05(dd, J=2.6, 9.0 Hz, 1H), 6.49(d, J=2.6 Hz, 1H), 4.17(m, 1H), 4.08(m, 1H), 3.19-3.27(m 2H), 2.73-2.83(m, 2H), 2.7(s, 3H), 1.22(s, 9H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C@@H:19]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:20][C:21]([O:23]C)=[O:22])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1.[Li+].[OH-].O>O1CCCC1>[F:1][C:2]1[C:3]([NH:18][C@@H:19]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:20][C:21]([OH:23])=[O:22])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: COC(=O)C[C@@H](Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[C@@H](CC(=O)O)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Temperature: 50 °C

Procedure:
(R)-Methyl 3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoate, 9a, (18.4 g, 47.1 mmol) was dissolved in tetrahydrofuran (275 mL) and aqueous 1M LiOH (141 mL) was added. The mixture was heated to 50° C. for 3.5 h. The reaction mixture was cooled to room temperature and 180 mL of water was added. The tetrahydrofuran was removed under reduced pressure and the residue was then flushed twice with hexanes. Diethylether (60 mL) was added and the layers separated. The pH of the aqueous layer was adjusted to 6 with 1N HCl. Ethyl acetate (540 mL) was added, the layers were separated and the aqueous layer was extracted with ethyl acetate (720 mL), then again with ethyl acetate (300 mL). The organic layers were combined, washed with brine (100 mL) and dried (Na2SO4). The solvents were removed while flushing with heptanes to provide the desired product, 2, (17.5 g): 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 12.03 (s, 1H), 8.68-8.52 (m, 1H), 8.27 (s, 1H), 8.19 (d, J=2.5 Hz, 1H), 8.13 (d, J=4.0 Hz, 1H), 7.39 (d, J=9.2 Hz, 1H), 4.83 (t, J=9.3 Hz, 1H), 2.71-2.51 (m, 2H), 0.97 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, RT=1.96 minutes (M+H) 377.02.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]CC1C=CC=CC=1)=O.[NH2:25][C:26]1[CH:31]=[N:30][CH:29]=[C:28]([Cl:32])[N:27]=1>>[Cl:32][C:28]1[N:27]=[C:26]([NH:25][C:15]([C:3]2[N:4]([CH3:14])[S:5](=[O:12])(=[O:13])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:17])[CH:31]=[N:30][CH:29]=1
Reactant: CN1C(C(=O)OCc2ccccc2)=C(O)c2ccccc2S1(=O)=O
Reactant: Nc1cncc(Cl)n1
Product: CN1C(C(=O)Nc2cncc(Cl)n2)=C(O)c2ccccc2S1(=O)=O

Procedure:
This compound was prepared from benzyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 2-amino-6-chloro-pyrazine analogous to Example 1.
Reaction SMILES: [N:1]1[C:6]([OH:7])=[CH:5][C:4]([OH:8])=[N:3][CH:2]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1>C1COCC1.C(=O)([O-])[O-].[Ag+2]>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][O:8][C:4]2[N:3]=[CH:2][NH:1][C:6](=[O:7])[CH:5]=2)=[CH:12][CH:11]=1
Reactant: Oc1cc(O)ncn1
Reactant: Clc1ccc(CBr)cc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: O=c1cc(OCc2ccc(Cl)cc2)nc[nH]1
Temperature: 25 °C
Yield: 9.5 %

Procedure:
To a stirred solution of pyrimidine-4,6-diol (2.5 g) in THF (25 ml) was added silver carbonate (15.3 g) at room temperature followed by dropwise addition of 4-chlorobenzyl bromide (4.58 g), and the resultant mixture was heated at reflux for 2 h. The reaction mixture was then cooled to room temperature, filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (500 mg) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]([O:9][CH3:10])[C:5]([O:7][CH3:8])=[O:6].O[N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.N#N>O>[O:22]=[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:21])[N:12]1[O:1][CH2:2][CH2:3][C@H:4]([O:9][CH3:10])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COC(=O)[C@H](CCO)OC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: COC(=O)[C@H](CCON1C(=O)c2ccccc2C1=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 42.6 %

