Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: IC.[H-].[Na+].[C:5]([CH:9]1[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][C:11](=[O:17])[N:10]1[C@@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])([CH3:8])([CH3:7])[CH3:6].[C:26](O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:5]([CH:9]1[C@@:13]([CH3:26])([C:14]([OH:16])=[O:15])[CH2:12][C:11](=[O:17])[N:10]1[C@@H:18]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:19])([CH3:6])([CH3:7])[CH3:8]
Reactant: C[C@H](c1ccccc1)N1C(=O)CC(C(=O)O)C1C(C)(C)C
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: C[C@H](c1ccccc1)N1C(=O)C[C@](C)(C(=O)O)C1C(C)(C)C
Temperature: 30 °C
Yield: 33.7 %

Procedure:
Under a nitrogen gas atmosphere, iodomethane (26.0 mL, 59.28 g, 0.418 mol) and sodium hydride (oil content: 55%, 11.35 g, 0.260 mol) were sequentially added at room temperature to a solution of t-butyl 5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid (30.05 g, 0.104 mol) in N,N′-dimethylformamide (210 mL) with stirring. When the internal temperature reached to about 50° C., the mixture was cooled to 30° C. in an ice-water bath. Subsequently, the bath was changed to a water bath having an external temperature of 17° C., followed by stirring for 23 hours. The reaction mixture was poured into cold aqueous citric acid (a mixture of 10% citric acid (1 L) and ice (500 g)), followed by stirring for 30 minutes and extracting with ethyl acetate (800 mL, 500 mL). The organic layers were combined. The combined organic layer was washed with saturated brine, followed by drying over sodium sulfate anhydrate and filtration. The filtrate was evaporated to dryness under reduced pressure. The residue was purified through flash silica gel column chromatography (eluent; hexane:ethyl acetate=5:1 to 4:1), to thereby yield the title compound as white solid (10.63 g, 33.7%) as a high-polar isomer. In addition, t-butyl (3R)-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid (14.91 g, 47.3%) was produced as a low-polar isomer.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][OH:12])[N:8]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[S:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[O:16][N:15]=2)[N:7]=1)=[O:5])C.[OH-].[Na+].Cl>C1COCC1.O>[Cl:24][C:21]1[S:20][C:19]([C:17]2[O:16][N:15]=[C:14]([CH2:13][N:8]3[C:9]([CH2:11][OH:12])=[CH:10][C:6]([C:4]([OH:5])=[O:3])=[N:7]3)[CH:18]=2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cc(CO)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(CO)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 380 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-hydroxymethyl-1H-pyrazole-3-carboxylic acid ethyl ester in 5 ml THF and 5 ml of water 3 ml of a 1M NaOH were added and the reaction mixture was stirred for 3 h at RT. Then the mixture was acidified with half concentrated hydrochloric acid to pH 3 and the precipitate collected by filtration and washed with 10 ml water. The product was obtained as a white solid which was dried under reduced pressure. Yield: 320 mg.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:25])[NH:11][CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[CH:5][CH:4]=1>Cl>[NH:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:26])[F:27])=[CH:4][CH:5]=2)=[O:25])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Agent: Cl
Product: O=C(Nc1ccc(C(F)(F)F)cc1)NC1CCNCC1

