Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[O:18])[C:5]([OH:16])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH:7]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.Cl.C(NCC1C(O)=C(C2C=CC(Cl)=C(Cl)C=2)C=C(C2C=CC(Cl)=CC=2)C=1)(C)(C)C>>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[C:5]([OH:16])=[C:4]([CH:17]=[O:18])[CH:3]=[C:2]([C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)[CH:7]=2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: O=Cc1cc(Br)cc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: OB(O)c1ccc(Cl)cc1
Agent: CC(C)(C)NCc1cc(-c2ccc(Cl)cc2)cc(-c2ccc(Cl)c(Cl)c2)c1O
Agent: Cl
Product: O=Cc1cc(-c2ccc(Cl)cc2)cc(-c2ccc(Cl)c(Cl)c2)c1O

Procedure:
3,4,4″-Trichloro-6′-hydroxy-[1,1′:3′,1″-terphenyl]-5′-carbaldehyde was prepared from 5-bromo-3′,4′-dichloro-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde and 4-chlorophenylboronic acid using the same procedure described in Intermediate 5.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][CH2:11][C:12]2[O:16][C:15]([C:17]3[CH:27]=[CH:26][C:20]([C:21](OCC)=[O:22])=[CH:19][CH:18]=3)=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[C-]#[N:29].[K+]>CO.N>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][CH2:11][C:12]2[O:16][C:15]([C:17]3[CH:27]=[CH:26][C:20]([C:21]([NH2:29])=[O:22])=[CH:19][CH:18]=3)=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(CNCCc3cccc(F)c3)o2)cc1
Reactant: [C-]#N
Agent: N
Agent: [K+]
Solvent: CO
Product: NC(=O)c1ccc(-c2ccc(CNCCc3cccc(F)c3)o2)cc1
Temperature: 125 °C
Reaction time: 8 h
Yield: 3.3 %

Procedure:
To a 50 mL sealed tube was added ethyl 4-[5-({[2-(3-fluorophenyl)ethyl]amino}methyl)-2-furanyl]benzoate (100 mg, 0.27 mmol, Example X-1), 2.0 M MeOH/NH3 (20 mL), and KCN (30 mg). The reaction mixture was stirred at 125° C. overnight. The crude mixture was purified on RP-preparative HPLC to give 3 mg of 4-[5-({[2-(3-fluorophenyl)ethyl]amino}methyl)-2-furanyl]benzamide. (M+1) 339.23, 1.42 min (LC/MS method A)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[N:12]([O-])=O.[Na+].[Sn](Cl)(Cl)(Cl)Cl>Cl.O>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[NH2:12]
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(NN)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 112.7 %