Procedure:
To a solution of (S)-methyl 4-hydroxy-2-methoxybutanoate (46b, 1.48 g, 10.0 mmol) in CH2CT2 (25.0 mL) was added 2-hydroxyisoindolin-1,3-dione (1.63 g, 10.0 mmol) and triphenylphosphine (3.93 g, 15.0 mmol). The resultant mixture was cooled to 0° C. and diisopropylazodicarboxylate (2.95 ml, 15.0 mmol) was slowly added drop wise under N2 atmosphere. The reaction mixture was stirred at ambient temperature for 48 h. To the reaction mixture, H2O (100 mL) was added and extracted with CH2Cl2. The organic layers washed with brine. Dried over anhydrous Na2SO4, filtered and concentrated to provide yellow oil, which was purified by flash chromatography (50% EtOAc-hexane) to afford (S)-methyl 4-(1,3-dioxoisoindolin-2-yloxy)-2-methoxybutanoate (46c, 1.25 g, 42%) as light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.98-2.10 (m, 1H) 2.23-2.37 (m, 1H) 3.51 (s, 3H) 3.79 (s, 3H) 4.24 (dd, J=9.47, 3.66 Hz, 1H) 4.31-4.40 (m, 2H) 7.74-7.82 (m, 2H) 7.81-7.90 (m, 2H).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:10][C:9]([P:11]([O:16][CH2:17][CH3:18])(=[O:15])[O:12][CH2:13][CH3:14])=[CH:8][CH:7]=1)CCC.I[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=1[N+:37]([O-:39])=[O:38]>O1CCOCC1.[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>[N+:34]([C:31]1[CH:32]=[C:33]([C:6]2[O:10][C:9]([P:11]([O:12][CH2:13][CH3:14])(=[O:15])[O:16][CH2:17][CH3:18])=[CH:8][CH:7]=2)[CH:28]=[C:29]([N+:37]([O-:39])=[O:38])[CH:30]=1)([O-:36])=[O:35]
Reactant: O=[N+]([O-])c1ccc(I)c([N+](=O)[O-])c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(P(=O)(OCC)OCC)o1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOP(=O)(OCC)c1ccc(-c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)o1
Temperature: 80 °C

Procedure:
A mixture of diethyl 5-tributylstannyl-2-furanphosphonate (1 mmol), 1-iodo-2,4-dinitrobenzene (1 mmol) and tetrakis(triphenylphosphine)-palladium(0) (0.05 mmol) in 6 mL of dioxane was heated at 80° C. for 16 h. Evaporation of solvent and chromatography provided diethyl 5-(3,5-dinitrophenyl)-2-furanphosphonate as solid foam.
Reaction SMILES: [CH3:1][C:2]([Mg]Br)=[CH:3][CH3:4].[F:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][CH2:13][C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:10][CH:9]=1.[Cl-].[NH4+]>O1CCCC1>[F:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][CH2:13][C:14]2[N:15]=[CH:16][CH:17]=[C:18]3[C:3]([CH3:4])=[C:2]([CH3:1])[NH:20][C:19]=23)=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1cccnc1COc1ccc(F)cc1
Reactant: CC=C(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1[nH]c2c(COc3ccc(F)cc3)nccc2c1C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
1-Methyl-1-propenyl magnesium bromide (0.5 M in tetrahydrofuran solution, 1.7 ml, 0.851 mmol) was added at −78° C. to a solution of 2-(4-fluorophenoxymethyl)-3-nitropyridine (71 mg, 0.284 mmol) prepared in Preparation 1 in anhydrous tetrahydrofuran (5 ml). The reaction mixture was stirred overnight and a saturated ammonium chloride solution was added thereto. The reaction mixture was extracted with ethyl acetate (15 ml). The organic layer was washed with water (5 ml), dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (dichloromethane/n-hexane=2/1, v/v) to give 15 mg of the titled compound as brown oil.
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:17])=[N:6][C:5]=2[N:18]=1.[ClH:19].N([O-])=O.[Na+]>C(#N)C.O>[Cl:19][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])=[N:8][C:7]([S:17][S:17][C:7]3[N:8]=[C:9]([NH:10][C@@H:11]([CH2:12][OH:13])[CH2:14][CH2:15][CH3:16])[C:4]4[S:3][C:2]([Cl:19])=[N:18][C:5]=4[N:6]=3)=[N:6][C:5]=2[N:18]=1
Reactant: CCC[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCC[C@H](CO)Nc1nc(SSc2nc(N[C@@H](CO)CCC)c3sc(Cl)nc3n2)nc2nc(Cl)sc12
Reaction time: 48 h
Yield: 78 %

Procedure:
(2R)-2-[(2-Amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]pentan-1-ol (4.0 g, 14 mmol) was dissolved in acetonitrile (100 ml) and concentrated hydrochloric acid (150 mL). Sodium nitrite (1.93 g, 28 mmol) was dissolved in water (10 mL) and added at 0° C. The reaction mixture was left at 0° C. for 2 days until the reaction was complete by LCMS. The reaction mixture was poured onto ice and the precipitated product was collected by filtration. The solid was dried in vacuo to give 3.3 g (78% yield) of the title compound.
Reaction SMILES: C([O:9][C:10]1[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13](=[O:20])[NH:12][C:11]=1[C:21]([O:23][CH3:24])=[O:22])(=O)C1C=CC=CC=1.N1C=CC=CC=1.[O:31](S(C(F)(F)F)(=O)=O)[S:32]([C:35]([F:38])([F:37])[F:36])(=O)=[O:33]>ClCCl>[OH:9][C:10]1[C:11]([C:21]([O:23][CH3:24])=[O:22])=[N:12][C:13]([O:20][S:32]([C:35]([F:38])([F:37])[F:36])(=[O:33])=[O:31])=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1[nH]c(=O)c2cccnc2c1OC(=O)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1nc(OS(=O)(=O)C(F)(F)F)c2cccnc2c1O
Temperature: 0 °C

