Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:15][N:16]([CH2:18][CH2:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH:27]=2)[CH:22]=[CH:21]1)[CH3:17]>C(O)(=O)C>[C:1]1([C:22]2[C:23]3[C:28](=[CH:27][C:26]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)[N:20]([CH2:19][CH2:18][N:16]([CH3:17])[CH3:15])[CH:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C1CCCCC1
Reactant: CN(C)CCn1ccc2ccc(-c3cccnc3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CN(C)CCn1cc(C2=CCCCC2)c2ccc(-c3cccnc3)cc21
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
In a 20 mL vial equipped with a screw cap and a stir bar was added cyclohexanone (0.1 mL; 0.88 mmol), trifluoroacetic acid (1 mL) and acetic acid (0.75 mL). The mixture was heated at 110° C. under argon for 15 minutes. A solution of compound (a), above, (0.07 g; 0.25 mmol) in acetic acid (1 mL) was added. The resulting mixture was stirred for an additional 20 minutes at 110° C. The reaction mixture was quenched with potassium hydroxide (1N) (pH: 10; 80 mL) and extracted with ethyl acetate (30 mL). The organic phase was successively washed with water (3×30 mL), brine (30 mL), dried (sodium sulfate), filtered and solvent was removed in vacuo. The residue was purified by column chromatography on silica gel using chloroform:methanol (95:5) to yield the title compound (0.6 g; 64%). 13C NMR (CDCl3): δ148.6, 147.8, 138.0, 137.3, 134.5, 131.5, 130.9, 125.9, 123.5, 122.5, 121.8, 118.9, 118.4. 107.8, 45.8, 44.8, 34.2, 28.6, 25.8, 23.2, 22.5.
Reaction SMILES: Br[CH2:2][C:3]1[CH2:4][CH2:5][N:6]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:7][C:8]=1[C:9]1[N:13]([CH:14]([CH3:16])[CH3:15])[N:12]=[CH:11][CH:10]=1.[OH:24][C:25]1[C:30]([CH:31]=[O:32])=[CH:29][C:28]([O:33][CH3:34])=[N:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.CCOC(C)=O>[CH:31]([C:30]1[CH:29]=[C:28]([O:33][CH3:34])[N:27]=[CH:26][C:25]=1[O:24][CH2:2][C:3]1[CH2:4][CH2:5][N:6]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:7][C:8]=1[C:9]1[N:13]([CH:14]([CH3:16])[CH3:15])[N:12]=[CH:11][CH:10]=1)=[O:32]
Reactant: COc1cc(C=O)c(O)cn1
Reactant: CC(C)n1nccc1C1=C(CBr)CCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C=O)c(OCC2=C(c3ccnn3C(C)C)CN(C(=O)OC(C)(C)C)CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
To a solution of tert-butyl 4-(bromomethyl)-5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (18 mg, 0.05 mmol) and 5-hydroxy-2-methoxyisonicotinaldehyde (10 mg, 0.06 mmol) in DMF (1 mL) was added K2CO3 (14 mg, 0.1 mmol). After stirred at room temperature for 1 h, it was diluted with water and EtOAc, organic layer was separated, and the aqueous layer was extracted with EtOAc, organic layer was combined, washed with brine, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=2:1) to give tert-butyl 4-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)-3-(1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (7.2 mg). 1H NMR (400 MHz, CDCl3) (ppm) 10.39 (s, 1H), 7.79 (s, 1H), 7.56 (d, J=1.6 Hz, 1H), 7.05 (s, 1H), 6.11 (d, J=1.6 Hz, 1H), 4.40 (s, 2H), 4.38 (m, 1H), 4.01 (s, 2H), 3.88 (s, 3H), 3.66 (bs, 2H), 2.46 (bs, 2H), 1.48 (s, 9H), 1.43 (d, 6.4 Hz, 6H). MS (ESI) m/z 457.3 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([C:7]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[NH:15][CH:16]=[CH:17][C:9]=2[C:8]=1[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[C:3]([O:5][CH3:6])=[O:4].[C:25]([O-])([O-])=O.[Cs+].[Cs+].CI.Cl>C(#N)C.O>[CH3:25][N:15]1[C:10]2[C:11](=[O:14])[N:12]([CH3:13])[C:7]([CH:2]([OH:1])[C:3]([O:5][CH3:6])=[O:4])=[C:8]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)[C:9]=2[CH:17]=[CH:16]1
Reactant: COC(=O)C(O)c1c(-c2ccc(C)cc2)c2cc[nH]c2c(=O)n1C
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Solvent: O
Product: COC(=O)C(O)c1c(-c2ccc(C)cc2)c2ccn(C)c2c(=O)n1C
Temperature: 50 °C
Reaction time: 3 h
Yield: 101.1 %

