Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.[CH3:31][S-:32].[Na+]>CN(C=O)C.C(OCC)(=O)C>[OH:29][C@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@@H:23]1[N:13]1[C:12](=[O:30])[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([S:32][CH3:31])=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3cnccc3c2ncn1[C@H]1CCCC[C@@H]1O
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ccc(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccncc23)cn1
Temperature: 130 °C

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]pyrido[3,4-h]quinazolin-4(3H)-one (Example 1, 0.120 g, 0.285 mmol) in 2 mL of DMF was added sodium thiomethoxide (0.100 g, 1.43 mmol). The mixture was heated in a sealed tube at 130° C. for 18 h, cooled to rt, and diluted with ethyl acetate. The organic solution was washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane, to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 432.9 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 9.41 (s, 1H), 8.73-8.63 (m, 2H), 8.39 (s, 1H), 8.29-8.19 (m, 1H), 8.09 (s, 1H), 7.32-7.26 (m, 1H), 7.08 (d, J=8.3 Hz, 1H), 4.61 (br s, 1H), 4.50 (s, 2H), 4.05 (br s, 1H), 2.53 (s, 3H), 2.40-2.27 (m, 2H), 2.13-1.75 (m, 3H), 1.55-1.35 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[C:8]([CH:13]=O)=[CH:7]2.[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[C:8](/[CH:13]=[N:21]/[S@@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])=[CH:7]2
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1cc2cccc(Br)c2nc1Cl
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CC(C)(C)[S@@](=O)/N=C/c1cc2cccc(Br)c2nc1Cl
Yield: 86.2 %

Procedure:
Following the procedure described for Intermediate 1, 8-bromo-2-chloro-quinoline-3-carbaldehyde (280 mg, 1.04 mmol), (R)-(+)-2-methyl-2-propanesulfinamide (125 mg, 1.04 mmol) and titanium isopropoxide (0.61 mL, 2.08 mmol) afforded the title compound (335 mg, 87%) as a yellow solid. δH (CDCl3) 9.12 (1H, s), 8.82 (1H, s), 8.15 (1H, dd, J 7.52, 1.31 Hz), 7.92 (1H, dd, J 8.17, 1.30 Hz), 7.52-7.44 (1H, m), 1.33 (9H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[N:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14].C(OCC)(=O)C.[H][H]>C(O)C.[Pt](=O)=O>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])[CH:4]=1
Reactant: N#Cc1cccnc1-c1cc([N+](=O)[O-])ccc1F
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1cccnc1-c1cc(N)ccc1F

Procedure:
A solution of 2-(2-fluoro-5-nitrophenyl)nicotinonitrile (1.2 g, 4.9 mmol) and platinum(IV) oxide in ethanol (50 ml) with ethyl acetate (50 ml) was reduced under 40 psi hydrogen for 30 minutes then filtered and the solvent removed to give an orange oil. Purification by chromatography (silica gel, 1% MeOH/CH2Cl2) gave 2-(5-amino-2-fluorophenyl)-nicotinonitrile as an orange oil: 1H NMR (360 MHz, CDCl3) δ 8.88 (1H, dd, J 2, 5 Hz), 8.07 (1H, dd, J 2, 8 Hz), 7.42 (1H, dd, J 5, 8 Hz), 7.04 (1H, t, J 9 Hz), 6.85 (1H, dd, J 3, 6 Hz), 6.76-6.81 (1H, m); MS (ES+) m/z 214 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].C(N(CC)CC)C.[C:14](Cl)(=[O:17])[CH:15]=[CH2:16]>ClCCl>[C:14]([O:5][CH2:4][CH:3]=[C:2]([CH3:6])[CH3:1])(=[O:17])[CH:15]=[CH2:16]
Reactant: C=CC(=O)Cl
Reactant: CC(C)=CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)OCC=C(C)C
Temperature: 0 °C
Yield: 72.1 %