Procedure:
Methyl 4-aminobenzoate (5.0 g, 0.0331 moles) was taken up in conc. HCl (50 mL) and cooled to 0° C. Sodium nitrite (2.5 g, 0.0331 moles) solution in water was added at 0° C. over 30 minutes and stirred at RT for 90 min. Tin chloride (19.40 g, 0.0927 moles) in HCl (100 mL) was added drop wise at 0° C. and stirred at RT for 2 hr. The reaction was filtered and the solid obtained was washed with diethyl ether and dried on a rotary evaporator to give 6.2 g, 92.53% yield of Methyl 4-hydrazinylbenzoate as a white solid.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:8]([F:15])=[C:9]([OH:14])[C:10](=[O:13])[NH:11][CH:12]=2)[CH:2]=1.[OH-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[CH2:24]([O:14][C:9]1[C:10](=[O:13])[NH:11][CH:12]=[C:7]([C:3]2[CH:2]=[C:1]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:6]=[CH:5][CH:4]=2)[C:8]=1[F:15])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=c1[nH]cc(-c2cccc(-c3ccccc3)c2)c(F)c1O
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=c1[nH]cc(-c2cccc(-c3ccccc3)c2)c(F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
To a suspension of 5-biphenyl-3-yl-4-fluoro-3-hydroxypyridin-2(1H)-one (60 mg, 0.213 mmol) was added 1 N aqueous NaOH solution (0.235 mL, 0.235 mmol) and the resulting mixture was sonicated to make a clear solution. To this mixture was added a solution of benzyl bromide (37 mg, 0.213 mmol) in MeOH (0.3 mL) dropwise, stirred overnight at room temperature and then concentrated. Purification by preparative HPLC (10-70% CH3CN/H2O over 20 min, 0.05% added TFA) afforded 25 mg (32%) of 3-(benzyloxy)-5-(biphenyl-3-yl)-4-fluoropyridin-2(1H)-one as a white solid. LC/MS (M+H)+ 372.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]3[CH:22]=[CH:23][N:24]=[C:12]23)=[C:4]([F:25])[CH:3]=1.C(OCC)(=O)C.C(O)(=O)C>[Fe].O>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:25])=[C:5]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]3[CH:22]=[CH:23][N:24]=[C:12]23)[CH:6]=1
Reactant: O=c1cc(C(F)(F)F)n2ccnc2n1-c1cc([N+](=O)[O-])c(Cl)cc1F
Agent: [Fe]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cc(-n2c(=O)cc(C(F)(F)F)n3ccnc23)c(F)cc1Cl

Procedure:
A mixture of 8-(4-chloro-2-fluoro-5-nitrophenyl)-7,8-dihydro-5-trifluoromethylimidazo[1,2-a]pyrimidin-7-one (0.6 g), ethyl acetate (5 ml), acetic acid (2 ml) and water (10 ml) was added with iron powder (0.5 g) and heated to reflux for 3 hours. The mixture was filtered through Celite and the thus obtained solid was washed with hot ethyl acetate. The organic layer was separated from the filtrate and the washing, and dried on anhydrous magnesium sulfate after washing with water. The solvent was distilled off under reduced pressure to give the compound of interest (0.52 g) as a solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[CH2:9][CH2:8][CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[S:34])[CH:29]=[CH:30][CH:31]=1>O1CCCC1>[OH:16][CH2:15][C:3]1([CH2:2][O:1][C:33](=[S:34])[NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=2)[CH2:9][CH2:8][CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14]
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Reactant: O=C1c2ccccc2CCCC1(CO)CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1c2ccccc2CCCC1(CO)COC(=S)Nc1cccc(C(F)(F)F)c1

Procedure:
To a solution of 6,6-bis(hydroxymethyl)-6,7,8,9-tetrahydrobenzocyclohepten-5-one (500 mg, 2.27 mmol) in 28 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.35 ml, 2.5 mmol) and 3-(trifluoromethyl)phenyl isothiocyanate (862 μl, 5.68 mmol). The mixture was heated to reflux for 72 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:2 ethyl acetate/hexane). The product was obtained in a yield of 284 mg (30%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[I:10][C:11]1[N:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].[OH-].[K+]>ClCCCl.O1CCOCC1.O>[I:10][C:11]1[N:16]=[CH:15][C:14]([NH:17][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:13][CH:12]=1
Reactant: Nc1ccc(I)nc1
Reactant: CS(=O)(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CS(=O)(=O)Nc1ccc(I)nc1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 79.3 %