Procedure:
tert-butyl 4-(3-(4-(trifluoromethyl)phenyl)ureido)piperidine-1-carboxylate (1.6 g, 4.13 mmol) was dissolved in HCl solution (2M, MeOH, 100 mL). The resulting solution was refluxed for 2 h. The solvent was removed under vacuo and the crude was basified by NaOH solution (2N). The final precipitates (0.9 g, 3.13 mmol, 78%) were filtered and dried under high vacuum. The final product (PTU) was served as a scaffold for the following urea inhibitors synthesis. 1H NMR (d6-DMSO, 300 Mhz): δ 8.77 (s, 1H), 7.57 (s, 4H), 6.30 (d, J=7.8 Hz, 1H), 3.55 (m, 1H), 2.91 (d, J=12.6 Hz, 2H), 2.48 (d, J=11.1 Hz, 2H), 1.77 (d, J=11 Hz, 2H), 1.22 (m, 2H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.C(O)(=O)C.[OH:32][C:33]1([C:37]([O:39][CH3:40])=[O:38])[CH2:36][NH:35][CH2:34]1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][N:35]2[CH2:36][C:33]([OH:32])([C:37]([O:39][CH3:40])=[O:38])[CH2:34]2)[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2
Reactant: COC(=O)C1(O)CNC1
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Solvent: CC(=O)O
Product: COC(=O)C1(O)CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)-benzaldehyde (0.209 g, 0.56 mmol) and methyl 3-hydroxyazetidine-3-carboxylate acetate (0.14 g, 0.73 mmol) according to Reference R and general procedure for reductive amination afforded methyl 1-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)-methyl)-3-hydroxyazetidine-3-carboxylate. MS (ESI) m/z: Calculated: 489.2; Observed: 490.0 (M++1).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:17](OCC)=[O:18])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH:8]=[CH:7][CH2:6]1.[H-].C([Al+]CC(C)C)C(C)C.O>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([CH2:17][OH:18])[CH:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:9][CH:8]=[CH:7][CH2:6]1
Reactant: CCOC(=O)C1(CCCCl)CC=CCC1c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: OCC1(CCCCl)CC=CCC1c1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
Ethyl 1-(3-chloropropyl)-6-phenyl-3-cyclohexene-1-carboxylate (8.65 g, 29.4 mmol) dissolved in toluene (200 ml) was added dropwise to a 1.0M stock solution of diisobutylaluminum hydride (DIBAL, 2.2 equiv., 64.6 ml). The contents were stirred for 16 hrs. under N2 at ambient temperature. The reaction was then chilled to 0° C. and water (100 ml) added. The resulting precipitate was filtered off and the filtrate was dried over MgSO4, filtered, and concentrated in vacuo to afford 7.21 g (92% yield) of 1-(3-chloropropyl)-6-phenyl-3-cyclohexene-1-methanol as a clear mobile oil. Infrared spectroscopy indicated the disappearance of an ester carbonyl band and the appearance of hydroxyl stretching between 3200-3400 cm-1. To this alcohol (27 mmol) dissolved in acetone (100 ml) and cooled to 0° C. was added Jones reagent (2.67M, 2.0 equiv., 20.3 ml). The contents were stirred for 2 hr. at which time isopropyl alcohol (20 ml) was added to quench unreacted Jones reagent. The solution was concentrated in vacuo. The residue was washed with water and extracted three times with 100 ml of ethyl ether. The combined organic extracts were dried over MgSO4, filtered through celite and concentrated in vacuo to afford 1-(3-chloropropyl)-6-phenyl-3-cyclohexene-1-carboxylic acid (4.95 g, 87% yield) as a clear viscous oil. Infrared spectroscopy indicated the appearance of the carboxyl stretch at 1700 cm-1.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][NH:6][N:5]=1.Br[CH2:15][C:16](=[O:20])[CH2:17][CH2:18][CH3:19]>CN(C=O)C>[NH2:3][C:4]1[N:5]([CH2:15][C:16](=[O:20])[CH2:17][CH2:18][CH3:19])[N:6]=[CH:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: CCCC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(=O)Cn1ncc(C(=O)OCC)c1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.4 %

Procedure:
To a mixture of sodium hydride (60% dispersion in mineral oil, 0.8 g) in DMF (50 ml) was added ethyl 3-amino-pyrazol-4-carboxylate (2.0 g) and the reaction mixture was stirred at room temperature for 15 minutes. After addition of 1-bromo-2-pentanone (4.0 g), the mixture was stirred at room temperature for 13 hours. The reaction mixture was concentrated to dryness, and the residue was dissolved in ethyl acetate-water. The organic layer was washed with water, dried and concentrated to dryness. The resulting yellow syrup was purified by column chromatography on silica gel to give pale yellow prisms (1.4 g, 45%).
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1.[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:12][C:11]([CH:8]1[CH2:9][CH2:10][NH:5][CH2:6][CH2:7]1)=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)C1CCNCC1
Solvent: O=S(Cl)Cl
Product: O=C(OCc1ccccc1)C1CCNCC1
Reaction time: 8 h
Yield: 97.25 %

