Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]([O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[C:28]1[C:32]([CH2:33]O)=[C:31]([CH:35]([CH3:37])[CH3:36])[O:30][N:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1C=CC=CC=1>[Cl:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[C:22]=1[C:28]1[C:32]([CH2:33][O:1][C:2]2[CH:3]=[C:4]([CH3:19])[C:5]([O:8][C:9]3[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=3)=[N:6][CH:7]=2)=[C:31]([CH:35]([CH3:37])[CH3:36])[O:30][N:29]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Reactant: COC(=O)c1ccc(Oc2ncc(O)cc2C)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COC(=O)c1ccc(Oc2ncc(OCc3c(-c4c(Cl)cccc4Cl)noc3C(C)C)cc2C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.2 %

Procedure:
To a suspension of methyl 4-(5-hydroxy-3-methylpyridin-2-yloxy)benzoate synthesised in step 3 (0.042 g, 0.162 mmol), [3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-yl]methanol (0.046 g; 0.162 mmol) (for preparation refer to: P. Maloney et al. “Identification of a chemical tool for the orphan nuclear receptor FXR” J. Med. Chem. 2000, 43(16), 2971-2974) and triphenylphosphine (0.052 g, 0.2 mmol) in benzene (2 ml) was added diisopropyl azodicarboxylate (0.051 g, 0.25 mmol). The mixture was stirred at room temperature for 20 h, the solvent was removed in vacuo and the residue was purified by preparative HPLC to provide methyl 4-(5-((3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl)methoxy)-3-methylpyridin-2-yloxy)benzoate (0.06 g, 70% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1.C(Cl)(Cl)[Cl:35]>>[Cl:35][C:28]1[CH:27]=[CH:26][C:25]([NH:29][C:30]([NH:1][CH2:2][C:3]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11](=[O:20])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)=[O:31])=[CH:24][C:23]=1[C:22]([F:32])([F:33])[F:21]
Reactant: ClC(Cl)Cl
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: NCc1nc2ccccc2c(=O)n1-c1ccc(F)cc1
Product: O=C(NCc1nc2ccccc2c(=O)n1-c1ccc(F)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 8 h
Yield: 98 %

Procedure:
To a mixture of the amine (4) (14 mg, 0.05 mmol) in chloroform (0.5 mL), was added 3-trifluoromethylphenyl isocyanate (10 mg, 0.05 mmol). After stirring overnight the solvent was removed in vacuo, triturated with hexanes, filtered and dried to give the title urea (5) (24 mg, 98%) as a white solid:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.Cl[C:13]([O:15][CH2:16][CH:17]1[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14]>C(=O)(O)[O-].[Na+].O1CCCC1>[C:13]([CH:8]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)[C:9]([OH:11])=[O:10])([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccc(C(C(=O)O)C(=O)OCC2c3ccccc3-c3ccccc32)cc1
Reaction time: 4 h
Yield: 56.3 %

Procedure:
4-aminophenyl acetic acid (204 mg, 1.35 mmol) in a 10 mL flask was dissolved in a mixture of 10% aqueous sodium bicarbonate (0.29 mL) and tetrahydrofuran (2.3 mL) then cooled in an ice/water bath. 9-fluorenylmethyl chloroformate (367 mg, 1.42 mmol) was added in small portions over 3 min. After 4 h the cooling bath was removed. After additional 4 h at room temperature, the reaction was extracted with deionized water (2 mL) and ethyl ether (2 mL) and the aqueous layer was brought to pH 4 with dilute HCl and placed in a refrigerator. After 1 h solid was collected by vacuum filtration and washed with deionized water then dried under vacuum to give 284 mg of product (56% yield). Mass spectrum (M+Na)+ calcd for C23H19NO4, 396.1. found, 396.1.
Reaction SMILES: C1CCC([N:7]=[C:8]=[N:9]C2CCCCC2)CC1.ON1C(=O)CCC1=O.[C:24]([NH:32][C@H:33]([C:38]([OH:40])=O)[CH2:34][CH:35]([CH3:37])[CH3:36])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N#CN.[Na]>C(#N)C.C1COCC1.O>[C:24]([NH:32][C@H:33]([C:38]([NH:9][C:8]#[N:7])=[O:40])[CH2:34][CH:35]([CH3:37])[CH3:36])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)C[C@H](NC(=O)c1ccccc1)C(=O)O
Agent: N#CN
Agent: O=C1CCC(=O)N1O
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: CC(C)C[C@H](NC(=O)c1ccccc1)C(=O)NC#N
Reaction time: 2 h
Yield: 42.9 %