Procedure:
A 1-liter flask was charged with 43.9 g (0.51 mol) of 3-methyl-2-buten-1-ol, 51.6 g (0.51 mol) of triethylamine and 300 ml of dichloromethane, and the mixture was cooled down to 0° C. While stirring the mixture at 0° C., 45.3 g (0.50 mol) of acryloyl chloride were added dropwise over 1 hour, and the mixture was stirred additionally for 5 hours at room temperature. Solids were separated by filtration from the resultant reaction mixture, and the filtrate was washed 3 times with water and then distilled in the presence of 5 g of p-methoxyphenol to obtain 50.5 g of 3-methyl-2-butenyl acrylate.
Reaction SMILES: CO[C:3]([C:5]1[C:14]([C:15]([O:17]C)=O)=[C:13]([OH:19])[C:12]2[C:7](=[CH:8][C:9]([Cl:21])=[CH:10][C:11]=2[Cl:20])[N:6]=1)=[O:4].[C:22]1([NH:28][NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[Cl:21][C:9]1[CH:10]=[C:11]([Cl:20])[C:12]2[C:13](=[O:19])[C:14]3[C:15](=[O:17])[N:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:29]=[C:3]([OH:4])[C:5]=3[NH:6][C:7]=2[CH:8]=1
Reactant: NNc1ccccc1
Reactant: COC(=O)c1nc2cc(Cl)cc(Cl)c2c(O)c1C(=O)OC
Solvent: CCO
Product: O=c1c2c(Cl)cc(Cl)cc2[nH]c2c(O)nn(-c3ccccc3)c(=O)c12
Temperature: 25 °C

Procedure:
To a stirred suspension of dimethyl-5,7-dichloro-4-hydroxyquinoline-2,3-dicarboxylate (3.00 g, 9.09 mM) in ethanol (42 mL) was added phenylhydrazine (6.26 mL, 63.6 mM). The resulting green solution was heated to reflux for 16 hours during which time a small amount of red precipitate formed. This suspension was cooled to room temperature with stirring and additional precipitation occurred to give a thick tan suspension. The solids were collected and washed with ethanol (the ethanol washes were saved). The collected solids were recrystallized from ethanol (1.20 L) to give the phenylhydrazine salt of the title compound (1.17 g) as a tan powder. This material was stirred and refluxed in glacial acetic acid (15 mL) for 2.5 hours and then cooled to room temperature with stirring. The resulting orange suspension was filtered to give the title compound (0.629 g, 19%) as an orange powder which was slightly impure. An analytical sample of the title compound was obtained from the above saved ethanol washes by filtration of a precipitate which formed after these washes stood for several hours. Recrystallization of this collected tan powder (0.126 g) from glacial acetic acid (2 mL) gave the pure title compound (0.083 g) as an orange powder, mp 364-367° C.; MS(CI): 374 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:14]2[C:15]([N+:35]([O-])=O)=[CH:16][C:17]3[O:21][C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[C:19]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:18]=3[CH:34]=2)[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.CC(O)=O.CCOC(C)=O.[Fe]>[NH2:35][C:15]1[C:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH:9]=2)=[CH:34][C:18]2[C:19]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[O:21][C:17]=2[CH:16]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3cccc(C(=O)OC(C)(C)C)c3)cc12
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3cccc(C(=O)OC(C)(C)C)c3)cc12
Reaction time: 1 h
Yield: 95.6 %