Procedure:
Thionyl chloride (5.42 g, 46 mmol) was added to a cold (0-4° C.) stirred solution piperidine-4-carboxylic acid (5 g, 38.7 mmol) in benzyl alcohol (150 mL) and stirring was continued overnight. Benzyl alcohol was removed by stirring with hexane, ether and decanting the solvent, dried to afford 8.26 g (97.25% yield) of piperidine-4-carboxylic acid benzyl ester. LCMS Purity: 94.8%.
Reaction SMILES: [Li]C(CC)C.C1CCCCC1.C(=O)=O.CC(C)=O.[CH2:19]([NH:21][C:22]([C:24]1[CH:28]=[CH:27][S:26][CH:25]=1)=[O:23])[CH3:20].CN(CCN(C)C)C.[CH3:37][Si:38](Cl)([CH3:40])[CH3:39]>C1COCC1>[CH2:19]([NH:21][C:22]([C:24]1[CH:28]=[CH:27][S:26][C:25]=1[Si:38]([CH3:40])([CH3:39])[CH3:37])=[O:23])[CH3:20]
Reactant: CCNC(=O)c1ccsc1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CCN(C)C
Agent: O=C=O
Agent: [Li]C(C)CC
Solvent: CC(C)=O
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCNC(=O)c1ccsc1[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
1.3M s-BuLi in cyclohexane (37.23 mL, 48.4 mmol) was added dropwise to a dry-ice/acetone cooled solution of N-ethyl-3-thiophenecarboxamide (3.41 g, 22 mmol) and TMEDA (5.62 g, 48.4 mmol) in THF (100 mL). After stirring for 30 min at −78° C., TMSCl (5.26 g, 48.4 mmol) was added in a single portion. The reaction was allowed to slowly warm to −10° C. over 1 h, then was quenched with dilute aq citric acid and extracted with ethyl acetate (3×). The combined organic solutions were dried (MgSO4), concentrated, and purified by HPLC with 3:7 EtOAc/hexanes to give 1.4 g of the title compound as a white solid, a 28% yield. m.p. 114-116° C.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[CH2:16][OH:17].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:15][C:11]1[C:10]([CH2:16][OH:17])=[C:9]([NH:8][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])[CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccc(F)c1CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cccc(F)c1CO
Reaction time: 1 h

Procedure:
Trimethylacetyl chloride (0.25 mL, 1.99 mmol) was added to a solution of (2-amino-6-fluorophenyl) methanol (268 mg, 1.90 mmol) in CH2Cl2 (10 mL) at 0° C., followed by the addition of DIEA (1.0 mL, 5.7 mmol). The mixture was stirred for 1 hr, followed by normal aqueous work-up to afford the expected crude product, N-(3-fluoro-2-(hydroxymethyl)phenyl)pivalamide, as a colorless oil (415 mg, 97% yield), which was used directly in the next step; 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (s, 9 H), 2.64 (s, 1 H), 4.78 (d, J=4.78 Hz, 2 H), 6.75-6.84 (m, 1 H), 7.23 (td, J=8.62, 5.92 Hz, 1 H), 7.86 (d, J=8.31 Hz, 1 H), 8.97 (s, 1 H); Mass spec. 226.11 (MH+), Calc. for C12H16FNO2 225.12.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][OH:27])[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:35](Cl)(=[O:39])[O:36][CH2:37][CH3:38]>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][O:27][C:35]([O:36][CH2:37][CH3:38])=[O:39])[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(-c2nn(CCO)c3ncccc23)cc(C(C)(C)C)c1O
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)OCCn1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cccnc21
Reaction time: 2 h
Yield: 85.9 %