Procedure:
DCC (2.41 g, 0.0117 mol) and N-hydroxysuccinimide (1.35 g, 0.0117 mol) were added to a solution of N-benzoyl-L-leucine (2.75 g, 0.0117 mol) in 100 ml of acetonitrile at ice bath temperature. The reaction was allowed to proceed at this temperature for 2 hours. The reaction mixture was filtered to remove the bulk of the DCU and the filtrate was evaporated in vacuo to dryness. The resulting semi-solid residue was redissolved in THF and the mixture filtered to remove any residual DCU. The filtrate was evaporated in vacuo to give crude N-benzoyl-L-leucine N-hydroxysuccinimide ester as a foamy residue. IR (neat, cm-1) 3340 NH), 3060 (C6H5), 1820, 1790, 1740 and 1650 (C=O); NMR (Silanor C, δ from TMS) 7.3-7.9 (m, C6H5), 5.1-5.3 (m, --NH--CH--C=O), 2.8 (s, cycl. --CH2 --CH2 --), 1.6-2.2 (m, CH--CH2 --), 0.9-1.1 (d, (CH3)3CH). This was dissolved in 100 ml of THF and added drop-wise to a solution of sodium cyanamide (1.50 g, 0.0234 mol) in 100 ml of distilled water at ice bath temperature. The reaction was allowed to proceed at room temperature for 24 hours. The reaction mixture was then concentrated in vacuo to half its original volume and filtered. The filtrate (pH 9) was extracted with ethyl acetate (2×50 ml). The aqueous layer was separated, acidified to pH 1.5 with 10% HCl, and extracted with methylene chloride (3×50 ml). The methylene chloride extract was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo to give 2.80 g (92.4% yield) of crude product as a tacky white solid. This was triturated with diethyl ether and collected to give 1.30 g (42.9% yield of white powdery 11, mp 136°-137° C. [α]D23 +0.7°(c 1.0, CH3OH); TLC: Rf =0.93 in EtOAc/petroleum ether/THF/CH2Cl2 / AcOH (50:50:10:50:4) and 0.24 in EtOAc/petroleum ether/AcOH (50:100:1), detected by UV quenching and orange color with ferricyanide spray reagent; IR (Nujol, cm-1) 3300, 3100 (NH), 2230 (C≡N), 1750 and 1630 (C=O); NMR (Silanor-DMSO, δ from TMS) 7.4-8.0 (d, C6H5 --), 4.2-4.6 (m, --NH--CH--C=O), 1.4-1.9 (m, CH--CH2 --), 0.8-1.1 (d, (CH3)2CH--) Anal. Calcd for C14H17N3O2 : C, 64.85; H, 6.61; N, 16.20. Found C, 64.62; H, 6.73; N, 15.93.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].C([O-])(O)=O.[Na+].[CH2:15]([N:19]([CH2:34][CH2:35][CH2:36][CH3:37])[C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[C:25]2[S:30](Cl)(=[O:32])=[O:31])[CH2:16][CH2:17][CH3:18]>O.CC(C)=O>[CH2:15]([N:19]([CH2:34][CH2:35][CH2:36][CH3:37])[C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[C:25]2[S:30]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])(=[O:32])=[O:31])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCN(CCCC)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCN(CCCC)c1cccc2c(S(=O)(=O)N[C@@H](CC(=O)O)C(=O)O)cccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Two mmoles of aspartic acid and 4 mmoles of NaHCO3 were dissolved in 5 ml of water. A solution containing 1 mmol of 5-dibutylamino-naphthalene-1-sulfonyl chloride (Bansyl chloride, Purchased from TCI) in acetone was slowly added. More acetone was added until the solution was clear. The mixture was stirred overnight at room temperature and protected from light. Acetone was removed by flash evaporation and the remaining water solution was acidified to a of pH=4.5 to 5 by adding 2M citric acid. Then, NaCl was added until saturation and the solution was extracted with three portions of ethyl acetate (20 ml each). Extracts were combined, dried over MgSO4 and the solution was filtered. The solvent was removed and the residue was purified by liquid chromatography on a silica gel. A gradient of 0 to 5% methanol in dichloromethane was used as eluent. Fractions containing the desired product were combined and solvents removed. The residue was triturated in 1:1 ether: petroleum ether. The precipitate was filtered out and dried in vacuum overnight thus affording 5-dibutylamino-naphthalene-1-sulfonyl)-L-aspartic acid (NST705).
Reaction SMILES: [NH2:1][C@H:2]([C:14]([NH:16][C:17]1[CH:18]=[N:19][N:20]([CH3:42])[C:21]=1[NH:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:15])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[C:43]([O:47][C:48]([NH:50][CH2:51][C:52](ON1C(=O)CCC1=O)=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44].C(Cl)(Cl)Cl>O1CCCC1>[C:43]([O:47][C:48]([NH:50][CH2:51][C:52]([NH:1][C@H:2]([C:14]([NH:16][C:17]1[CH:18]=[N:19][N:20]([CH3:42])[C:21]=1[NH:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:15])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: Cn1ncc(NC(=O)[C@@H](N)CCCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)CNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.2 %

