Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:9])[CH2:3]/[CH:4]=[CH:5]/[C:6]([OH:8])=O.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:40][NH:41][C:42](=[O:69])[C@H:43]([N:51]1[CH2:56][C@@H:55]([CH2:57][C:58]2[CH:67]=[CH:66][C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH:59]=2)[NH:54][CH2:53][C:52]1=[O:68])[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O>[C:14]([O:13][C:11](=[O:12])[NH:10][C:2]([CH3:1])([CH3:9])[CH2:3]/[CH:4]=[CH:5]/[C:6]([N:54]1[CH2:53][C:52](=[O:68])[N:51]([C@@H:43]([C:42](=[O:69])[NH:41][CH3:40])[CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:56][C@H:55]1[CH2:57][C:58]1[CH:67]=[CH:66][C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:59]=1)=[O:8])([CH3:17])([CH3:16])[CH3:15]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N1C[C@@H](Cc2ccc3ccccc3c2)NCC1=O
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CNC(=O)[C@@H](Cc1ccccc1)N1C[C@@H](Cc2ccc3ccccc3c2)N(C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C)CC1=O
Reaction time: 8 h

Procedure:
(2E)-5-Methyl-5-(tert-butyloxycarbonylamino)hex-2-enoic acid was dissolved in methylene chloride (10 ml). 1-Hydroxy-7-azabenzotriazol (60 mg, 0.46 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (100 mg, 0.51 mmol) were added and the mixture was stirred for 15 min. (2R)-N-Methyl-2-((5R)-5-((2-naphthyl)methyl)-2-oxopiperazin-1-yl)-3-phenylpropionamide (185 mg, 0.46 mmol) and diisopropylethylamine (0.08 ml) were added and the mixture was stirred overnight. Water (10 ml) and methylene chloride (10 ml) were added and the mixture was washed with an aqueous solution of sodium hydrogen sulphate (10%, 20 ml), a saturated aqueous solution of sodium hydrogen carbonate (20 ml), dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was chromatographed on silica (3×30 cm) using ethyl acetate/heptane (1:1) as eluent to afford 0.20 g of ((3E)-1,1-dimethyl-5-((2R)-4-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-2-((2-naphthyl)methyl)-5-oxopiperazin-1-yl)-5-oxopent-3-enyl)carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[N:23][C:24]=4[NH:34][NH2:35])[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:51][N:52]1[CH:56]=[C:55]([C:57](O)=[O:58])[N:54]=[CH:53]1>C(OCC)(=O)C.CN(C=O)C>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[N:23][C:24]=4[NH:34][NH:35][C:57]([C:55]4[N:54]=[CH:53][N:52]([CH3:51])[CH:56]=4)=[O:58])[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cnc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(NN)c4cc3-c3ccccc3)cc2)CCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cn1cnc(C(=O)NNc2nccc3nc(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)cc23)c1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
To a round bottom flask was added tert-butyl{1-[4-(5-hydrazino-3-phenyl-1,6-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-6) (3.94 g, 8.18 mmol), EDC (1.34 g, 10.6 mmol), HOBt (1.44 g, 10.6 mmol), 1-methyl-1H-imidazole-4carboxylic acid (1.34 g, 10.6 mmol), and DMF (40 mL). The reaction mixture was heated to 60° C. while stirring under an atmosphere of nitrogen in a hot oil bath. After 45 minutes the reaction mixture was permitted to cool to room temperature, suspended in ethyl acetate, washed with a saturated solution of sodium bicarbonate, followed by water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl{1-[4-(5-{2-[(1-methyl-1H-imidazol-4-yl)carbonyl]hydrazino}-3-phenyl-1,6-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-7) as red foam. MS (M+H)+: observed=590.3, calculated=590.69.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:31][CH2:32]OS(C)(=O)=O)[CH2:14][N:13]([CH2:15][C:16]3[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=3)[C:12](=[O:30])[CH2:11][O:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[N:38]1([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.O.[ClH:51]>CN(C=O)C.CCOCC>[OH2:10].[ClH:51].[ClH:51].[F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:31][CH2:32][N:47]3[CH2:48][CH2:49][CH:44]([N:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[CH2:45][CH2:46]3)[CH2:14][N:13]([CH2:15][C:16]3[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[C:18]([C:26]([F:27])([F:29])[F:28])[CH:17]=3)[C:12](=[O:30])[CH2:11][O:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:31][CH2:32][N:47]3[CH2:48][CH2:49][CH:44]([N:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[CH2:45][CH2:46]3)[CH2:14][N:13]([CH2:15][C:16]3[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[C:18]([C:26]([F:27])([F:29])[F:28])[CH:17]=3)[C:12](=[O:30])[CH2:11][O:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[ClH:51].[ClH:51]
Reactant: CS(=O)(=O)OCCC1(c2ccc(F)c(F)c2)CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)CO1
Reactant: C1CCN(C2CCNCC2)CC1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1COC(CCN2CCC(N3CCCCC3)CC2)(c2ccc(F)c(F)c2)CN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 70 °C