Procedure:
Iron (28 mg, 0.495 mmol) was added to a stirring solution of ethyl 5-(3-(tert-butoxycarbonyl)phenyl)-2-(4-fluorophenyl)-6-nitrobenzofuran-3-carboxylate (50 mg, 0.099 mmol) in EtOH (495 μL) and AcOH (495 μL) at 100° C. It was allowed to stir for 1 hr. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the titled compound (45 mg, 96%). 1H NMR (400 MHz, DMSO-d6) d ppm 7.99-8.06 (2 H, m), 7.89-7.96 (2 H, m), 7.65-7.72 (1 H, m), 7.61 (1 H, t, J=7.65 Hz), 7.55 (1 H, s), 7.31-7.40 (2 H, m), 7.00 (1 H, s), 5.10 (2 H, br. s.), 4.29 (2 H, q, J=7.03 Hz), 1.56 (9 H, s), 1.26 (3 H, t, J=7.15 Hz). LC-MS retention time: 2.03 min; m/z (MH+): parent does not ionize. 420 (-tBu) was observed. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-V is detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:7][O:6][C:5]([CH3:8])=[N:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:37][C:38]1[CH:39]=[C:40]([CH2:46][CH2:47]O)[CH:41]=[CH:42][C:43]=1[O:44][CH3:45].C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1COCC1>[F:37][C:38]1[CH:39]=[C:40]([CH2:46][CH2:47][O:17][C:14]2[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][C:3]3([CH2:2][OH:1])[CH2:7][O:6][C:5]([CH3:8])=[N:4]3)=[CH:16][CH:15]=2)[CH:41]=[CH:42][C:43]=1[O:44][CH3:45]
Reactant: COc1ccc(CCO)cc1F
Reactant: CC1=NC(CO)(CCc2ccc(O)cc2)CO1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CCOc2ccc(CCC3(CO)COC(C)=N3)cc2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[2-(4-hydroxymethyl-2-methyl-4,5-dihydro-oxazol-4-yl)-ethyl]-phenol (300 mg, 1.27 mmol) in dry THF (6 ml) is added under inert atmosphere polystyrene supported triphenylphosphine (loading 3 mmol·g−1, 1.27 g, 3.81 mmol, 3 eq.), 2-(3-fluoro-4-methoxyphenyl)-ethanol (647.7 mg, 3.81 mmol, 3 eq.) and DBAD (877.3 mg, 3.81 mmol, 3 eq.). The reaction mixture was stirred under inert atmosphere at room temperature overnight. Polystyrene supported triphenylphosphine was then filtered through frit and washed with ethyl acetate and methanol. The reaction mixture was then concentrated to dryness following by addition of 4M HCl in dioxane (3 ml), the reaction was stirred at room temperature for 3 hours. The reaction mixture was quenched by addition of saturated solution of NaHCO3 (10 ml) and ethyl acetate (40 ml). The organic layer is separated and the aqueous phase is extracted with ethyl acetate (3×40 ml). The combined organic extracts are washed with brine, dried over MgSO4, and evaporated to dryness. Purification using Flashmaster (chexane/ethyl acetate (1/9), ethyl acetate and ethyl acetate/methanol (98/2)) affords [4-(2-{4-[2-(3-fluoro-4-methoxy-phenyl)-ethoxy]-phenyl}ethyl)-2-methyl-4,5-dihydro-oxazol-4-yl]-methanol as colorless oil. MS (ESI+): 364.2 (MH+)
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[F:16][C:17]1[C:22]([O:23][CH2:24][O:25][CH3:26])=[CH:21][CH:20]=[C:19]([O:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[N:18]=1.[Br:33][C:34]1[CH:35]=[CH:36][C:37]([F:42])=[C:38]([CH:41]=1)[CH:39]=[O:40].[NH4+].[Cl-].C[N+]1([O-])CCOCC1>C1COCC1.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.CCOC(C)=O>[Br:33][C:34]1[CH:35]=[CH:36][C:37]([F:42])=[C:38]([C:39]([C:21]2[CH:20]=[C:19]([O:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[N:18]=[C:17]([F:16])[C:22]=2[O:23][CH2:24][O:25][CH3:26])=[O:40])[CH:41]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: COCOc1ccc(OCC(C)(C)C)nc1F
Agent: O=[Ru](=O)(=O)[O-]
Agent: CC1(C)CCCC(C)(C)N1
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCOc1c(C(=O)c2cc(Br)ccc2F)cc(OCC(C)(C)C)nc1F
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
A solution of n-butyllithium (1.6M in hexanes; 6.52 mL, 10.44 mmol) was added drop wise to a solution of 2,2,6,6-tetramethylpiperidine (1.897 mL, 11.24 mmol) in THF (30 mL) at −78° C. under nitrogen atmosphere. The reaction mixture was warmed to 0° C. and stirred for 25 min. The reaction mixture was cooled down again to −78° C. and a solution of 2-fluoro-3-(methoxymethoxy)-6-(neopentyloxy)pyridine (2.149 g, 8.83 mmol) in THF (5 mL) was added drop wise. The reaction mixture was kept for 1 h at −78° C., after which a solution of 5-bromo-2-fluorobenzaldehyde (1.63 g, 8.03 mmol) in THF (5 mL) was added. The reaction mixture was allowed to warm up to rt. Aqueous, saturated NH4Cl solution was added, followed by EtOAc. The organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure and the residue was dissolved in DCM (75 mL). 4-Methylmorpholine 4-oxide (1.176 g, 10.04 mmol) followed by tetrapropylammonium perruthenate (0.141 g, 0.401 mmol) were added. The reaction mixture was allowed to stir for 2 h at rt. The reaction mixture was filtered through a pad of celite and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (5-20% EtOAc/hexanes) to yield (5-bromo-2-fluorophenyl)(2-fluoro-3-(methoxymethoxy)-6-(neopentyloxy)pyridin-4-yl)methanone as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([N:19]([CH3:21])[CH3:20])=[CH:16][CH:17]=3)[C:11](=[O:12])[O:10]2)=[CH:5][CH:4]=1.[CH3:23][N:24]([CH3:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:28]2[CH:29]=[CH:30][C:25]([N:24]([CH3:31])[CH3:23])=[CH:26][CH:27]=2)[C:18]2[CH:17]=[CH:16][C:15]([N:19]([CH3:21])[CH3:20])=[CH:14][C:13]=2[C:11]([OH:10])=[O:12])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C2OC(=O)c3cc(N(C)C)ccc32)cc1
Reactant: CN(C)c1ccccc1
Product: CN(C)c1ccc(C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2C(=O)O)cc1