Procedure:
To a solution of tert-butyl (4S)-4-amino-5-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-5-oxopentylcarbamate (1.71 g) in tetrahydrofuran (30 ml) was added N-[2-(tert-butoxycarbonylamino)acetoxy]-succinimide (820 mg). The mixture was stirred at room temperature for 6 hours. To the reaction mixture was added chloroform (50 ml). The mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give tert-butyl (4S)-4-{[2-(tert-butoxycarbonylamino)acetyl]amino}-5-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-5-oxopentylcarbamate (2.1 g) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[CH:5]=[O:6].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[C:10]1([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=2)[CH:5]=[O:6])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1ccnc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=Cc1ccnc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
A mixture of commercially available 2-bromoisonicotinaldehyde (3.000 g; 16.12 mmol), phenylboronic acid (3.009 g; 24.19 mmol), and Pd(PPh3)4 (931 mg; 0.80 mmol) in toluene (40 ml) and aq. 2 M Na2CO3 (34 ml) was heated to reflux, under nitrogen, for 4 h. After cooling to rt, water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=7/3) afforded 2-phenylisonicotinaldehyde as a yellow oil. LC-MS (conditions A): tR=0.39 min.; [M+H]+: 184.47 g/mol.
Reaction SMILES: CC1(C)C(C)(C)[NH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1.[OH:15][C:16]([CH3:29])([CH3:28])[C:17]([CH3:27])([CH3:26])SC1C=CC=CC=1N>>[CH3:26][C:17]1([CH3:27])[O:15][C:16]1([CH3:29])[CH3:28].[NH2:6][C:5]1[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=1[SH:3]
Reactant: CC(C)(O)C(C)(C)Sc1ccccc1N
Reactant: CC1(C)Nc2ccccc2SC1(C)C
Product: CC1(C)OC1(C)C
Product: Nc1ccccc1S

Procedure:
Analogously to Example 1, the required 2,2,3,3-tetramethyl-2,3-dihydro-4H-1,4-benzothiazine is obtained as a colourless oil having a boiling point of 89° C./0.04 mbar using 2-(2-hydroxy-1,1,2-trimethylpropylthio)-aniline, melting point of from 60° to 62° C., boiling point of 125° C./0.1 mbar (obtained from tetramethyloxirane and 2-aminothiophenol). nD20 =1.5955; the mass spectrum shows a molecular ion at 207 (74% relative intensity) and as main fragments 192 (24%), 177 (14%), 164 (100%), 150 (44%), 132 (70%), 125 (24%), 109 (15%), 92 (22%), 42 (17%) and 41 (16%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:6]=[C:5]2[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(C)(C)OC(=O)Cc1c[nH]c2ccc(F)cc12
Reactant: O=C(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)Cc1cn(C(=O)c2ccccc2)c2ccc(F)cc12

Procedure:
Prepare by a method similar to Example 116 using t-butyl [5-fluoro-indol-3-yl]-acetate and benzoyl chloride.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:17]([F:20])([F:19])[F:18])=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])C.ClCCl>[OH-].[Na+]>[OH:16][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:17]([F:20])([F:18])[F:19])[C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc2ccccc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(O)c1c(C(F)(F)F)nc2ccccc2c1O

Procedure:
A suspension of 4-hydroxy-2-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (5 g, 17.5 mmol) in 10% aqueous NaOH solution was heated at reflux for 2 h. After cooling, dichloromethane was added and the aqueous phase was separated and acidified with concentrated HCl to pH 4. The resulting precipitate was collected via filtration, washed with water and Et2O to provide 4-hydroxy-2-trifluoromethyl-quinoline-3-carboxylic acid (A-15) (3.6 g, 80%). 1H NMR (DMSO-d6) δ 8.18-8.21 (d, J=7.8 Hz, 1 H), 7.92-7.94 (d, J=8.4 Hz, 1 H), 7.79-7.83 (t, J=14.4 Hz, 1 H), 7.50-7.53 (t, J=15 Hz, 1 H); ESI-MS 257.0 m/z (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([C:11]1[CH:12]=[C:13]([NH:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=[CH:15][CH:16]=1)=[O:10].N1C=CC=CC=1.[CH2:31]([S:33](Cl)(=[O:35])=[O:34])[CH3:32]>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([C:11]1[CH:12]=[C:13]([N:17]([CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[S:33]([CH2:31][CH3:32])(=[O:35])=[O:34])[CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: CCS(=O)(=O)Cl
Reactant: COc1ccccc1S(=O)c1cccc(NCc2cccnc2)c1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(S(=O)c2ccccc2OC)c1
Temperature: 0 °C
Yield: 8.4 %

