Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([Br:12])[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Br[CH:15]([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][CH:15]([CH3:17])[CH3:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Oc1c(Br)cc(Br)c2cccnc12
Reactant: CC(C)Br
Product: CC(C)Oc1c(Br)cc(Br)c2cccnc12
Yield: 97 %

Procedure:
Reaction of 5,7-dibromo-quinolin-8-ol with 2-bromopropane following the method described in Example 8 gave 5,7-dibromo-8-isopropoxy-quinoline 6 (97%): 1H NMR (CDCl3): δ 8.94 (dd, J=1.5 and 4.2, 1 H), 8.48 (dd, J=1.5 and 8.4, 1H), 8.00 (s, 1 H), 7.52 (dd, J=4.2 and 8.4, 1 H), 5.22 (m, 1 H), 1.43 (d, J=6.1, 6 H); mass spectrum: m/z 344, 346, 348 (M++1, 50, 100 and 50%, respectively). Reaction of 6 with aryl boronic acids, and cleavage of the isopropoxy group following the method outlined in Example 8 gave compounds L1 and L2 (data in Table 4).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[OH:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].C(#N)C>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([O:12][C:13]2[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:24][CH:25]=2)=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Cl
Reactant: COC(=O)C(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2[N+](=O)[O-])cc1
Yield: 93.1 %

Procedure:
38.6 g (0.20 mole) of 2.5-dichloro-3-nitropyridine, 41.2 g (0.21 mole) of methyl 2-(4-hydroxyphenoxy)propionate, 400 ml of acetonitrile, 35.9 g (0.26 mole) of potassium carbonate and 0.33 g (0.002 mole) of potassium iodide are heated for 13 hours to 80° C. The reaction mixture is filtered and the filter cake is washed with acetonitrile. The filtrate is concentrated by evaporation and the residue is taken up in 500 ml of methylene chloride. After treating the solution with 15 g of activated carbon, it is filtered through a layer of silica gel and the filtrate is concentrated by evaporation. The residue is crystallised from a mixture of hexane and ethyl acetate, affording 65.7 g (93.1% of theory) of methyl 2-[4-(5-chloro-3-nitropyridin-2-yloxy)phenoxy]propionate with a melting point of 91°-92° C.
Reaction SMILES: [Br:1][C:2]1(O)[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1.[H-].[Na+].CC1C=CC(S([O:21][CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[S:28]([C:31]2[CH:39]=[CH:38][C:37]3[N:36]4[CH2:40][C:41]([CH3:45])([CH3:44])[CH2:42][N:43]=[C:35]4[C:34]4(OCCC[O:46]4)[C:33]=3[CH:32]=2)(=[O:30])=[O:29])(=O)=O)=CC=1.CN(C=O)C>C1COCC1>[Br:1][C:2]1[C:7]([O:21][CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[S:28]([C:31]2[CH:39]=[CH:38][C:37]3[N:36]4[CH2:40][C:41]([CH3:44])([CH3:45])[CH2:42][N:43]=[C:35]4[C:34](=[O:46])[C:33]=3[CH:32]=2)(=[O:29])=[O:30])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OC1(Br)C=CC=CN1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2S(=O)(=O)c2ccc3c(c2)C2(OCCCO2)C2=NCC(C)(C)CN23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1(C)CN=C2C(=O)c3cc(S(=O)(=O)N4CCC[C@H]4COc4cccnc4Br)ccc3N2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of 2-bromo pyridinol (0.089 g, 0.510 mmol) in THF (3 mL) was added NaH (60% dispersion in mineral oil) (0.020 g, 0.085 mmol) and the reaction was stirred at rt for 1 hr. {(2S)-1-[(3′,3′-Dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indol]-8′-yl)sulfonyl]pyrrolidin-2-yl}methyl 4-methylbenzenesulfonate (0.100 g, 0.170 mmol) in THF (2 mL)/DMF (2 mL) was added and the reaction was heated overnight at 100° C. The reaction was quenched with water and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, concentrated and purified on Biotage Si 12+M cartridge silica gel eluting with acetone/hexane (30/70). The resulting product was dissolved in CH2Cl2 (3 mL) and methanesulfonic acid (2 mL) was added and the solution stirred at 35° C. overnight. The reaction mixture was poured onto ice, basified to pH 11 with ammonium hydroxide and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, concentrated and purified on Biotage Si 12+M cartridge silica gel eluting with acetone/hexane (30/70) to give the title compound as a yellow foam (0.058 g, 56%). NMR (400 Mz, DMSO-d6): consistent. MS: (ESI+) m/z 533.1 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](=[CH:7][CH:8]=1)[OH:6].[O:10]=[C:11]1[C:16](=[O:17])[N:15]([CH2:18][CH3:19])[CH2:14][CH2:13][N:12]1[C:20]([NH:22][CH:23](O)[C:24]([OH:26])=[O:25])=[O:21].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(O)(=O)C.S(=O)(=O)(O)O>[O:10]=[C:11]1[C:16](=[O:17])[N:15]([CH2:18][CH3:19])[CH2:14][CH2:13][N:12]1[C:20]([NH:22][CH:23]([C:8]1[CH:7]=[C:5]([OH:6])[C:4]([OH:9])=[CH:3][C:2]=1[Br:1])[C:24]([OH:26])=[O:25])=[O:21]
Reactant: Oc1ccc(Br)cc1O
Reactant: CCN1CCN(C(=O)NC(O)C(=O)O)C(=O)C1=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCN1CCN(C(=O)NC(C(=O)O)c2cc(O)c(O)cc2Br)C(=O)C1=O
Reaction time: 18 h