Procedure:
To a stirring suspension of the compound of Step 2 (25 g, 77 mmol) in dry dichoromethane (150 ml) under argon was added pyridine (31 ml, 385 mmol). The suspension was then cooled to 0° C. and Tf2O (32.6 g, 19.4 ml, 116 mmol) was added dropwise which caused the formation of a red color. The ice bath was then removed and after 1 hour the red solution was poured into a saturated aqueous solution of NaHCO3 (200 ml). The organic phase was separated and the aqueous phase was extracted three times with chloroform. The combined organics were dried over sodium sulfate, filtered and concentrated to give a green solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.[C-]#N.[CH3:28][N+:29](C)(C)C.C1CCN2C(=NCCC2)CC1>CC#N>[C:20]1([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:11][C:2]([C:28]#[N:29])=[N:3]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[N+](C)(C)C
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Agent: [C-]#N
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Temperature: 80 °C
Reaction time: 12 h
Yield: 44.5 %

Procedure:
To a solution of 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (5.0 g, 14 mmol) in CH3CN (50 mL) was added tetramethylammonium cyanide (4.5 g, 29 mmol) followed by DBU (4.39 g, 28.88 mmol). Upon completion of addition, the reaction mixture was heated to 80° C. where it stirred for 12 h. After this time, the reaction mixture was quenched with water and then extracted with ethyl acetate. The organic layer was washed successively with water and brine, and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting concentrate was purified by flash column chromatography using 28% ethyl acetate in petroleum ether to yield 5-phenyl-4-(pyridin-2-ylmethylamino)quinazoline-2-carbonitrile (2.1 g) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.15-8.14 (d, J=4.0 Hz, 1H), 7.96-7.87 (m, 2H), 7.75-7.70 (dt, J=7.6, 2.0 Hz, 1H), 7.62-7.45 (m, 6H), 7.34-7.29 (m, 2H), 7.25-7.22 (m, 1H), 4.60 (d, J=3.6 Hz, 2H). LCMS Method O: retention time 1.52 min, [M+1]=338.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.[CH3:25][NH:26][C@H:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:28][OH:29]>>[CH3:9][O:8][C:6]1[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=[C:2]([N:26]([CH3:25])[C@@H:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][OH:29])[N:7]=1
Reactant: CN[C@@H](CO)c1ccccc1
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Product: COc1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(N(C)[C@H](CO)c2ccccc2)n1
Yield: 32 %

Procedure:
This compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and (R)-2-methylamino-2-phenyl-ethanol in analogy to example 1c. Purification by chromatography on Si—NH2 gel (Isolute) using ethyl acetate as an eluent gave the title compound as a colorless solid in 32% yield.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:6]2[CH2:5][CH2:4]1.Cl[C:14]1[C:18]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=2[O:16][N:15]=1>>[Cl:23][C:21]1[CH:20]=[CH:19][C:18]2[C:14]([N:10]3[CH2:9][CH2:8][N:7]4[CH2:12][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5][CH:6]4[CH2:11]3)=[N:15][O:16][C:17]=2[CH:22]=1
Reactant: Clc1ccc2c(Cl)noc2c1
Reactant: OCC1CCC2CNCCN2C1
Product: OCC1CCC2CN(c3noc4cc(Cl)ccc34)CCN2C1
Yield: 53.8 %

