Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH:11]=[O:12])[N:10]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[CH:29][C:30]([N:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)=[N:31][CH:32]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:11]([C:9]1[N:10]=[C:6]2[C:5]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:4][CH:3]=[C:2]([C:27]3[CH:28]=[CH:29][C:30]([N:33]4[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]4)=[N:31][CH:32]=3)[N:7]2[CH:8]=1)=[O:12]
Reactant: O=Cc1cn2c(Br)cnc(N3CCOCC3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(C=O)cn34)cn2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a suspension of compound 2a (200 mg, 0.643 mmol) and tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (300 mg, 0.771 mmol) in 1,4-dioxane (10 mL) was added Na2CO3 solution (2 M, 1.61 mL, 3.21 mmol). The mixture was purged with Argon gas before the addition of PdCl2(dppf) (47.0 mg, 0.0643 mmol). The reaction mixture was stirred at 80° C. for 2 h. After cooling to rt, water (50 mL) was added and the mixture was extracted with DCM (2×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/heptane (3:2 v/v) to obtain compound 19a as a yellow solid (276 mg, 87% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C25H31N7O4: 494.2 (M+H). Found 494.2.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7].Cl[CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38])[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7]
Reactant: OCCOCCCl
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C[C@@H]2CN(CCOCCO)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 70 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (500 mg), 2-(2-chloroethoxy)ethanol (168 mg), potassium carbonate (233 mg) and potassium iodide (56 mg) in N,N-dimethylformamide (2 ml) was heated with stirring at 50° C. for 17 hours, 60° C. for 13 hours and 70° C. for 1 hour. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the resulting residue was purified by column chromatography on silica gel using dichloromethane-methanol (10:1) as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-(2-hydroxyethoxy)ethyl]piperazine (359 mg).
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:5]=[CH:6][C:7](/[CH:12]=[CH:13]/[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[N:8][C:9]=1[O:10][CH3:11])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:27][O:28][CH:29]([O:32][CH3:33])[CH2:30]Br>CN(C=O)C>[CH3:27][O:28][CH:29]([O:32][CH3:33])[CH2:30][C:1]([NH:3][C:4]1[CH:5]=[CH:6][C:7](/[CH:12]=[CH:13]/[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[N:8][C:9]=1[O:10][CH3:11])=[O:2]
Reactant: COC(CBr)OC
Reactant: COc1nc(/C=C/C(=O)OC(C)(C)C)ccc1NC=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1nc(/C=C/C(=O)OC(C)(C)C)ccc1NC(=O)CC(OC)OC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
tert-Butyl (E)-3-(5-formylamino-6-methoxypyridin-2-yl)acrylate synthesized according to the method in Examples 168 and 169 (4 g) was dissolved in DMF (60 mL). Cesium carbonate (9.38 g) was added and the reaction solution was heated to 60° C. Bromoacetaldehyde dimethylacetal (2.08 mL) was added to the reaction solution. The reaction solution was stirred for two hours, heated to 110° C. and stirred for 10 hours. The reaction solution was left to cool. Ice water was added under ice-cooling, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (carrier: Chromatorex Si; elution solvent: heptane:ethyl acetate=7:1→heptane:ethyl acetate=1:2) to obtain the title compound (3.99 g). The property values of the compound are as follows.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:14]=[O:15])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-])=O>Cl.CCO.CC(O)=O.O.[Fe]>[NH2:1][C:4]1[C:5]([CH:14]=[O:15])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2
Reactant: O=Cc1ccc2cccnc2c1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Nc1c(C=O)ccc2cccnc12