Procedure:
To a solution of 3.7 g of the compound of Example 43 in 20 ml of chloroform is added 1.5 g of triethylamine, and to the mixture with stirring at -10°--2° C. is added 1.4 g of ethyl chlorocarbonate dropwise. After completion of the addition, the whole mixture is stirred at 0° C. for 3 hours, and then at room temperature for 2 hours. The reaction solution is washed with water, dried and concentrated, and then the resulting residue is recrystallized from isopropyl ether to give 3.8 g of 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1-(2-ethoxycarbonyloxyethyl)-1H-pyrazolo[3,4-b]-pyridine as white crystals, melting at 103°-105° C.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[F:26])=[C:16]([C:27](OCC)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[F:26])=[C:16]([C:27]([N:42]3[CH2:43][CH2:44][CH:39]([C:36]4[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=4)[CH2:40][CH2:41]3)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC(C)(C)C)cnn2c1Nc1cc(Cl)ccc1F
Product: CC(C)(C)NS(=O)(=O)c1cnn2c(Nc3cc(Cl)ccc3F)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 39.4 %

Procedure:
Using ethyl 3-(N-tert-butylsulfamoyl)-7-(5-chloro-2-fluorophenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (1.82 g, 3.87 mmol) obtained in step 3 and 4-(4-fluorophenyl)piperidine (0.88 g, 4.89 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (0.92 g, 47%) was obtained.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[F:14])[C:8](Cl)=[O:9])(=[O:4])=[O:3].[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:17][C:16]1=[CH:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)=[O:26]>O1CCOCC1>[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:17][C:16]1=[C:24]([C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)=[O:26])[C:8]([C:7]1[CH:11]=[CH:12][C:13]([F:14])=[C:5]([S:2]([Cl:1])(=[O:4])=[O:3])[CH:6]=1)=[O:9]
Reactant: O=C(C=C1Nc2ccccc2N1)c1cccc(F)c1
Reactant: O=C(Cl)c1ccc(F)c(S(=O)(=O)Cl)c1
Solvent: C1COCCO1
Product: O=C(C(C(=O)c1ccc(F)c(S(=O)(=O)Cl)c1)=C1Nc2ccccc2N1)c1cccc(F)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
At room temperature, 3-(chlorosulfonyl)-4-fluorobenzoyl chloride (3.19 g) was added to a dioxane (75 mL) suspension of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-(3-fluorophenyl)ethanone (1.50 g), followed by heating up to 110° C. and stirring for 1 hour. The reaction mixture was cooled to room temperature, the insoluble matter was separated by filtration, and then this was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to obtain 5-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]-2-fluorobenzenesulfonyl chloride (2.10 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:11]=[C:12]([NH2:17])[C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:6]=[CH:5][N:4]=1.[Cl:18][C:19]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=S)=[CH:29][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1.C(Cl)CCl>CC#N>[Cl:18][C:19]1[CH:32]=[CH:31][C:30]([NH:33][C:34]2[NH:16][C:13]3[CH:14]=[CH:15][C:10]([O:9][C:7]4[CH:6]=[CH:5][N:4]=[C:3]([NH:2][CH3:1])[N:8]=4)=[CH:11][C:12]=3[N:17]=2)=[CH:29][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1
Reactant: CN1CCN(Cc2cc(N=C=S)ccc2Cl)CC1
Reactant: CNc1nccc(Oc2ccc(N)c(N)c2)n1
Solvent: ClCCCl
Solvent: CC#N
Product: CNc1nccc(Oc2ccc3[nH]c(Nc4ccc(Cl)c(CN5CCN(C)CC5)c4)nc3c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(2-methylamino-pyrimidin-4-yloxy)-benzene-1,2-diamine (Step C, 300 mg, 1.3 mmol, 1.0 eq) in anhydrous CH3CN (20 mL) was added drop-wise a solution of 1-(2-chloro-5-isothiocyanato-benzyl)-4-methyl-piperazine (405 mg [residual imidazole present], 1.3 mmol, 1.0 eq) in anhydrous CH3CN (10 mL). The solution was stirred for 16 h at RT. EDC (250 mg, 1.3 mmol, 1.0 eq) was added and the reaction was heated to 80° C. and stirred for 2 h. The solvent was removed under reduced pressure and residue was dissolved in CH2Cl2/MeOH (50 mL). The organic solution was washed with H2O (25 mL), NaHCO3 (aq, 25 mL) and brine (25 mL). The aqueous layers were back extracted with CH2Cl2 and the combined organic layers were dried over MgSO4, filtered and concentrated. The crude was further purified by column chromatography (0-10% MeOH/CH2Cl2 with 1% NH4OH) followed by preparative TLC and finally reverse phase HPLC (5-100% H2O/CH3CN with 0.1% TFA) to yield [4-chloro-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-[5-(2-methylamino-pyrimidin-4-yloxy)-1H-benzimidazol-2-yl]-amine. MS m/z=479.2 (M+H)+; MW Calc'd for C24H27ClN8O: 478.20.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[CH3:18])=O)=[N:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[CH3:18])=[N:9][N:8]=2)[CH:7]=1
Reactant: C[C@H]1CCCCN1C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CCCCN1c1nnc2ccc(F)cn12
Temperature: 60 °C
Yield: 82.8 %