Procedure:
N-(3-(2-Methoxyphenylsulfinyl)phenyl)pyrid-3-ylmethylamine (159 mg, 0.44 mmol) was taken up in 1,2-dichloroethane (2.0 ml) and anhydrous pyridine (1.0 ml) and cooled under nitrogen to 0° C. Ethanesulfonyl chloride (103 mg, 0.80 mmol) is added dropwise via syringe and the reaction allowed to stir at 0° C. for thirty minutes. The ice bath is removed and the mixture stirred 88 hours at room temperature, as a matter of convenience. Solid potassium carbonate was added, the reaction stirred an additional hour, and then filtered and concentrated to a dark oil. Radial silica gel chromatography (2 mm Chromatotron® plate, eluting with 20/1 methylene chloride/methanol) afforded the title compound (16 mg, 8%). 1H NMR(400 MHz): 1.39(3H,t,J=7.3), 3.04(2H,q,J=7.3), 3.78(3H,s), 4.88(2H,s), 6.86(1H,d,J=7.8), 7.11-7.21(2H,m), 7.25-7.30(1H,m), 7.35(1H,t,J=7.8), 7.42(1H,dt,J=7.3, 2.0), 7.56-7.62(2H,m), 7.68(1H,m), 7.81(1H,dd,J=7.3, 1.5), 8.31(1H,br s), 8.46(1H,br s); MS(HRMS)m/z 431.1116([M+H]+calcd for C21H23N2O4S 431.1099).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH:8]=2)=[C:4]([F:22])[CH:3]=1.COC1C=CC(CNC2N=CN=C(OC3C=CC(N[C:45]([NH:47][C:48](=[O:57])[CH2:49][C:50]4[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=4)=[O:46])=CC=3F)C=2)=CC=1.C(Cl)[Cl:62]>>[ClH:62].[CH3:19][N:17]([CH3:18])[CH2:16][CH2:15][CH2:14][NH:13][C:9]1[CH:8]=[C:7]([CH2:6][C:5]2[CH:20]=[CH:21][C:2]([NH:1][C:45]([NH:47][C:48](=[O:57])[CH2:49][C:50]3[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=3)=[O:46])=[CH:3][C:4]=2[F:22])[CH:12]=[CH:11][N:10]=1
Reactant: ClCCl
Reactant: CN(C)CCCNc1cc(Cc2ccc(N)cc2F)ccn1
Reactant: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Product: CN(C)CCCNc1cc(Cc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)ccn1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14 %

Procedure:
To a solution of 4-(4-amino-2-fluorobenzyl)-N-(3-(dimethylamino)propyl)pyridin-2-amine (30 mg, 0.1 mmol) in DCM (2 mL) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate (Compound D of Example 11, 0.347 M in toluene, 0.25 mL). The mixture was stirred at room temperature for 0.5 h before it was quenched with MeOH. The solution was concentrated in vacuo and the residue was purified by prep. HPLC. The desired fractions were collected and concentrated in vacuo. The residue was dissolved in MeOH and polymer bound diethylene triamine (50 mg) was added to remove trifluoroacetic acid. After filtration and concentration, the residue was converted to a hydrochloride salt by the addition of 1 N HCl (0.5 mL) and lyophilized to give 1-(4-((2-(3-(dimethylamino)propylamino)pyridin-4-yl)methyl)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea hydrochloride (8.0 mg, 14% yield). MS(ESI+): m/z 482.24 (M+H)+.
Reaction SMILES: C[Mg]Br.C([O:6][CH2:7][CH3:8])C.[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[CH2:23][S:24][C:25]1[N:30]=[C:29](O)[CH:28]=C(C)[N:26]=1)[C:18]#[N:19]>C1COCC1>[Cl:14][C:15]1[CH:16]=[C:17]([C:18](=[NH:19])[N:11]([CH2:12][CH3:13])[CH2:9][CH3:10])[CH:20]=[CH:21][C:22]=1[CH2:23][S:24][C:25]1[N:26]=[C:7]([OH:6])[CH:8]=[C:29]([CH3:28])[N:30]=1
Reactant: CCNCC
Reactant: CCOCC
Reactant: Cc1cc(O)nc(SCc2ccc(C#N)cc2Cl)n1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CCN(CC)C(=N)c1ccc(CSc2nc(C)cc(O)n2)c(Cl)c1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 15 %