Procedure:
4-Bromocatechol (4.77 g, 25.2 mmole) was added to an ice bath cooled suspension of N-(2,3-dioxo-4-ethylpiperazin-1-yl-carbonyl)-2-hydroxyglycine (2.59 g. 10 mmole) in glacial acetic acid (9 ml) and concentrated sulphuric acid (1 ml). The mixture was stirred for 18 hours then poured onto a mixture of ice, saturated sodium carbonate and ethyl acetate and adjusted to pH7 with sodium carbonate. The aqueous layer was collected, washed with ethyl acetate (50 ml), acidified to pH1 and extracted with ethyl acetate (3×50 ml). The extracts were dried and evaporated in vacuo to a buff solid, 2.4 g, 79%, δ[(CD3)2CO]1.13(3H, t, J7 Hz, CH2CH3), 3.57(2H, q, J7 Hz, CH2CH3), 3.5-4.3(4H, m, 2×NCH2), 5.3-7.6(3H, broad, 2×OH, CO2H), 5.73 (1H, d, J6.5 Hz, CHNH), 6.87 and 7.03 (2H, 2×s, Ar), 9.73(1H, d, J6.5 Hz, CHNH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[C:12]1[S:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=1.[OH-:19].[Na+]>O.CS(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[C:12]1[S:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(-c2ncnc3ccc(Br)cc23)s1
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1ccc(-c2ncnc3ccc(Br)cc23)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.6 %

Procedure:
A solution of 2.19 g silver nitrate in 40 mL water and a solution of 1.96 g 5-(6-bromoquinazolin-4-yl)thiophen-2-carboaldehyde (compound in Production Example 381) in 20 mL dimethyl sulfoxide were added little by little successively to a solution of 1.0 g sodium hydroxide in 40 mL water under ice-cooling, and the mixture was stirred at room temperature for 24 hours. The reaction solution was filtered through Celite and acidified with hydrochloric acid, and the precipitated crystals were filtered. This product was recrystallized from dichloromethane/methanol/ether, to give 1.7 g of the title compound as pale yellow crystals.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[S:10][CH:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=2)[CH:3]=[N:2]1.CCN(C(C)C)C(C)C.[F:23][C:24]([F:37])([F:36])[CH2:25][N:26]1[CH:35]2[CH:30]([CH2:31][CH2:32][CH2:33][CH2:34]2)[NH:29][CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[NH:2]1[CH:3]=[C:4]([C:6]2[S:10][CH:9]=[C:8]([C:11]([N:29]3[CH:30]4[CH:35]([CH2:34][CH2:33][CH2:32][CH2:31]4)[N:26]([CH2:25][C:24]([F:36])([F:37])[F:23])[CH2:27][CH2:28]3)=[O:13])[CH:7]=2)[CH:5]=[N:1]1
Reactant: O=C(O)c1csc(-c2cn[nH]c2)c1
Reactant: FC(F)(F)CN1CCNC2CCCCC21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(c1csc(-c2cn[nH]c2)c1)N1CCN(CC(F)(F)F)C2CCCCC21
Reaction time: 24 h
Yield: 12.2 %