Procedure:
To a stirred solution of Intermediate 2c (14.70 g, 58.27 mmol), Ph3P (30.56 g, 116.51 mmol) and Et3N (33 mL, 236.76 mmol) in THF (300 mL) at RT was added hexachloroethane (27.60 g, 116.58 mmol) during 10 min before then heating at 60° C. overnight. The cooled mixture was filtered and concentrated in vacuo to give a residual oil which was dissolved in DCM (200 mL) and extracted into dilute HCl (2M) until most product had been removed from the DCM phase by LCMS. These aqueous extracts were treated with solid NaOH (with cooling) to achieve ˜pH9 and extracted into DCM. Combined DCM extracts were washed with brine, dried (MgSO4), passed through a phase separation cartridge and concentrated in vacuo to give Intermediate 2d (11.30 g, 82%). LCMS (Method 3) Rt 2.99 min, m/z 235 [MH+]. 1H NMR (300 MHz, d6-d6-DMSO): 0.89 (3H, d, J 6.3), 1.40-1.88 (6H, m), 2.85-2.96 (1H, m), 3.18 (1H, dt, J 12.0, 4.5), 3.28-3.35 (1H, m), 7.42 (1H, ddd, J 10.0, 8.0, 2.3), 7.76 (1H, ddd, J 10.0, 4.9, 0.9), 8.31-8.35 (1H, m).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][CH:35]=1)[C:6]([NH:8][C:9]1[C:10]([NH:21][C:22](=[O:32])[C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)=[CH:11][C:12]([CH2:15][C:16]([O:18]CC)=[O:17])=[CH:13][CH:14]=1)=[O:7])#[N:2].[Li+].[OH-]>C1COCC1.CO.CCOCC>[C:1]([C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][CH:35]=1)[C:6]([NH:8][C:9]1[C:10]([NH:21][C:22](=[O:32])[C:23]2[CH:24]=[CH:25][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:28]=2)=[CH:11][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:13][CH:14]=1)=[O:7])#[N:2]
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2cccc(C#N)c2)c(NC(=O)c2ccc(C(C)C)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1ccc(C(=O)Nc2cc(CC(=O)O)ccc2NC(=O)c2cccc(C#N)c2)cc1
Reaction time: 2.5 h
Yield: 99.7 %