Procedure:
N,N-Diisopropylethylamine (0.992 mL, 5.68 mmol) was added to a solution of 6-iodopyridin-3-amine (0.500 g, 2.273 mmol) and methanesulfonyl chloride (0.186 mL, 2.386 mmol) in 1,2-dichloroethane (10.0 mL), and the mixture stirred at 50° C. for 2.5 h. The reaction mixture was concentrated to afford a brown oil which was dissolved in 1,4-dioxane (5.0 mL) and water (1.0 mL). Potassium hydroxide (0.128 g, 2.273 mmol) was added and the mixture stirred at 80° C. for 4 h. The reaction mixture was cooled to room temperature and then partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford a brown oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-50% ethyl acetate-hexane) to afford N-(6-iodopyridin-3-yl)methanesulfonamide (0.537 g, 79%) as a tan solid. MS (ESI, pos. ion) m/z 299 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)=[CH:4][C:3]=1[CH2:16][NH:17][C:18]1[C:19]([CH3:33])=[C:20]([CH:29]=[CH:30][C:31]=1[CH3:32])[O:21][CH2:22][C:23]([O:25]C(C)C)=[O:24].[Li+].[OH-]>C1COCC1>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)=[CH:4][C:3]=1[CH2:16][NH:17][C:18]1[C:19]([CH3:33])=[C:20]([CH:29]=[CH:30][C:31]=1[CH3:32])[O:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: Cc1cc(-c2cccc(F)c2)cc(CNc2c(C)ccc(OCC(=O)OC(C)C)c2C)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(-c2cccc(F)c2)cc(CNc2c(C)ccc(OCC(=O)O)c2C)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
To a solution of isopropyl 2-[3-[[2-fluoro-5-(3-fluorophenyl)-3-methyl-phenyl]methyl amino]-2,4-dimethyl-phenoxy]acetate (70 mg, 0.15 mmol, 1.0 eq) in THF (5 mL) at 0° C. was added LiOH (2M aqueous solution, 2.0 mL, 4.0 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The THF was removed in vacuo and the remaining aqueous mixture diluted with water and adjusted to pH 5 by addition of 3M HCl. The solid that precipitated was collected by filtration and dried in vacuo to give the title compound as a yellow solid (40 mg, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[CH:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:17]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>CN(C)C=O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:7]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]2[CH:17]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:9][C:8]1=[O:10])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C1Oc2ccc(Cl)cc2C1c1ccccc1
Reactant: O=C(CBr)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CC1(c2ccccc2)C(=O)Oc2ccc(Cl)cc21)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.204 mol of 5-chloro-2,3-dihydro-2-oxo-3-phenylbenzofuran in 200 ml of anhydrous dimethylformamide is added to a suspension of 0.204 mol of sodium hydride in 100 ml of anhydrous dimethylformamide. The medium is maintained with stirring at room temperature for one hour, 0.224 mol of benzyl bromoacetate is then added slowly and the medium is left for 12 hours at room temperature. The reaction mixture is concentrated under vacuum and hydrolyzed using one liter of water, the aqueous phase extracted with twice 250 ml of benzene, the organic phase dried over anhydrous sodium sulfate and the solvent evaporated off. The residue is washed with isopropyl ether and then filtered. 0.173 mol is thereby obtained.
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].C([Li])CCC.C(#N)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][N:19]=1>C1COCC1.O>[NH2:25][C:24]([C:21]1[CH:20]=[N:19][C:18]([O:17][CH3:16])=[CH:23][CH:22]=1)=[CH:2][C:1]#[N:4]
Reactant: COc1ccc(C#N)cn1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: COc1ccc(C(N)=CC#N)cn1
Temperature: 25 °C

Procedure:
A solution of 0.258 ml (1.844 mmol) diisopropylamine in dry THF (1.5 ml) was cooled to −70° C. under inert gas atmosphere, and 1.152 ml (1.844 mmol) n-butyllithium (1.6 M solution in hexanes) were added dropwise. Then, a solution of 85.6 μl (1.627 mmol) acetonitrile in dry THF (1.5 ml) was slowly added over 10 min. The resulting solution was stirred for further 30 min at −70° C. before a solution of 150 mg (1.085 mmol) 2-methoxypyridine-5-carbonitrile in dry THF (1.5 ml) was added. The mixture was allowed to warm to room temperature and stirred for 1 h before water (2 ml) was added slowly. The mixture was extracted several times with dichloromethane (50 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to yield 188 mg (99% of th.) of the crude title compound which was used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)[CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][CH2:12]1.[H-].[Na+].Br[CH2:35][CH2:36][O:37][Si:38]([CH3:41])([CH3:40])[CH3:39]>C1COCC1.CN(C=O)C>[C:17]([CH:14]1[CH2:15][CH2:16][CH:11]([N:10]([CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)[C:2]2[N:3]([CH2:35][CH2:36][O:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH2:12][CH2:13]1)([CH3:18])([CH3:19])[CH3:20]
Reactant: COC(=O)c1ccc(CN(c2nc3ccccc3[nH]2)C2CCC(C(C)(C)C)CC2)cc1
Reactant: C[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(c2nc3ccccc3n2CCO[Si](C)(C)C)C2CCC(C(C)(C)C)CC2)cc1
Temperature: 40 °C