Procedure:
A suspension of methyl 2-hydroxy-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (30 mg, 0.092 mmol) and Cs2CO3 (35.9 mg, 0.110 mmol) in Acetonitrile (1 mL) was treated with MeI (6.90 μL, 0.110 mmol) and heated to 50° C. for 3 hours. Additional MeI (10 uL) was added, the reaction was stirred at 50° C. for 3 hours. The mixture was cooled to rt, diluted with water, acidified with 1N HCl, extracted with EtOAc 3×, washed with brine, dried with Na2SO4, filtered, and concentrated. Combined with crude product from the same reaction (0.040 mol scale) and purified with column chromatography (0-100% EtOAc/Hexane) to give methyl 2-(1,6-dimethyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-hydroxyacetate (31.7 mg, 0.093 mmol, 70.6% yield) as clear oil. LCMS (m/z) ES+=341 (M+1).
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13]([OH:15])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+:9]([O-:11])=[O:10].Cl.[NH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1.C([N:36](CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[C:19]([O:18][C:16]([NH:1][C@@H:2]([C:13]([NH:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)=[O:15])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH2:12])=[N:8][N+:9]([O-:11])=[O:10])=[O:17])([CH3:22])([CH3:21])[CH3:20].[NH3:36]
Reactant: NCCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O
Reactant: CCN(CC)CC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)NCCc1ccc(O)cc1
Product: N
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 1.0 g (3.13 Mol) of Boc-D-Arg(NO2)-OH, 0.57 g (3.28 mMol) of tyramine-hydrochloride, 0.91 ml (0.66 g =6.53 mMol) of triethylamine and 20 ml of anhydrous acetonitrile were added 1.05 g (3.27 mMol) of TBTU, with stirring and external cooling with ice water. The mixture was allowed to come up to ambient temperature and stirring was continued overnight under these conditions. The precipitate was filtered off, the filtrate was evaporated down in vacuo, the residue was distributed between water and ethyl acetate. The ethyl acetate phase was then purified by column chromatography on silica gel (Macherey-Nagel, 35-70 mesh ASTM) using dichloromethane/methanol/cyclohexane/conc. aqueous ammonia =68/15/15/2 (v/v/v/v). 0.8 g (58% of theory) of the title compound were obtained in the form of an amorphous foam, Rf 0.49 (Macherey-Nagel Polygram® SIL G/UV254, ready-made films for TLC; eluant: dichloromethane/methanol/cyclohexane/conc. aqueous ammonia =68/15/15/2 (v/v/v/v)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)=[N:10]1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)=[CH:24][CH:25]=2)=[N:10]1
Reactant: COc1nccc2c1c(-c1ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc1)nn2-c1c(F)cccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1nccc2c1c(-c1ccc(N3CCNCC3)cc1)nn2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.1 %

Procedure:
To a solution of tert-butyl 4-(4-(1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)piperazine-1-carboxylate (920 mg) in dichloromethane (10 mL) was added trifluoroacetic acid (4 mL) under ice-cooling, and the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure. The residue was diluted with dichloromethane, and the mixture was adjusted to pH=9 with saturated aqueous sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (744 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:31])([CH3:33])[CH3:32])([CH3:28])[CH3:29]
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(Br)c2)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCO[Si](C)(C)C(C)(C)C)c(Br)c2)cc1
Yield: 64.3 %