Procedure:
In a second synthetic route to CVL, which is also a multi-step synthesis, 4-dimethylaminobenzaldehyde is reacted with 3-dimethylaminobenzoic acid to obtain 3-(4-dimethylaminophenyl)-6-dimethylaminophthalide in the first step. In a second step, the 3-(4-dimethylaminophenyl)-6-dimethylaminophthalide from step one is interacted with N,N-dimethylaniline in the presence of a Friedel-Crafts type catalyst to obtain 2-[bis(4-dimethylaminophenyl)methyl]-5-dimethylaminobenzoic acid. In a third step, the benzoic acid from step two is oxidized to obtain 3,3-bis(4-dimethylaminophenyl)-6-dimethylaminophthalide.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]>C(O)C.[Pd]>[NH2:13][C:10]1[CH:11]=[CH:12][C:2]([CH3:1])=[C:3]([CH:9]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc(N)ccc1C
Reaction time: 18 h
Yield: 101 %

Procedure:
A mixture of ethyl 2-methyl-5-nitrobenzoate (11.5 g, 54 mmol) and 10% Pd/C (1.2 g) in ethanol (200 mL) was shaken under an atmosphere of hydrogen at 40 psi for 18 h. After this time, the mixture was filtered through diatomaceous earth and concentrated under reduced pressure to provide ethyl 5-amino-2-methylbenzoate (9.77 g, 98%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 7.25 (d, J=2.6 Hz, 1H), 7.02 (d, J=8.1 Hz, 1H), 6.74 (d, J=8.1 Hz, 1H), 4.33 (q, J=7.2 Hz, 2H), 2.46 (s, 3H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[CH2:14]([NH2:24])[C:15]1[CH:23]=[CH:22][C:21]2[O:20][CH2:19][O:18][C:17]=2[CH:16]=1>C(O)C>[O:20]1[C:21]2[CH:22]=[CH:23][C:15]([CH2:14][NH:24][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=4)[N:3]=[C:2]([Cl:1])[N:11]=3)=[CH:16][C:17]=2[O:18][CH2:19]1
Reactant: Clc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: NCc1ccc2c(c1)OCO2
Solvent: CCO
Product: Clc1ccc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1
Temperature: 55 °C
Yield: 96.2 %