Procedure:
5-(1H-Pyrazol-4-yl)-thiophene-3-carboxylic acid (0.080 g, 0.41 mmol) was suspended in acetonitrile (2 mL) then DIPEA (0.158 mL, 0.90 mmol) and 1-(2,2,2-trifluoro-ethyl)-decahydro-quinoxaline (0.119 g, 0.54 mmol) were added followed by HATU (0.192 g, 0.50 mmol). The resulting mixture was stirred for about 24 hours and then further amounts of DIPEA (79 μL) and HATU (0.192 g) were added and stirring continued over the weekend. The mixture was evaporated and the residue was taken up in sodium hydroxide (1 N) and stirred for 30 minutes. HCl (1 N, 2.5 mL) was added and the solution extracted with ethyl acetate (×3). The organics were dried over sodium sulfate, filtered and evaporated. The material was purified by HPLC, eluting with 5%-95% acetonitrile in water (0.1% formic acid) and the fractions containing the desired product were combined and freeze-dried to give the title compound as a white solid (0.020 g). LCMS m/z 399.17 [M+H]+ R.T.=10.05 min (Analytical Method 2).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[Br:19][CH:20](Br)[CH3:21].[NH4+].[Cl-]>O1CCCC1.CCCCC>[Br:19][CH2:20][CH2:21][C:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(Br)Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: BrCCc1cccc2c1Cc1ccccc1-2
Reaction time: 1 h