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 770.4 %

Procedure:
8-nitroquinoline-7-carbaldehyde 204 (100 mg, 0.49 mmol), iron powder (0.02 ml, 4.95 mmol) and conc. HCl (2 drops) was suspended in a mixture of EtOH/AcOH/water (2:2:1) and the mixture was heated under reflux for 15 min and then stirred at room temperature for 25 min. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was diluted with EtOAc and washed with sat. NaHCO3 solution until the pH remained neutral. The organic phase was purified by column chromatography with heptane/EtOAc (80:20) as the eluent to yield the title compound (650 mg, 38%).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:22])([N:16]3[CH2:21][CH2:20][S:19][CH2:18][CH2:17]3)[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:23][C:24]([C:26]2[NH:27][CH:28]=[C:29]([C:31]#[N:32])[N:30]=2)=[O:25])=[CH:4][CH2:3]1.OO.CC[O:38]C(C)=O>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:1][C:2]1([CH3:33])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:15])([N:16]3[CH2:17][CH2:18][S:19](=[O:38])[CH2:20][CH2:21]3)[CH3:22])[CH:11]=[CH:10][C:9]=2[NH:23][C:24]([C:26]2[NH:27][CH:28]=[C:29]([C:31]#[N:32])[N:30]=2)=[O:25])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)N3CCSCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: CCOC(C)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: OO
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(C(C)(C)N3CCS(=O)CC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a solution of 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-methyl-1-thiomorpholin-4-yl-ethyl)-phenyl]-amide (as prepared in Example 14, step (e), 30.0 mg, 0.0647 mmol) in 0.5 mL of DCM at RT was added titanium (IV) isopropoxide (19 μL, 0.065 mmol). The mixture was cooled to 0° C. and H2O2 (13 μL, 0.13 mmol, 30 wt % in H2O) was added. After stirring at 0° C. for 4 h, the mixture was treated with EtOAc (50 mL) and washed with H2O (2×10 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo, the residue was purified by silica gel chromatography (1-4% MeOH/DCM) to afford the title compound (30 mg, 95%) as a colorless oil. 1H-NMR (CDCl3; 400 MHz): δ 13.06 (s, 1H), 9.63 (s, 1H), 8.34 (d, 1H, J=8.6 Hz), 7.71 (s, 1H), 7.51 (dd, 1H, J=8.6, 2.0 Hz), 7.27 (d, 1H, J=2.0 Hz), 5.78 (m, 1H), 3.17 (m, 2H), 2.84-3.08 (m, 4H), 2.71 (m, 2H), 2.28 (m, 2H), 2.11 (m, 2H), 1.60 (t, 2H, J=6.3 Hz), 1.40 (s, 6H), 1.11 (s, 6H). Mass spectrum (ESI-neg, m/z): Calcd. for C26H33N5O2S, 478.2 (M−H). found 478.3.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=1)[CH3:14].CI.Cl>O1CCCC1>[CH2:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:1])[C:23]#[N:24])=[CH:18][CH:17]=1)[CH3:14]
Reactant: CCOc1ccc(CC#N)cc1
Reactant: CC(C)NC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCOc1ccc(C(C)C#N)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a solution of 8.8 g of diisopropylamine in 150 ml of dry tetrahydrofuran were added 50 ml (1.5 mmole/ml) of n-butyl lithium at -50° C. After stirring at -20° C. for 30 minutes, 10.0 g of 4-ethoxyphenylacetonitrile was added thereto at -50° C. After stirring at the same temperature for 1 hour, 10.1 g of methyl iodide was added dropwise at -50° C. After stirring at the same temperature for 3 hours and then at 20° C. for 10 hours, the reaction solution was poured into 10% aqueous hydrochloric acid and extracted with ethyl acetate. After concentrating the ethyl acetate layer, the residual oil was column-chromatographed on silica gel (developing solvent, n-hexane: ethyl acetate=20:1) to obtain 9.50 g of the desired 2-(4-ethoxyphenyl) propionitrile [corresponding to the compound represented by the foregoing formula (II) wherein R1 is an ethoxy group, R2 is a hydrogen atom and R4 is a methyl group] as a pale yellow oil.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]1[C:12](=[O:23])[NH:13][N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH:16]=1.[CH2:24]([Sn](CCCC)(CCCC)C=C)[CH2:25]CC.[F-].[K+].CCOC(C)=O>[Cl-].C([N+](CC)(CC)CC)C.CN(C=O)C.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>[N:20]1[CH:21]=[CH:22][C:17]([C:15]2[CH:16]=[C:11]([C:3]3[NH:4][C:5]4[C:10]([C:2]=3[CH:24]=[CH2:25])=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:12](=[O:23])[NH:13][N:14]=2)=[CH:18][CH:19]=1