Procedure:
A solution of 2,4,6-trichloroquinazoline (0.186 g, 0.80 mmol) in ethanol (20 ml) was heated to 55° C. and piperonylamine (0.145 g, 0.96 mmol) was added. The resulting mixture was stirred at 55° C. over night. Volatiles were evaporated and the residue was partitioned between methylene chloride and saturated solution of ammonium hydroxide. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to yield 0.268 g (96% yield) of the title compound as a white solid. 1H NMR (300 MHz, DMSO) δ 4.59-4.63 (d, 2 H), 5.98 (s, 2 H), 6.86 (s, 2 H), 6.96 (s, 1 H), 7.62-7.66 (d, 1 H), 7.79-7.84 (d, 1 H), 8.46 (s, 1 H), 9.24-9.28 (t, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[C:14]1([S:20]([N:23]2[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[CH:25]=[C:24]2[C:32](=[O:39])[CH2:33][CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[C:14]1([S:20]([N:23]2[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[CH:25]=[C:24]2[C:32]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)([OH:39])[CH2:33][CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38]2)(=[O:21])=[O:22])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Brc1ccc(I)nc1
Reactant: O=C(CC1CCCC1)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1c(C(O)(CC2CCCC2)c2ccc(Br)cn2)cc2cccnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a solution of 5-bromo-2-iodopyridine (4.27 g, 15.0 mmol) in anhydrous tetrahydrofuran (60 mL) at 0° C. was added a solution of isopropylmagnesium chloride in tetrahydrofuran (2 M, 7.5 mL, 15.04 mmol) dropwise. After stirring for 30 min at 0° C., a solution of 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-ethanone (prepared as in Example 43, 1.38 g, 3.76 mmol) in dry tetrahydrofuran (10 mL) was added dropwise. The resulting mixture was stirred for 14 h at room temperature, quenched with a saturated sodium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 20% ethyl acetate/hexanes) afforded 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-(5-bromo-pyridin-2-yl)-2-cyclopentyl-ethanol (870 mg, 15%) as a light yellow solid: LC/MS m/e calcd for C25H24BrN3O3S [M+H]+ 527.46, observed 527.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH3:28][C:29]1([CH3:35])[O:33][C:32](=[O:34])[NH:31][CH2:30]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:31]4[CH2:30][C:29]([CH3:35])([CH3:28])[O:33][C:32]4=[O:34])=[CH:3][C:4]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC1(C)CNC(=O)O1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)(C)OC4=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 31.8 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (679 mg) described in Preparation Example 61 and 5,5-dimethyloxazolidin-2-one (259 mg) described in Preparation Example 43, the title compound (232 mg) was obtained.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[C:11]=2[F:18])[N:7]=[C:6]([C:19]([O:21]C)=[O:20])[C:5]=1/[CH:23]=[CH:24]/[Si:25]([CH3:28])([CH3:27])[CH3:26].Cl>CO>[NH2:3][C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[C:11]=2[F:18])[N:7]=[C:6]([C:19]([OH:21])=[O:20])[C:5]=1/[CH:23]=[CH:24]/[Si:25]([CH3:26])([CH3:28])[CH3:27]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(F)c2F)nc(N)c1/C=C/[Si](C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[Si](C)(C)/C=C/c1c(N)nc(-c2ccc(Cl)c(F)c2F)nc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
A 2M solution of aqueous sodium hydroxide (400 μL, 0.80 mmol, 2.0 equiv) was added to a stirred suspension of (E)-methyl 6-amino-2-(4-chloro-2,3-difluorophenyl)-5-(2-(trimethylsilyl)vinyl)pyrimidine-4-carboxylate (160 mg, 0.40 mmol, 1.0 equiv) in methanol (4.0 mL) at 23° C. The resulting heterogeneous yellow mixture was stirred at room temperature for 3 h. The reaction mixture was adjusted to approximately pH 4 via dropwise addition of concentrated hydrochloric acid and concentrated under vacuum. The residue was slurried in water and vacuum filtered to afford the title compound as an off-white powder (130 mg, 87%): mp 155-157° C.; 1H NMR (300 MHz, (CD3)2SO) δ 7.77 (m, 1H), 7.51 (m, 1H), 7.31 (br s, 2H); 6.77 (d, J=19 Hz, 1H), 6.30 (d, J=19 Hz, 1H), 0.12 (s, 9H); IR (neat) 3514 (s), 3475 (s), 3407 (s), 3336 (s), 3218 (m), 2963 (m), 1768 (m), 1640 (m), 1612 (m); ESIMS m/z 384 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([C:9]([NH:11][O:12][CH2:13][CH2:14][OH:15])=[O:10])[C:3]=1[NH:16][C:17]1[CH:36]=[CH:35][C:20]([C:21](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:22])=[CH:19][CH:18]=1.[BH4-].[Na+].Cl>C1COCC1.O>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:36]=[CH:35][C:20]([CH2:21][OH:22])=[CH:19][CH:18]=2)=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[C:9]([NH:11][O:12][CH2:13][CH2:14][OH:15])=[O:10]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.7 %