Procedure:
By the method of Example 7, the alcohol-amine title product of Example 6 (203 mg, 1.19 mmol) and 3,6-dichlorobenzo[d]isoxazole were converted into present title product (206 mg, 53.8% yield) isolated as a pale yellow amorphous solid. In this product the 7-and 9a-hydrogen substitutents are trans. TLC Rf (methylene chloride/methanol=9:1 in volume; potassium permanganate spray): 0.41. 13CNMR (CDCl3) delta 164.2, 160.6, 136.1, 123.3, 122.8, 114.9, 110.8, 65.9, 60.2, 58.7, 54.1, 53.4, 48.0, 39.0, 28.8, 26.7.
Reaction SMILES: [CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)([CH3:3])C.CO[C:29](=O)[CH2:30][C:31]1C=CC(I)=[CH:33][CH:32]=1>C(N(CC)CC)C.[Cu]I.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>[CH2:1]([O:4][C:5]1([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)=[CH:12][CH:13]=2)[CH2:7][CH2:6]1)[C:3]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC(C)C)CC3)cc2)cc1
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-benzene (Intermediate 71, 60.0 mg, 0.20 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 66.0 mg, 0.24 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (15.0 mg, 0.08 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (56 mg, 0.08 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-7% EtOAc-hexanes) afforded 64.0 mg (81%) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:20]([O:22][C:23](=[O:30])[CH2:24][CH:25](Br)[CH2:26][CH2:27][CH3:28])[CH3:21].O>CN(C=O)C>[CH2:20]([O:22][C:23](=[O:30])[CH2:24][CH:25]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:17][CH:16]=2)[CH:12]=[CH:13]1)[CH2:26][CH2:27][CH3:28])[CH3:21]
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: CCCC(Br)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(CC(=O)OCC)n1ccc2cc(OCc3ccccc3)ccc21
Reaction time: 0.33 h
Yield: 40 %

Procedure:
A solution of 5-benzyloxyindole (5.00 g, 22.4 mmol) in DMF (20 mL) was added dropwise to a stirred solution of sodium hydride (0.91 g, 38.1 mmol) in DMF (50 mL) at 0° C. and stirred for 20 minutes. Ethyl-β-bromocaproate (5.59 g, 26.9 mmol) in DMF (20 mL) was added and the reaction was stirred at room temperature overnight. The reaction was then poured into cold H2O (150 mL) and extracted with ethyl acetate (3×50 mL), dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (40% ethyl acetate in hexane) to give the title compound as oil (40% yield). 1H NNR (CDCl3) δ 7.47 (d, 2H, J=7.2 Hz), 7.38 (t, 2H, J=7.1 Hz), 7.32 (d, 2H, J=8.8 Hz), 7.12 (dd, 2H, J=2.4, 13.7 Hz), 6.94 (dd, 1H, J=2.4, 10.2 Hz), 6.44 (d, 1H, J=3.1 Hz), 5.09 (s, 2H), 4.79 (m, 1H), 3.98 (q, 2H, J=7.1 Hz), 2.80 (m, 2H), 1.90 (m, 2H), 1.25 (m, 2H), 1.07 (t, 3H, J=7.2 Hz), 0.86 (t, 3H, J=7.3 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH2:14][C:15]([OH:17])=O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=2[N:23]=1.[OH:33][CH:34]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:33][CH:34]1[CH2:39][CH2:38][CH2:37][N:36]([C:15](=[O:17])[CH2:14][NH:13][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([O:28][C:29]([F:31])([F:30])[F:32])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:35]1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Reactant: OC1CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N3CCCC(O)C3)ccc21
Yield: 71.3 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(3-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide (63 mg) was prepared by following General Procedure F starting from {[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid (75 mg), 3-hydroxypiperidine (18 mg), HBTU (73 mg), and DIEA (42 uL), with a modification of General Procedure F where DIEA was slowly added to the reaction mixture as the last reagent. LC/MS: m/z 549.8. 1H NMR (DMSO-d6, 400 MHz): δ 8.53-8.42 (m, 1H), 8.11 (s, 1H), 7.94 (s, 1H), 7.79 (d, 1H), 7.66 (bs, 1H), 7.51 (d, 1H), 7.37 (d, 1H), 4.19-4.08 (m, 4H), 3.75-3.60 (m, 5H), 3.20 (dd, 1H), 3.05 (t, 1H), 2.01-1.95 (m, 2H), 1.57-1.27 (m, 2H), —NH proton signal was not observed.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][C:14]=3[F:25])=[O:9])=[CH:4][CH:3]=1.C(Cl)Cl>[Pd].C([O-])([O-])=O.[Ca+2].CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](/[CH:21]=[CH:22]\[CH2:23][OH:24])=[CH:15][C:14]=3[F:25])=[O:9])=[CH:26][CH:27]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(C#CCO)cc2c1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(/C=C\CO)cc2c1O
Reaction time: 2 h

Procedure:
To a solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Example No. 53 (0.24 g) in 60 mL 3:1 CH2Cl2 :MeOH was added a spatula tip of 5% Pd/CaCO3. The reaction was placed under hydrogen balloon atmosphere. After 2 hours, the Pd catalyst was filtered over Celite, new catalyst added to the filtrate and the reaction again placed under a hydrogen balloon. This regeneration of catalyst was repeated 8 times and the reaction monitored by MS until complete. The reaction mixture was filtered over celite and the filter cake washed thoroughly with MeOH and CH2Cl2. The filtrate was concentrated under reduced pressure to give a tan solid which was a 2:1 mixture of desired product and over-reduced material as shown by NMR. This mixture was further purified by HPLC (Cyclobond 2000) to give the desired product (0.072 g, 30%).