Reactant: O=c1[nH]nc(-c2ccncc2)cc1-c1[nH]c2ccccc2c1I
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1c(-c2cc(-c3ccncc3)n[nH]c2=O)[nH]c2ccccc12
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
A mixture of 104 mg 4-(3-iodo-1H-indol-2-yl)-6-pyridin-4-yl-2H-pyridazin-3-one (example 25), 123 mg tributyl(vinyl)tin, 41 mg tetraethylammonium-chloride and 9 mg bis(triphenylphosphine)palladium(II) chloride in DMF is stirred at 80° C. for 40 min. After cooling to room temperature, 4 ml aqueous potassium fluoride solution (30%) are added and the mixture stirred for 30 min at room temperature before extraction with EtOAc. The organic layer is dried over MgSO4 and the solvent evaporated ion prior to purification of the crude product by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% HCOOH).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:8]=1)(=O)=O.[NH2:25][C:26]1[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:18]1([N:9]2[C:10]3[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=3[C:7]([NH:25][C:26]3[CH:27]=[C:28]([S:32]([NH2:35])(=[O:33])=[O:34])[CH:29]=[CH:30][CH:31]=3)=[N:8]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCCC1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1nccc2c1c(Nc1cccc(S(N)(=O)=O)c1)nn2C1CCCC1
Yield: 33.1 %

Procedure:
To a solution of 1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (150 mg) obtained in Step C of Example 12 in toluene were added 3-aminobenzenesulfonamide (106 mg), tris(dibenzylideneacetone)dipalladium (37.6 mg), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (47.5 mg) and cesium carbonate (401 mg), and the mixture was heated overnight with reflux under nitrogen atmosphere. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (52.6 mg).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1.[Cl:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([N:18]=[C:19]=[S:20])=[C:12]([F:21])[CH:11]=1>CCOCC>[Cl:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([NH:18][C:19]([N:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]2[CH2:2][OH:1])=[S:20])=[C:12]([F:21])[CH:11]=1
Reactant: COc1cc(N=C=S)c(F)cc1Cl
Reactant: OCC1CCCCN1
Solvent: CCOCC
Product: COc1cc(NC(=S)N2CCCCC2CO)c(F)cc1Cl
Temperature: 30 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
11.5 g (0.10 mol) of 2-hydroxymethylpiperidine are dissolved in 100 ml of ether, and 21.8 g (0.10 mol) of 4-chloro-2-fluoro-5-methoxyphenyl isothiocyanate are added dropwise at RT. The mixture is stirred for 2 hours at 30° C., washed with twice 100 ml of water and dried over sodium sulfate, and the solvent is removed. 32.6 g (98% of theory) of 1-[N-(4-chloro-2-fluoro-5-methoxyphenyl)thiocarbamoyl]-2-hydroxymethylpiperidine are obtained in the form of a pale yellow viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C(OCl)(C)(C)C.[CH3:23][S:24][CH2:25][C:26]([NH:28][CH3:29])=[O:27].C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:4](=[O:5])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:12][C:13]([Cl:16])=[CH:14][C:15]=1[CH:25]([S:24][CH3:23])[C:26]([NH:28][CH3:29])=[O:27]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CNC(=O)CSC