Procedure:
To a solution of 3.0 M methyl magnesium bromide in diethyl ether (1.3 mL, 3.86 mmol) dissolved in anhydrous THF (4 mL) was added diethyl amine in anhydrous THF (1 mL). The mixture was stirred for 15 minutes at 40° C. Then, 3-chloro-4-{[(4-hydroxy-6-methylpyrimidin-2-yl)sulfanyl]methyl}benzonitrile (375 mg, 1.3 mmol) was added and stirred at 40° C. for 3.5 hours. The solvent was evaporated, and the residue was dissolved in DCM and purified on silica gel using 20% DCM/MeOH to afford 3-chloro-N,N-diethyl-4-{[(4-hydroxy-6-methylpyrimidin-2-yl)sulfanyl]methyl}benzene-1-carboximidamide (111 mg, 15% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.15 (t, J=7.9 Hz, 6H), 2.21 (s, 3H), 2.90 (q, J=7.2 Hz, 4H), 4.51 (s, 2H), 6.0 (bs, 1H), 7.51-7.54 (m, 1H), 7.81-7.84 (m, 2H); LRMS (ES+) m/z 365 (100%, M+1).
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=1[C:13]([OH:15])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[O:42]=[C:43]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)[CH2:44][NH:45][C:46](=[O:60])[C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:49][CH:48]=1.Cl>CN(C=O)C.O>[Br:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=1[C:13]([N:64]1[CH2:65][CH2:66][N:61]([C:43](=[O:42])[CH2:44][NH:45][C:46](=[O:60])[C:47]2[CH:48]=[CH:49][C:50]([NH:53][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)=[CH:51][CH:52]=2)[CH2:62][CH2:63]1)=[O:15]
Reactant: O=C(O)c1cc(F)ccc1Br
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Nc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2Br)CC1)c1ccc(Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
DIPEA (114 mg, 0.15 mL, 0.88 mmol) was added drop wise to 2-bromo-5-fluoro-benzoic acid (77 mg, 0.35 mmol) in DMF (5 mL). EDCI (114 mg, 0.88 mmol) and HOBT (47 mg, 0.35 mmol) were added consecutively and, after 10 minutes, N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenylamino-benzamide in its HCl salt form (100 mg, 0.29 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 70% EtOAc in Hexane as eluent) to afford 80 mg (50% yield) of N-{2-[4-(2-bromo-5-fluoro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenylamino-benzamide. LC-MS purity: 94.48%. 1H-NMR (DMSO-d6): δ 8.6 (s, 1H), 8.3 (t, 1H), 7.8 (d, 3H), 7.4 (m, 4H), 7.2 (d, 2H), 7.1 (d, 2H), 6.9 (t, 1H), 4.1 (dd, 2H), 3.6 (m, 6H), 3.2 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:37]([O:39]CC)=[CH2:38])CCC.CCOC(C)=O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:37]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:23])[CH3:24])[CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[CH:3]=1)(=[O:39])[CH3:38]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(Br)cc1C1=CCCCC1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)c1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
A mixture of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4-bromo-2-cyclohex-1-enyl-phenyl)-amide (as prepared in the previous step, 100 mg, 0.199 mmol), tributyl(1-ethoxyvinyl)stannane (86.3 mg, 0.239 mmol) and Pd(PPh3)2Cl2 (10.5 mg, 0.0149 mmol) in 2 mL of 1,4-dioxane was stirred at 90° C. for 2 h under Ar. After cooling to RT, the reaction was treated with EtOAc (40 mL) and washed with 15% citric acid aqueous solution (2×10 mL), H2O (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (10-20% EtOAc/hexane) to give 80.1 mg (86%) of the title compound as a light brown oil. Mass spectrum (ESI, m/z): Calcd. for C25H32N4O3Si, 465.2 (M+H), found 465.1.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>C(Cl)Cl>[CH2:17]([O:16][C:14](=[O:15])[NH:3][CH2:1][CH3:2])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Ethylamine (1.3 mL, 20.0 mmol) and diisopropylethylamine (7 mL, 40.0 mmol) were combined in CH2Cl2 (200 mL) and cooled to 0° C. Benzyl chloroformate (2.86 mL, 20.0 mmol) was added dropwise, and the reaction was stirred at 0° C. for 30 minutes. The mixture was warmed to room temperature and washed with H2O, 0.1N aqueous HCl, and H2O, and then dried and concentrated to give ethyl-carbamic acid benzyl ester.