Procedure:
In a manner similar to that of Example 2a, by reacting 3 g of ethyl 3′-bromo-4′-hydroxy-biphenyl-4-carboxylate (9.3 mmol) in 100 mL of dimethylformamide with 448 mg (11 mmol) of sodium hydride and 2.6 mL of 1-bromo-3-(tert-butyldimethylsilanyloxy)propane (11 mmol). 2.95 g of ethyl 3′-bromo-4′-[3-(tert-butyldimethylsilanyloxy)propoxy]biphenyl-4-carboxylate are obtained (yield=64%) in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:18]2[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:19]=2[O:25][CH2:26][CH3:27])[N:3]=1.[N:28]1([OH:37])C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.NO.C(N(CC)CC)C>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:28][OH:37])=[O:14])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:18]2[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:19]=2[O:25][CH2:26][CH3:27])[N:3]=1
Reactant: On1nnc2ccccc21
Reactant: CCOc1ccc(Br)cc1-c1cc(Nc2ccc(C(=O)O)cc2)nc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1ccc(Br)cc1-c1cc(Nc2ccc(C(=O)NO)cc2)nc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
To a stirred solution of 4-[2-amino-6-(5-bromo-2-ethoxy-phenyl)-pyrimidin-4-ylamino]-benzoic acid (0.086 g, 0.20 mmol) in dimethylformamide (3.0 ml) was added benzotriazol-1-ol (0.054 g, 0.40 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.086 g, 0.44 mmol). After stirring at room temperature for 1 hour, hydroxylamine hydrochloride (0.070 g, 1.0 mmol) was added followed by triethylamine (0.1 g, 1.0 mmol). After stirring for 16 hours, the solvent was evaporated under reduced pressure and the residue was treated with 1 M aqueous sodium carbonate solution (10 ml). Filtration provided the title compound (0.065 g, 73% yield) as a light brown solid. 1H NMR (DMSO-d6) δ 1.38 (t, 3H, J=6.9 Hz, CH3), 4.12 (q, 2H, J=6.9 Hz, CH2), 6.32 (s, 2H, NH2), 6.79 (s, 1H, Ar), 7.08 (d, 1H, J=8.9 Hz, Ar), 7.52 (dd, 1H, J=8.9 Hz, J=2.6 Hz, Ar), 7.66 (b, 4H, Ar), 8.04 (d, 1H, J=2.6 Hz, Ar), 9.24 (s, 1H, NH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CN(C)CCN(C)C.C([Li])CCC.[Li].CON(C)[C:29](=[O:32])[CH2:30][Cl:31]>CCCCCC.C1COCC1.O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH3:11])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[C:29](=[O:32])[CH2:30][Cl:31]
Reactant: CON(C)C(=O)CCl
Reactant: COc1cc(C)cc(OC)c1
Agent: CN(C)CCN(C)C
Agent: [Li]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(C)cc(OC)c1C(=O)CCl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 15.7 %

Procedure:
7.61 g of 3,5-dimethoxytoluene and 6.10 g of tetramethylethylenediamine are dissolved under nitrogen in 150 ml of hexane. The solution is cooled to 0° C., 32.8 ml of 1.6 M butyllithium in hexane are added and the mixture is stirred at 10° C. for 20 minutes and then at 20° C. for 1 hour. To the lithium derivative cooled to -10° C., a solution, cooled to 0° C., of 6.13 g of N-methoxy-N-methylchloroacetamide in 50 ml of THF is added in the course of 20 minutes. The reaction mixture is left for one hour at a temperature of between 0° and 5° C. and for one hour at 20° C., and then poured into 100 ml of water. The resulting mixture is extracted with twice 300 ml of diethyl ether, the ether phases are washed with saturated sodium chloride solution, and the organic phases are dried over magnesium sulphate, filtered and concentrated under vacuum. The residue is chromatographed on silica, eluting with a DCM/hexane (50:50; v/v) mixture. Concentration of the pure fractions yields 1.6 g of the expected product; m.p. 82°-84° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH:18]([N:21]1[CH2:26][CH2:25][CH:24](OS(C)(=O)=O)[CH2:23][CH2:22]1)([CH3:20])[CH3:19]>CN(C=O)C.CC(OC)(C)C.O.[OH-].[Na+]>[CH:18]([N:21]1[CH2:26][CH2:25][CH:24]([O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:23][CH2:22]1)([CH3:20])[CH3:19]
Reactant: N#CC1(c2ccc(O)cc2)CCOCC1
Reactant: CC(C)N1CCC(OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC(C)N1CCC(Oc2ccc(C3(C#N)CCOCC3)cc2)CC1
Temperature: 75 °C
Reaction time: 1 h
Yield: 19.5 %