Procedure:
To the title compound from Example 1 Step C (0.5 mmol, 210 mg) in 1 mL of THF was added a solution of NaH (1 mmol, 40 mg of 60% slurry in mineral oil) in 1 mL of DMF (exothermic, H2 evolution). After gas evolution ceased for several minutes, (2-bromoethoxy)(trimethyl)silane was added to the solution via syringe. The reaction mixture was heated to 40° C. After 2.5 h the reaction was quenched by addition of saturated ammonium chloride. The product was extracted 3× with EtOAc and the organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica eluting with 5% EtOAc/hexanes. HPLC A: 3.14 min.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:58]1[CH2:63][CH2:62][CH:61]([NH2:64])[CH2:60][CH2:59]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:64][CH:61]5[CH2:62][CH2:63][O:58][CH2:59][CH2:60]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCOCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and tetrahydro-2H-pyran-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.43 (m, 3 H) 1.49-1.90 (m, 11 H) 3.19-3.32 (m, 3 H) 3.32-3.46 (m, 2 H) 3.84-3.92 (m, 2 H) 3.94 (d, J=9.0 Hz, 3 H) 3.97-4.08 (m, 1 H) 4.07-4.23 (m, 2 H) 4.38-4.58 (m, 1 H) 7.42-7.61 (m, 2 H) 8.06-8.17 (m, 1 H) 8.24 (br. s., 2 H) 8.62 (br. s., 1 H). [M+H] calc'd for C27H34F2N6O4 545; found 545.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:16][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:10]=2[N:9]=1.[OH-].[Na+].Cl[CH2:20][C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH:22]=1>CN(C=O)C>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]2[CH:22]=[C:21]([CH2:20][N:13]3[CH:14]=[CH:15][C:10]4=[N:9][C:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])=[N:16][C:11]4=[CH:12]3)[O:25][N:24]=2)=[CH:31][CH:30]=1
Reactant: ClCc1cc(-c2ccc(Cl)cc2)no1
Reactant: Fc1ccccc1-c1nc2ccncc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1ccccc1-c1nc2ccn(Cc3cc(-c4ccc(Cl)cc4)no3)cc-2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a suspension of 2-(2-fluorophenyl)-3H-imidazo[4,5-c]pyridine (11.0 g, 50.0 mmoles) in DMF was added a 10% (w/v) solution of aqueous NaOH. To this solution, 5-(chloromethyl)-3-(4-chlorophenyl)isoxazole (13.68 g, 60.0 mmoles) dissolved in DMF was added. The reaction mixture was stirred at room temperature and monitored every half hour by LCMS. The reaction was stopped at 4 hours, after LCMS showed no progress between at 2 hour and 4 hour monitor points. The reaction product was triturated with first with water and then with EtoAc (3×). The material was crystallized by dissolving the material in MeOH with heat, followed by precipitation with water. This crystallization process was then repeated yielding 5-((3-(4-chlorophenyl)isoxazol-5-yl)methyl)-2-(2-fluorophenyl)-5H-imdazo[4,5-c]pyridine (15.385 g, 38 mmole) as white crystal at a yield of 74%. 1H 300 Mhz (d6-DMSO) sigma 6.02 (s, 2p); 7.13 (s, 1p); 7.26-7.35 (m, 2p); 7.43-7.52 (m, 1p); 7.56 (d, 2p); 7.84 (d, 1); 7.89 (d, 2p); 8.24 (d, 1); 8.28-8.36 (m, 1p); and 9.19 (s, 1p). LCMS data M/Z=405.31
Reaction SMILES: COP([CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[O:8]1)(=O)OC.C(N(CC)CC)C.[F:24][C:25]1[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][C:26]=1[C:27]#[N:28]>O1CCCC1>[F:24][C:25]1[CH:32]=[CH:31][C:30]([CH:33]=[C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[O:8]2)=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: COP(=O)(OC)C1OC(=O)c2ccccc21
Reactant: N#Cc1cc(C=O)ccc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1cc(C=C2OC(=O)c3ccccc32)ccc1F
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a mixture of (3-oxo-1,3-dihydro-isobenzofuran-1-yl)phosphonic acid dimethyl ester (G) in tetrahydrofuran and 2-fluoro-5-formylbenzonitrile (F) in tetrahydrofuran was added triethylamine drop-wise over 25 min, with the temperature kept below 15° C. The reaction mixture was warmed slowly to 20° C. over 1 hour and concentrated in vacuo. The white residue was slurried in water or 30 minutes, filtered, washed with water, hexane and ether, and dried to yield 2-fluoro-5-(3-oxo-3H-isobenzofuran-1-ylidenemethyl)benzonitrile (E) as a 50:50 mixture of E and Z isomers (yield: 96%).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[C:19]2([CH2:21][CH2:20]2)[C@@H:18]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[NH:24][C:23]2=[O:29])[C@@H:12]2[O:13]C(C)(C)[O:15][C@H:11]12)(C(C)(C)C)(C)C>C(O)(C(F)(F)F)=O.O>[OH:13][C@@H:12]1[C@H:11]([OH:15])[C@@H:10]([CH2:9][OH:8])[C:19]2([CH2:21][CH2:20]2)[C@H:18]1[N:22]1[CH:27]=[CH:26][C:25](=[O:28])[NH:24][C:23]1=[O:29]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO[Si](C)(C)C(C)(C)C)C1(CC1)[C@H]2n1ccc(=O)[nH]c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=c1ccn([C@H]2[C@H](O)[C@H](O)[C@@H](CO)C23CC3)c(=O)[nH]1
Temperature: 50 °C
Yield: 79.3 %