Agent: CC(C)(C)OCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)C(SC)c1cc(Cl)cc(C(=O)c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 38.3 g (0.166 mole) of 2-amino-5-chlorobenzophenone in 1 liter of methylene chloride cooled to -70° C. under an atmosphere of nitrogen was added 18.05 g (0.167 mole) of t-butylhypochlorite. The solution was stirred for 15 min and then a solution of 20.3 g (0.171 mole) of 2-methylthio-N-methylacetamide in 100 ml of methylene chloride was added. The solution was stirred at -70° C. for 2 hrs and 25 ml of triethylamine was added. While stirring, the solution was allowed to warm to room temperature followed by extraction with water and drying of the organic layer with magnesium sulfate. The volume of the solution was reduced to about 400 ml, ether was added and the solution placed in a refrigerator at about 0° C. overnight. The solid which crystallized was dried under high vacuum for about 4 hr at 50° C. Weight of the product was 31.56 g (54.6%) which melted at 170°-171° C.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][S:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)#[N:2].C[Si]([N:19]=[N+:20]=[N-:21])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[NH:19]1[C:1]([C:3]2[CH:4]=[CH:5][C:6]([CH2:7][S:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:13][CH:14]=2)=[N:2][N:21]=[N:20]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1ccc(CSCC(=O)O)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=C(O)CSCc1ccc(-c2nnn[nH]2)cc1
Reaction time: 6 h

Procedure:
(4-Cyanobenzylthio)acetic acid (from Example 3; 207 mg, 1 mmol) was added to a stirred solution of trimethylsilylazide (400 μL, 3 mmol) and dibutyltin oxide (25 mg, 100 μmol) in toluene (0.5 mL) at 110° C. After 6 hours, the reaction was quenched with MeOH (1 mL) and evaporated. The residue was purified by flash chromatography (silica gel; 1000:100:3 to 1000:100:13 CHCl3 /MeOH/HOAc) to give the title compound. Rf (silica; 1000:100:6 CHCl3 /MeOH/HOAc)=0.2 compared to the nitrile starting material of Rf =0.67. 1H NMR (d6DMSO); δ3.15 (s, 2H), 3.88 (s, 2H), 7.51 (d, 2H, J=8.1 Hz), 7.99 (d, 2H, J=8.1 Hz). FAB mass spectrum m/z=251 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:16][CH2:15][N:14](C(OCC)=O)[CH2:13][CH2:12]3)[C:6]=2[CH:22]=1.[OH-].[Na+]>Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[C:6]=2[CH:22]=1
Reactant: CCOC(=O)N1CCC(n2c(=O)[nH]c3ccc(F)cc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c2ccc(F)cc2n1C1CCNCC1
Yield: 106.3 %

Procedure:
D3 (9.6 g, 30 mmol) was suspended in a 2.5M aqueous solution of sodium hydroxide (75 mL). The suspension was refluxed for 15 hours and then allowed to cool. The solution was acidified with 6M HCl (˜40 mL) until no more effervescence was observed (˜pH 2) and then the pH was carefully adjusted to pH 8.5 using 2.5 M aqueous NaOH. The resulting precipitate was collected by filtration, washed with cold water (20 mL) and then dried under vacuum at 40° C. for 15 hours to give the title compound (7.5 g, 100% yield) as a light purple solid (Rf: Baseline (ethyl acetate)). 1H-NMR (300 MHz, DMSO-d6) □ 10.98 (1H, br s), 8.93 (1H, br s), 7.40 (1H, d), 6.93 (1H, dd), 6.79 (1H, dd), 4.51-4.48 (1H, m), 3.35-3.32 (2H, m), 3.02-2.98 (2H, m), 2.55-2.52 (2H, m), 1.78-1.74 (2H, m); m.p.>190° C. (decomp).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:27]1[CH2:28][CH2:29][CH2:30][O:31][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.O>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:29]3[CH2:28][CH2:27][CH2:32][O:31][CH:30]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: BrC1=COCCC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2ccc(C3=COCCC3)cc2C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a stirred solution of 1.59 mmol 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and 1.44 mmol 5-bromo-3,4-dihydro-2H-pyran (CAS: 26274-19-1) in 9 ml ethanol and 21 ml toluene was added 0.08 mmol 1,1-bis(diphenylphosphino)ferrocene dichloro palladium (II) dichloromethane adduct. The mixture was heated to 80° C. and then 10 ml of a solution of 2 M aqueous sodium carbonate was added dropwise. After stirring for a further 2 h at 80° C., the reaction mixture was diluted with 50 ml water and extracted with 3×50 ml ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a yellow oil (40% yield). MS (m/e): 246.1 ([M+H-Me2C═CH2]+, 100%).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](\[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:16]Br)/[C:5]([O:7][CH3:8])=[O:6].[C:18]1([CH3:25])[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][O:2]/[N:3]=[C:4](\[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:16][O:24][C:23]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:25])/[C:5]([O:7][CH3:8])=[O:6]