Procedure:
4-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (459 mg, 2.26 mmol) in DMF (2 ml) was added to a solution of NaH (100 mg, 2.5 mmol) in DMF (2 ml) at room temperature under N2. The reaction was stirred for 1 hr and a solution of methanesulfonic acid 1-isopropyl-piperidin-4-yl ester (400 mg, 1.81 mmol) in DMF (1.3 ml) was slowly added. The reaction was heated to 75° C. and stirred for 6 hrs. The reaction was allowed to cool to room temperature and diluted with TBME (20 ml), water (10 ml) and 5M NaOH solution (10 ml). The organic layer was washed with 2.5M NaOH (2×20 ml), brine (2×20 ml), dried over MgSO4, filtered and concentrated in vacuo. The crude reaction was purified by successive column chromatography, eluting with DCM:MeOH:NH3 (98:1:1) to give the title compound as a pale yellow solid (116 mg, 19%). 1H NMR (400 MHz, CDCl3) δ 7.37 (d, 2H), 6.93 (d, 2H), 4.30 (m, 1H), 4.12-4.02 (m, 2H), 3.89 (td, 2H), 2.84-2.68 (m, 3H), 2.45-2.34 (m, 2H), 2.15-1.96 (m, 6H), 1.88-1.75 (m, 2H), 1.06 (d, 6H).
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=O)[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:39]([NH2:47])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1>[NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([NH:47][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:16])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Reactant: NCCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)NCCc1ccccc1
Temperature: -15 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a stirred solution of Boc-Asp(OBzl), 5.0 g (15.5 mmol) and N-methyl morpholine (15.5 mmol) in 50 mL of dry THF under an Ar atmosphere was added isobutylchloroformate (15.5 mmol) at -15° C. After a few minutes, phenethylamine 2.0 mL (15.5 mmol) in 15 mL of dry THF was added. The mixture was maintained at -15° C. for 15 min. and allowed to warm to room temperature. After stirring for an additional 2 hours, the reaction mixture was filtered and the filtrate was concentrated in vacuo to dryness. The resulting residue was dissolved in ethyl acetate (100 mL) and washed successively with 1M HCl (2×50 mL), water (50 mL), 10% sodium carbonate (2×50 mL), and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to yield 5.59 gm (85%) of an amorphous white solid.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]([NH2:7])=[NH:6])=[NH:3].Br[CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].C(O)(=O)C>CN(C)C=O>[NH:4]([C:5]1[NH:7][CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[C:16](=[O:25])[C:17]3=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]3[C:19]2=[O:20])[N:6]=1)[C:2]([NH2:1])=[NH:3]
Reactant: N=C(N)NC(=N)N
Reactant: O=C(CBr)CCCCN1C(=O)c2ccccc2C1=O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: N=C(N)Nc1nc(CCCCN2C(=O)c3ccccc3C2=O)c[nH]1
Reaction time: 3 h

Procedure:
Biguanide (1.01 g.) was stirred in dry dimethylformamide (15 ml.) and N-(6-bromo-5-oxohexyl)phthalimide (1.5 g.) added. The mixture was stirred for 3 hours, acetic acid (5 ml.) was then added and the total reaction mixture evaporated to dryness. The residue was dissolved in water (10 ml.) and extracted with ethyl acetate (5×20 ml.). The combined ethyl acetate extracts were evaporated to give a brown foam which was purified by column chromatography on silica gel using chloroform/methanol/ammonia (s.g. 0.880) 80:20:0.5 v/v/v. The appropriate fractions were evaporated to give 2-guanidino-4-(4-phthalimidobutyl)imidazole as a brown foam (0.3 g.).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:17]O.C(N(CC)CC)C.S(Cl)([Cl:28])=O>ClCCl>[Cl:28][CH2:17][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])[C:6]=1[O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCOc1cccc(CO)c1OCCOC
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOc1cccc(CCl)c1OCCOC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.8 %