Procedure:
In this reaction, 8.3 g (0.05 m) of fluorene was dissolved in 150 ml of tetrahydrofuran. Then 31.8 ml (0.05 m) of butyl lithium (1.6 molar in hexane) was added dropwise to this solution. After one hour, this solution was added gradually to a stirred solution of 9 ml (0.1 m) of dibromoethane in 300 ml of pentane within 2 hours. Then the reaction mixture was treated with 50 ml of an aqueous NH4Cl solution, and then washed with 50 ml of water. The organic phase was dried over Na2SO4. Then the solvent was removed in vacuo. The yellow residue was dissolved in pentane. The pentane solution was filtered over silica. The solution was concentrated to about 20% of the original volume and then the product was crystallized at -30° C. A yield of 10.88 g of 1-bromo-2-(fluorenyl)ethane was obtained. The product was characterized through 1H NMR, 13C NMR, and Mass spectroscopy.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:5][C@H:4]([NH:6][C:7]2[C:8]3[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)[N:12]=2)[CH2:3]1.CCN(C(C)C)C(C)C.[C:40](Cl)(=[O:43])[CH:41]=[CH2:42]>C(Cl)Cl>[CH3:19][N:17]1[CH:18]=[C:14]([NH:13][C:11]2[N:12]=[C:7]([NH:6][C@H:4]3[CH2:3][C@H:2]([NH:1][C:40](=[O:43])[CH:41]=[CH2:42])[CH2:5]3)[C:8]3[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:9]=3[N:10]=2)[CH:15]=[N:16]1
Reactant: C=CC(=O)Cl
Reactant: Cn1cc(Nc2nc(N[C@H]3C[C@H](N)C3)c3ccn(COCC[Si](C)(C)C)c3n2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)N[C@H]1C[C@H](Nc2nc(Nc3cnn(C)c3)nc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N4-((trans)-3-aminocyclobutyl)-N2-(1-methyl-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (87 mg, 0.2 mmol) was dissolved in DCM (5 mL). DIPEA (53 μL, 0.3 mmol) was added and the reaction was cooled to 0° C. Acryloyl chloride (16 μL, 0.2 mmol) was added via a 10 μL syringe and the reaction was allowed to stir at 0° C. for 1 hr. The reaction was concentrated and purified via flash chromatography eluting with a gradient of 1%-20% EtOH in DCM. The fractions containing the product were pooled and dried down to afford the title compound as a tan solid (confirmed to be product by LCMS). This tan solid was taken directly to the final step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[C:15]2[O:14][CH2:13][C:12](=[O:16])[C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH3:2].[BrH:18].[NH+]1C=CC=CC=1.O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[C:15]2[O:14][CH:13]([Br:18])[C:12](=[O:16])[C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: Br
Reactant: CCOC(=O)COc1cccc2c1OCC2=O
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)COc1cccc2c1OC(Br)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl[(3-oxo-2,3-dihydrobenzofuran-7-yl)oxy]acetate (1.00 g, 4.23 mmol) in chloroform (30 mL) was added pyridinium hydrobromide perbromide (1.35 g, 4.23 mmol) at 0° C. and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water. The organic layer was washed with water, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide 1.20 g of ethyl[(2-bromo-3-oxo-2,3-dihydrobenzofuran-7-yl)oxy]acetate. A mixture of this compound (1.20 g, 3.80 mmol) and 1-phenyl-2-thiourea (580 mg, 3.80 mmol) in acetic acid (20 mL) was refluxed for 3 hours. The solvent was then distilled off under reduced pressure. To that residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane=1:5) to provide 180 mg of the title compound. Yield 12%.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([S:14](Cl)(=[O:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>CN(C)C(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([S:14]([NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[F:18])(=[O:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Nc1ccccc1F
Reactant: CCOC(=O)c1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc(S(=O)(=O)Nc2ccccc2F)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To ethyl 2,4-dichloro-5-(chlorosulfonyl)benzoate (1 g, 3.15 mmol) in N,N-dimethylacetamide (10.5 mL) was added 2-fluoroaniline (1.215 mL, 12.60 mmol) dropwise over 1 minute at room temperature. The mixture was stirred at room temperature for 1 hour, and then it was diluted with ethyl acetate (35 mL). The organic solution was washed with 1 N HCl (2×13 mL) and saturated NaCl (13 mL). The organic layer was concentrated, ethanol (38 mL) was added, and the mixture concentrated to give ethyl 2,4-dichloro-5-{[(2-fluorophenyl)amino]sulfonyl}benzoate.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[NH2:15][CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:15][CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)#[N:2]
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Solvent: CO
Product: N#CNC(=NC(c1ccccc1)c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and aminodiphenylmethane (0.54 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 40 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure to give N-cyano-N'-diphenylmethyl-3-pyridinecarboximidamide (0.48 g, 1.5 mmol, yield: 58%) as colorless syrup. Next, to this syrup was added a solution of 5% hydrogen chloride in methanol (2 ml) to form a solution. The solution was further crystallized from methanol-diethyl ether to give N-cyano N'-diphenylmethyl 3-pyridinecarboximidamide hydrochloride as colorless powder.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C(N(CC)CC)C.[Cl:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)Cl>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:19](=[O:20])[CH2:18][Cl:17]
Reactant: Cc1cccc(C)c1N
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1NC(=O)CCl
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a 3-necked, 1-liter flask provided with a reflux condenser, an additional funnel and a magnetic stirring bar was charged 36.3 grams (0.3 mole) of 2,6-dimethyl aniline and 30.36 grams (0.3 mole) of triethylamine in 550 milliliters of methylene chloride. To the stirred solution, maintained at 0° to 5° C. by means of an ice bath, was added dropwise, over a period of 30 minutes, 33.9 grams (0.3 mole) of chloroacetyl chloride. The reaction mixture was then stirred at ambient temperature for 21 hours after which it was transferred to a separatory funnel and washed consecutively with 300 milliliter portions of 1 Normal hydrochloride acid, 10 percent aqueous sodium carbonate solution and water. The organic layer was removed, dried over magnesium sulfate and concentrated on a rotary evaporator at 55° C. leaving a bluish-gray solid. This solid was recrystallized from a hot 20:80 volume/volume ethylacetate-ligroin solution yielding 41 grams of gray, solid N-(2,6-dimethylphenyl)-α-chloroacetamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[CH:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][C:18]=1[N+:27]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Rh]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=1[NH2:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C=Cc2ccccc2OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Rh]
Solvent: CCO
Product: Nc1cc(C(=O)O)ccc1CCc1ccccc1OCc1ccccc1