Procedure:
Compound 16 (0.2 g, 0.47 mmol) was dissolved in 20 mL of CF3COOH/H2O (2:1, v/v) and heated to 50° C. for 3 hr. The solvent was removed under vacuum and the residue was co-evaporated with ethanol (10 mL×3) under vacuum. The residue was purified by column chromatography on a silica gel (7% MeOH/CH2Cl2) to give 17 (100 mg, 79%) as white foam. mp 114-116° C.; [α]24D 9.84° (c 0.26, MeOH); UV (MeOH) λmax 265 nm (ε11713, pH 2), 265 nm (ε11887, pH 7), 264 nm (ε9153, pH 11); 1H NMR (500 MHz, CD3OD-d6) δ 7.50 (d, J=8.5 Hz, 1H), 5.68 (d, J=8.5 Hz, 1 H), 4.77-4.73 (m, 2 H), 4.62 (d, J=3 Hz, 1 H), 3.71 (dd, J=4.5 & 11.0 Hz, 1 H), 3.62 (dd, J=5 & 11.0 Hz, 1 H), 2.26 (m, 1 H), 0.87 (m, 2H), 0.81 (m, 1H), 0.33 (m, 1H); 13C NMR (125 MHz, CD3OD) δ 165.1, 152.2, 146.3, 109.9, 74.3, 72.4, 63.4, 51.1, 29.8, 28.7, 10.9; HR-MS Calcd. For (C12H16N2O5+H)+ 269.1059. found 269.1261.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]=[C:14]=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Cl:16][C:17]1[CH:18]=[C:19]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C@H:28]([NH2:32])[CH:29]([CH3:31])[CH3:30])[CH2:23][CH2:22]1>C(Cl)Cl>[Cl:16][C:17]1[CH:18]=[C:19]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:20][CH:21]1[CH2:22][CH2:23][N:24]([CH2:27][C@H:28]([NH:32][C:14]([NH:13][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)=[O:15])[CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:26]1
Reactant: CC(C)[C@@H](N)CN1CCC(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Solvent: ClCCl
Product: COc1cc(NC(=O)N[C@@H](CN2CCC(Cc3ccc(Cl)c(Cl)c3)CC2)C(C)C)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90.5 %