Reactant: CO/N=C(/C(=O)OC)c1c(C)cccc1CBr
Reactant: Cc1ccccc1O
Product: CO/N=C(/C(=O)OC)c1c(C)cccc1COc1ccccc1C

Procedure:
methyl E-2-bromomethyl-6-methylphenylglyoxylate O-methyl oxime is reacted with o-cresol under a basic condition to give methyl E-2-((2-methylphenyl)oxymethyl)-6-methylphenylglyoxylate O-methyl oxime (step 1); and
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[C:16](Cl)(=[O:18])[CH3:17]>C(N(CC)CC)C>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:16](=[O:18])[CH3:17])[CH:11]=1
Reactant: Clc1ccc(NCc2cccnc2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N(Cc1cccnc1)c1ccc(Cl)cc1

Procedure:
N-[(3-pyridyl)methyl]-N-(4-chlorophenyl)acetamide was prepared by reacting 5.0 g. of N-(4-chlorophenyl)-[(3-pyridyl)methyl]amine with 2.0 g. of acetyl chloride in 250 ml. containing 3.0 g. of triethylamine according to the method of Example 11. Weight 1.1 g. M.P. 64°-65° C.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][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[C:25]([F:28])([F:27])[F:26])=[O:9])=[CH:4][CH:3]=1>C(OCC)C.CCCCCC.[Pd]>[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]([CH2:21][CH2:22][CH2:23][OH:24])=[CH:15][C:14]=3[C:25]([F:28])([F:26])[F:27])=[O:9])=[CH:29][CH:30]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(C(F)(F)F)cc(C#CCO)cc2c1O
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(C(F)(F)F)cc(CCCO)cc2c1O
Yield: 10.7 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-8-(trifluoromethyl)-3-quinolinecarboxamide (397 mg) from Example No. 121 is dissolved in methanol/dichloromethane (1/1, 87 mL) and palladium on carbon (5%, 80 mg) are added. The mixture is placed under a hydrogen atmosphere (28 psi) for 1 h, filtered through celite, and concentrated. The crude product is purified by column chromatography (dichloromethane/methanol, 100/1 to 100/3) to afford 43 mg (10%) of the title compound as a white solid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:31]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:32])[C:22]=2[N:21]=[C:20]1[CH2:33][CH2:34][CH2:35][CH3:36].[CH3:37][N:38]1[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]1>CN1C(=O)CCC1>[CH2:33]([C:20]1[N:19]([CH2:18][CH2:17][CH2:16][NH:15][CH:41]2[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]2)[C:31]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:32])[C:22]=2[N:21]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC1CCN(C)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Sodium triacetoxyborohydride (1.07 g) was added to a stirred mixture of the product from example 1 step (vii) (502 mg) and 1-methylpiperidin-4-one (0.21 mL) in NMP (2 mL) at rt. The resulting solution was stirred at 50° C. for 3 h, then purified by SCX, yield 335 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>ClCCl>[C:25]([N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:13][CH2:14]1)(=[O:27])[CH3:26]
Reactant: COc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(N2CCN(C(C)=O)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
To a solution of 1-[3-(methyloxy)-4-nitrophenyl]piperazine (0.5 g, 2.11 mmol) and triethylamine (1.27 g, 12.63 mmol, Aldrich) in dichloromethane (25 mL) was added acetic anhydride (0.64 g, 6.35 mmol, Aldrich). After stirring 3 hrs at rt, the reaction was washed with water (25 mL), organic layer adsorbed to silica gel and purified by column chromatography (dichloromethane to 10% methanol/dichloromethane) to give 1-acetyl-4-[3-(methyloxy)-4-nitrophenyl]piperazine (0.4 g, 68%). ESIMS (M+H)+=280.