Procedure:
A mixture of methyl 4-[2-(2-benzyloxyphenyl)ethenyl)-3-nitrobenzoate (2.5 g) and 5% Rhodium on alumina (520 mg) in ethanol (200 ml) was stirred under 1 atm. of hydrogen for 20 hours. The mixture was filtered and the solvent evaporated. The residue was purified by subjecting to chromatography using ethylacetate: dichloromethane (9:1) as eluant. There was thus obtained methyl 4-[2-(2-benzyloxyphenyl)ethyl]-3-aminobenzoate (1.71 g).
Reaction SMILES: Cl[CH2:2][C@H:3]([CH3:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C@@H:3]([CH3:13])[CH2:2][N:28]2[CH2:29][CH2:30][CH:25]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=3)[CH2:26][CH2:27]2)=[CH:7][CH:8]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: C[C@@H](CCl)COc1ccc(Br)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](C)COc3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 4-bromophenyl(2R)-3-chloro-2-methylpropyl ether and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 473.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[ClH:11].[CH3:12][OH:13]>>[ClH:11].[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7](=[NH:8])[O:13][CH3:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(C#N)cc1
Reactant: CO
Agent: Cl
Product: COC(=N)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-methoxybenzonitrile (12.5 g, 91.1 mmol) was dissolved in methanol (140 mL), through this cooled (−5° C.) solution gaseous HCl was bubbled for about 3 hours. The reaction mixture was then stirred, in a closed flask, at r.t. for 24 hours. Then the excess HCl was stripped by bubbling nitrogen and the resulting solution was concentrated, the residue was taken up with TBME (100 mL) and stirred for 30 min., then filtrated and dried to provide the title product as a colourless powder 19.0 g (quantitative). C9H11NO2.HCl, MW: 201.69 1H-NMR (300 MHz, D2O) ppm: 4.20 (s, 3H), 6.9 (m, 1H); 7.65 (m, 1H); 8.40 (m, 1H).
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(F)=CC=1)C.C=O.[C:22]1([CH2:28][CH2:29][CH2:30][NH2:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[F:32][C:33]1[CH:51]=[CH:50][C:36]([CH2:37][N:38]([CH3:49])[C:39]([C:41]2[CH2:42]N(C)[C:44](=[O:47])[C:45]=2[OH:46])=[O:40])=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:51]=[CH:50][C:36]([CH2:37][N:38]([CH3:49])[C:39]([C:41]2[CH2:42][N:31]([CH2:30][CH2:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:44](=[O:47])[C:45]=2[OH:46])=[O:40])=[CH:35][CH:34]=1
Reactant: NCCCc1ccccc1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(F)cc2)=C(O)C1=O
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(F)cc1
Product: CN(Cc1ccc(F)cc1)C(=O)C1=C(O)C(=O)N(CCCc2ccccc2)C1

Procedure:
3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 1-D) was treated with paraformaldehyde and 3-phenyl-propylamine as described in the preparation of Compound 1. 1H NMR (500 MHz, CDCl3) δ: 1.93 (p, 2, J=7), 2.64 (t, 2, J=7), 2.99 (s, 3), 3.53 (t, 2, J=2), 4.10 (s, 2), 4.60 (s, 2), 7.02–7.28 (overlapping m, 9). 13C (125 MHz, CDCl3) δ: 29.77, 33.05, 34.56, 42.81, 48.79, 51.47, 109.25, 115.66, 115.83, 126.14, 128.30, 128.49, 129.34, 129.40, 132.16, 132.79, 140.88, 152.46, 161.39, 163.34, 165.02, 166.08.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33][O:34][CH2:35][CH2:36][CH2:37]N.C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH2:37][CH2:36][CH2:35][O:34][CH3:33])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCN
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCCCNC(=O)Nc1cn(-c2cccc(F)c2)cc1C(=O)N[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Yield: 71 %

Procedure:
Following general method 6, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester and 3-methoxy-propylamine afforded the crude desired product. Column chromatography (silica, 12 g column, ISCO, 0-60% ethyl acetate in DCM) afforded the title compound as a glass (100 mg, 71%). LCMS (method B): RT=3.67 min, M+H+=518.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCCC1=O.[CH3:18][C:19]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:20]=1[C:21](Cl)=[O:22]>O>[CH3:18][C:19]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:20]=1[C:21]([NH:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22]
Reactant: NNC(=O)c1ccccc1
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(C(=O)NNC(=O)c2ccccc2)c(C)c1
Reaction time: 24 h
Yield: 65 %

Procedure:
First, 16.7 g (123.3 mmol) of benzoylhydrazine and 100 mL of N-methyl-2-pyrrolidinone (NMP) were put into a 300-mL three-neck flask and stiffed under nitrogen flow while being cooled with ice. To this mixed solution, a mixed solution of 25.0 g (137.3 mmol) of 2,4,6-trimethylbenzoyl chloride and 20 mL of NMP was slowly added dropwise, and the mixture was stiffed at room temperature for 24 hours. After reaction for the predetermined time, this reacted solution was slowly added to 500 mL of water, so that a white solid was precipitated. The precipitated solid was washed by repeating twice ultrasonic cleaning in which water and then 1M hydrochloric acid were used. Then, ultrasonic cleaning using hexane was performed, so that 22.7 g of a white solid of 1-(2,4,6-trimethylbenzoyl)-2-benzoylhydrazine was obtained in a yield of 65%. A synthesis scheme of Step 1 is shown in (e-1).