Procedure:
The product of Example 17, Step C, 2,3,4,5,6-pentafluorophenyl 4-[[2,3-difluoro-6-[[(2-hydroxyethoxy)amino]carbonyl]phenyl]amino]benzoate (150 mg, 0.29 mmol) was dissolved in THF (2 mL), then added dropwise to a solution of NaBH4 (110 mg, 2.90 mmol) in water (2 mL). This mixture was stirred at room temperature for 2 hours, acidified with 1 M HCl, and diluted with water (50 mL). The resulting aqueous mixture was extracted with EtOAc (2×50 mL), then the combined EtOAc fractions washed with water (50 mL), saturated NaCl (50 mL), and dried (Na2SO4). The solvent was removed under reduced pressure and the resulting residue purified by column chromatography on flash silica (50% EtOAc/hexanes as eluant) to afford 3,4-difluoro-N-(2-hydroxyethoxy)-2-[[4-(hydroxymethyl)phenyl]amino]benzamide as a cream solid (36 mg, 37%); m.p. (EtOAc/hexanes) 73–77° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.73 (br s, 1 H), 8.68 (br s, 1 H), 7.41–7.35 (m, 1H), 7.15 (d, J=8.5 Hz, 2 H), 7.14–7.06 (m, 1 H), 6.79 (dd, J=8.5, 2.3 Hz, 2 H), 4.99 (t, J=5.7 Hz, 1 H), 4.72 (br s, 1 H), 4.38 (d, J=5.6, 2 H), 3.80 (t, J=4.9 Hz, 2 H), 3.54 (t, J=4.9 Hz, 2 H). Anal. Calcd for C16H16F2N2O4: C, 56.8; H, 4.8; N, 8.3. Found: C, 56.3; H, 4.7; N, 8.1.
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[N:11]=[C:10]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:9]([CH2:22][CH2:23][CH2:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH:2]=C.C(=O)([O-])[O-].[K+].[K+].[C:37]1([CH2:43][CH2:44][CH2:45]Cl)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C)C=O>[CH:1]([C:4]1[C:12]2[N:11]=[C:10]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:9]([CH2:22][CH2:23][CH2:24][CH:25]3[CH2:26][CH2:27][N:28]([CH2:45][CH2:44][CH2:43][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:29][CH2:30]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)=[CH2:2]
Reactant: C=CCc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCNCC1
Reactant: ClCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(CCCc2ccccc2)CC1
Temperature: 60 °C

Procedure:
In a 50 ml round bottom flask, under a nitrogen atmosphere, were added 4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]benzimidazole (898 mg, 2.12 mmol), potassium carbonate (1.46 g, 10.58 mmol), 3-(phenyl)propyl chloride (0.2 ml, 506 mg, 2.54 mmol) and N,N-dimethylformamide (7 ml). The resulting mixture was heated to 60° C. and maintained at this temperature overnight. The progress of the reaction was monitored by thin layer chromatography. The reaction was quenched by the addition of water. The aqueous fraction was extracted wtih ethyl acetate. The organic fractions were combined, washed thrice with saturated sodium bicarbonate solution, and then dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by radial chromatography.