Procedure:
3,4,5-Trimethoxyphenyl isocyanate (1.9 g, 9.11 mmol) was added to a solution of 1-(R)-[4-(3,4-dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropylamine (2.5 g, 7.59 mmol) in methylene chloride (25 ml) under argon atmosphere. The solution was stirred for 45 min., at room temperature, followed by 30 min., at 38° C. The reaction mixture was concentrated in vacuo. The crude product was chromatographed on a silica gel column, eluting with 1.5-2.5% MeOH/CH2Cl2 containing 1% NH4OH to give 1-{1-(R)-[4-(3,4-dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3,4,5-trimethoxyphenyl)urea (3.7 g).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:18]1([CH2:24][CH2:25]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.O>[C:18]1([CH2:24][CH2:25][C:4]2([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2][NH:1][CH2:11][CH2:10]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CCc2ccccc2)CCNCC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
A mixture of ethyl isonipecotate (64 mmol; 10.0 g), anhydrous potassium carbonate (192 mmol; 26.5 g) and phenylethyl bromide (77 mmol, 14.25 g) in anhydrous N,N-dimethylformamide (100 ml) was stirred at 70° C. for 5 hours 30 minutes. After cooling, the reaction mixture was diluted with water (300 ml) and extracted with ethyl acetate (3×200 ml). The combined organic phases were washed with saturated NaCl solution (3×100 ml), dried over sodium sulfate and evaporated under reduced pressure. A crude product was obtained, which was purified on a column of alumina (eluting with 2/1 n-hexane/ethyl acetate) to give 14.0 g (84%) of pure product as a yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([P:7]([O:15]CC)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])[OH:6])C>Cl>[OH:6][CH:5]([P:7]([OH:15])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8])[C:4]([OH:18])=[O:3]
Reactant: CCOC(=O)C(O)P(=O)(OCC)c1ccccc1
Agent: Cl
Product: O=C(O)C(O)P(=O)(O)c1ccccc1
Yield: 89.9 %

Procedure:
To a solution of (ethoxy-phenyl-phosphinoyl)-hydroxy-acetic acid ethyl ester (382 mg, 1.41 mmol) in 10 mL of 6 M HCl was heated to reflux overnight. The resulting mixture was concentrated to a minimum volume and lyophilized affording a pale yellow solid (274 mg, 90%)
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.BrC1C=CC(N[C:18]2[O:19][C:20]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:21]=3[N:22]=2)=CC=1>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18]2[O:19][C:20]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:21]=3[N:22]=2)=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: Cc1cc(C)c2oc(Nc3ccc(Br)cc3)nc2c1
Product: Cc1cc(C)c2oc(Nc3ccc(Br)cc3F)nc2c1

Procedure:
N2-(4-Bromo-2-fluorophenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine was prepared from 4-bromo-2-fluoroaniline (2.000 g, 10.53 mmol) in a manner similar to that used for the preparation of N2-(4-bromophenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine. The compound was formed as a pink solid (1.916 g, 54%). RP-HPLC Rt 17.96 min, 95% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 337 (MH+).