Procedure:
To a mixture of N1-(3-cyanobenzoyl)-N2-(4-isopropylbenzoyl)-4-(ethoxycarbonyl-methyl)-1,2-benzenediamine (1.41 g, 3.00 mmol) in THF (30 mL) and MeOH (10 mL) was added 1 M LiOH (10 mL) and stirred for 2.5 h. The reaction was diluted with Et2O (300 mL) and washed with 1N HCl (40 mL) and H2O (40 mL). The organic layer was concentrated to give the title compound as a pale yellow solid (1.32 g, quant.); IR(KBr): 1326, 1515, 1625, 1672, 3326 cm−1; NMR(300 MHz, DMSO-d6): 1.19 (d, 6H, J=6.9 Hz); 2.97 (m, 1H); 3.65 (s, 2H); 7.12 (d, 1H, J=8.1 Hz); 7.35 (d, 2H, J=7.8 Hz); 7.49 (d, 1H, J=8.1 Hz); 7.54 (s, 1H); 7.71 (t, 1H, J=8.0 Hz); 7.86 (d, 2H, J=7.8 Hz); 8.02 (d, 1H, J=7.2 Hz); 8.22 (d, 1H, J=8.4 Hz); 8.34 (s, 1H); 9.96 (s, 1H); 10.27 (s, 1H); MS(FD): 441.0.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:10](OCC)(=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(O)C>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C(C1C=C(O)C(C(C)(C)C)=CC=1O)(C)(C)C>[C:1]([O:6][CH2:7][CH2:8][O:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:16])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCO
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)c1cc(O)c(C(C)(C)C)cc1O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCO
Product: C=C(C)C(=O)OCCOC(=O)C(=O)OCC
Yield: 73.1 %

Procedure:
A 500 ml flask equipped with a decanter, a thermometer, a stirrer and an inlet for nitrogen gas was charged with 65.1 g (0.5 mol) of 2-hydroxyethyl methacrylate and 365.4 g (2.5 mol) of diethyl oxalate, to which 2 g (10 mmol) of dibutyltin dilaurate (catalyst) and 4 g ob 2,5-di-t-butylhydroquinone (polymerization inhibitor) were added. The mixture was heated to keep it at about 120° C. for 2 hours in nitrogen atmosphere with distilling 32.5 ml (0.56 mol) of ethanol away. The reaction mixture was evaporated to remove excess diethyl oxalate and then distilled under vacuum to obtain 84.2 g (yield 73.2%) of 2-ethoxalyloxyethyl methacrylate (bp 124° C./0.4 mmHg).
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]([O:21]CC)=O)[C:9](=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[Na].C(O)(=O)C>O1CCOCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:18][C:19]([OH:21])=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10][C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCC(=O)N(CC(=O)OCC)Cc1ccccc1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(O)CN(Cc2ccccc2)C(=O)C1
Temperature: 25 °C
Yield: 36.3 %

Procedure:
Ethyl 4-(benzyl(2-ethoxy-2-oxoethyl)amino)-4-oxobutanoate (123.2 g, 0.4 mol) in ethanol (37 g, 0.8 mol) and dioxane (200 ml) was added dropwise to a suspension of sodium (18.4 g, 0.8 mol) in dioxane (500 mL). The resulting mixture was heated at reflux until the sodium metal was no longer visible. After cooling the mixture to ambient temperature, acetic acid (48 g, 0.8 mol) was added. Standard extractive workup with ethyl acetate, gave a crude product that was purified by re-crystallization from ether/acetone to afford the title product as a yellow solid (40 g; yield=40%). 1H NMR (300 MHz, CD3OD) δ: 11.81 (s, 1H), 7.19-7.41 (m, 5H), 4.65 (s, 2H), 4.25 (q, J=7.2 Hz, 2H), 3.91 (t, J=3 Hz, 2H), 3.27 (t, J=3 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H). LC-MS: m/z=276 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:22])[CH2:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])=[CH:6][CH:5]=1.O.C(Cl)[Cl:26]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:22])[CH:11]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[Cl:26])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(C(=O)CC(=O)OCc2ccccc2)cc1
Reactant: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)C(Cl)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4.0 g (12.8 mmols) of 4-benzyloxycarbonylacetyl-benzoic acid methylester, dissolved in 40 ml of toluene, are mixed with 19.2 ml of a 1 M solution of SO2Cl2 in CH2Cl2 and stirred for 30 min at RT. At 0° C., water is added and the aqueous phase is separated and extracted twice with EtOAc. The organic phases are washed twice with sat. NaHCO3 solution, H2O and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; hexane/EtOAc 9:1→4:1; crude product dissolved in CH2Cl2) yielded the title compound as an oil: MS: [M+1]+=347; TLC(hexane/EtOAc 4:1) Rf=0.19.