Procedure:
To a solution of (2,3-bis{[2-(methyloxy)ethyl]oxy}phenyl)methanol (1.12 g, 4.37 mmol) and triethylamine (0.49 g, 4.84 mmol) in dichloromethane (20 mL) was slowly added thionyl chloride (0.78 g, 6.58 mmol) at 0° C. The solution was stirred at 0° C. for 15 min, and then at rt for 3 h. Dichloromethane (80 mL) was added, the solution was washed with water (50 mL), sat. sodium bicarbonate (50 mL), and brine (50 mL), dried with sodium sulfate, and concentrated to give crude 1-(chloromethyl)-2,3-bis{[2-(methyloxy)-ethyl]oxy}benzene (1.15 g, 96% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ7.02 (m, 2H), 6.90 (dd, 1H), 4.72 (s, 2H), 4.27 (m, 2H), 4.14 (m, 2H), 3.77 (m, 2H), 3.73 (m, 2H), 3.46 (s, 3H), 3.44 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.C([Li])CCC.CCCCCC.[O:20]1[CH:25]=[CH:24][C:23](=[O:26])[CH:22]=[CH:21]1>C1COCC1>[Br:8][C:4]1[CH:3]=[C:2]([C:23]2([OH:26])[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: O=c1ccocc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC1(c2cccc(Br)c2)CCOCC1
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To a stirred −78° C. solution of 1,3-dibromobenzene (19.71 g, 81.05 mmol) in THF (150 mL) is added 1.6 M butyl lithium in hexane (50.66 mL, 81.05 mmol) and the reaction is stirred 10 minutes. 4H-Pyran-4-one, tetrahydro- (5.41 g, 54.04 mmol) is added dropwise and the reaction is stirred at −78° C. for 2 h. The reaction is quenched by addition of saturated aqueous ammonium chloride (25 mL) and is then diluted with minimal water and extracted with EtOAc. The organic layer is dried over Na2SO4 and the solvent is removed under reduced pressure to afford a residue that is purified by silica gel chromatography eluting with a linear gradient of 5% to 100% EtOAc in hexanes to give the title compound (11.18 g, 76%). GC-MS (m/e): (79Br/81Br) 256, 258 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[NH:10][C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[CH:17]4)[N:13]=2)=[CH:4][C:3]=1[OH:31].Br[CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[NH:10][C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[CH:17]4)[N:13]=2)=[CH:4][C:3]=1[O:31][CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(O)c3)nc2-c2ccc3ncccc3c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(OCCNC(=O)OC(C)(C)C)c3)nc2-c2ccc3ncccc3c2)n1
Temperature: 60 °C
Reaction time: 20 h
Yield: 91.4 %

Procedure:
To a stirred solution of 2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenol (Example 81) (100 mg, 0.244 mmol) in acetone (5 mL) were added tert-butyl 2-bromoethylcarbamate (109 mg, 0.488 mmol) and K2CO3 (67 mg, 0.488 mmol) and the mixture was stirred at 60° C. for 20 hours. The reaction mixture was cooled to room temperature, diluted with H2O (20 mL), and extracted with CH2Cl2 (5 mL, 3 times). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by MPLC on NH silica gel (MeOH:CH2Cl2=1:50 (v/v)) to give tert-butyl 2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)ethylcarbamate (123.5 mg, 91%). This compound was dissolved in CH2Cl2 (5 mL), and p-anisole (224 uL, 2.23 mmol) and trifluoroacetic acid (1 mL) were added. The mixture was stirred for 1 hour, then concentrated, diluted with H2O (10 mL), and neutralized by addition of aqueous NH4OH solution to pH 7˜8. The aqueous solution was saturated with NH4Cl solid, extracted with CH2Cl2 (5 mL, 3 times), and then the organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by MPLC on NH silica gel (MeOH:CH2Cl2=3:100 (v/v)) to afford the title compound (70.2 mg, 69%). 1H NMR (300 MHz, CDCl3) δ 2.50 (3H, s), 3.09 (2H, t), 4.04 (2H, t), 4.16 (2H, s), 6.85-6.90 (1H, m), 6.95-7.07 (3H, m), 7.24 (1H, s), 7.36 (1H, d), 7.41 (1H, dd), 7.97 (1H, dd), 8.09-8.18 (3H, m), 8.92 (1H, dd), 10.40 (1H, bs). MS (ESI) m/z 454 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31]>>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[O:31]
Reactant: O=C=Nc1ccccc1Cl
Reactant: COC(=O)C(Cc1ccc(OC)c(CCO)c1)C(=O)OC
Product: COC(=O)C(Cc1ccc(OC)c(CCOC(=O)Nc2ccccc2Cl)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)-4-methoxybenzyl]malonate and 2-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [Si]([O:18][C:19]1[CH:64]=[CH:63][C:22]([O:23][CH2:24][C@@H:25]([OH:62])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:61]=[CH:60][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([S:41]([C:44]4[CH:49]=[CH:48][C:47]([NH:50][C:51]([NH:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[O:52])=[CH:46][CH:45]=4)(=[O:43])=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:54]([NH:53][C:51]([NH:50][C:47]1[CH:48]=[CH:49][C:44]([S:41]([N:38]2[CH2:37][CH2:36][CH:35]([NH:34][C:33]3[CH:60]=[CH:61][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:62])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:64][CH:63]=4)=[CH:31][CH:32]=3)[CH2:40][CH2:39]2)(=[O:43])=[O:42])=[CH:45][CH:46]=1)=[O:52])[CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]
Reactant: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1

Procedure:
N-[4-({4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-1-piperidinyl}sulfonyl)phenyl]-N′-hexylurea (0.18 g, 0.199 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound as the hydrochloride salt (0.1 g, 0.142 mmol).