Procedure:
A mixture of 0.86 g of the compound obtained in step C of EXAMPLE 26 and 0.7 g of 4-(piperid-1-yl)-piperidine in 3 ml of DMF is heated at 70° C. for 4 hours 30 minutes. After cooling to RT, the reaction mixture is poured into water and extracted with AcOEt, the organic phase is washed with 1N NaOH solution and with saturated NaCl solution and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (90/10; v/v) as the eluent. The product obtained is taken up with a saturated solution of hydrochloric acid in ether and the precipitate formed is wrung to give 0.49 g of the expected product. M.p.=260° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:19][C:20](=[O:35])[C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[O:28])=[C:23]([CH3:34])[CH:22]=3)[CH2:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[N:7]([CH2:36][C:37]([O:39]C)=[O:38])[C:6]=2[CH:41]=1.[OH-].[Na+].ClCCl.C(O)C.N.ClCl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:19][C:20](=[O:35])[C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[O:28])=[C:23]([CH3:34])[CH:22]=3)[CH2:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[N:7]([CH2:36][C:37]([OH:39])=[O:38])[C:6]=2[CH:41]=1
Reactant: COC(=O)Cn1c(C(Cc2ccc(O)cc2)NC(=O)c2ccc(C(=O)N3CCCC3)c(C)c2)nc2ccc(Cl)cc21
Agent: ClCl
Agent: N
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: Cc1cc(C(=O)NC(Cc2ccc(O)cc2)c2nc3ccc(Cl)cc3n2CC(=O)O)ccc1C(=O)N1CCCC1
Yield: 79 %

Procedure:
Prepared analogously to Example 19b from rac.-N-{1-[6-chloro-1-(methoxycarbonylmethyl)-1H-benzimidazol-2-yl]-2-(4-hydroxyphenyl)ethyl}-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide and sodium hydroxide solution in methanol. Yield: 79%; Rf value: 0.18 (silica gel; dichloromethane/ethanol/ammonia=9:1:0.1); C30H29ClN4O5 (561.04); mass spectrum: (M+H)+=561/563 (chlorine isotope).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:30])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:30])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:17]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1cccc(OCC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1cccc(OCC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
To a solution of ethyl (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((3-(2,2,3,3-tetrafluoropropyloxy)phenyl)methyl)propionate (4.75 g, 11.0 mmol) in methanol (40 ml) was added 2N aqueous sodium hydroxide solution (11 ml, 22.0 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((3-(2,2,3,3-tetrafluoropropyloxy)phenyl)methyl)propionic acid (3.91 g, 88%).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:8][C:7]1[C:2]([C:14]2[CH:15]=[CH:16][C:11]([C:10]([F:21])([F:20])[F:9])=[CH:12][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccnc1Cl
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cccnc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-3-methylpyridine (6.38 g, 50 mmol) and 4-(trifluoromethyl)benzeneboronic acid (9.59 g, 50 mmol) in DME (75 ml) and Na2CO3 solution (2M, 75 ml) was deoxygenated by bubbling nitrogen through the mixture for 15 mins. Tetrakis (triphenylphosphine) palladium (0) (1.155 g, 1.0 mmol) was added and the reaction was degassed for a further 10 mins. The reaction was heated at reflux for 16 hrs then cooled to rt. The mixture was extracted with EtOAc (×3), the combined extracts were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (silica, 10-30% EtOAc/isohexane) to give the pyridine (10.75 g, 91%). 1H NMR (360 MHz, CDCl3) δ: 2.36 (3H, s), 7.21-7.26 (1H, m), 7.60-7.72 (5H, m), 8.54-8.55 (1H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl.[CH2:10]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH:19]([C:24](OCC)=[O:25])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([N:17]1[CH2:22][CH2:21][C:20]2[C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=3[O:8][C:24](=[O:25])[C:19]=2[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cccc(O)c1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Agent: Cl
Product: Cc1ccc2c3c(c(=O)oc2c1)CN(Cc1ccccc1)CC3
Yield: 60 %

Procedure:
Prepared by the procedure of Example 1 from 3-methylphenol and ethyl 1-benzyl-4-oxo-3-piperidinecarboxylate hydrochloride. Yield 60%; mp 109°-111° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].Cl[CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.[Cl-].[Li+].CCCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:18])[CH:7]([OH:8])[C:6]=2[CH:9]=1
Reactant: CCOC(=O)C(C)Cl
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C)Oc2ccc(Cl)cc2C1O
Temperature: 70 °C
Reaction time: 18 h
Yield: 57.4 %

Procedure:
A stirred solution of 30.0 grams (0.192 mole) of 5-chloro-2-hydroxy-benzaldehyde, 31.4 grams (0.230 mole) ethyl 2-chloropropionate, and 31.8 grams (0.230 mole) of potassium carbonate in 200 mL of N,N-dimethylformamide was heated at 60°-70° C. for about 18 hours. The reaction mixture was cooled, diluted with 200 mL of aqueous 10% lithium chloride solution, and then extracted with two portions of ethyl acetate. The combined extracts were washed with 100 mL of aqueous 10% lithium chloride solution and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residual oil. Infrared spectroscopy indicated that the residual oil was an intermediate product that had not closed to form the benzofuran ring. A small sample (0.6 gram) was removed for other experiments. The remainder of the residual oil was dissolved in 100 mL of N,N-dimethylformamide, and 26.5 grams (0.182 mole) of potassium carbonate was added. The stirred mixture was warmed to 70 °C., where it stirred for about 18 hours. The reaction mixture was processed as described above, yielding about 45 grams of crude product. The product was subjected to column chromatography on silica gel, with 1.5:8.5 ethyl acetate:heptane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 28.3 grams of 5-chloro-2-ethoxycarbonyl-2,3-dihydro-3-hydroxy-2-methylbenzofuran. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: CS(NC1C(NC(=O)C2C=CC(F)=CC=2)=CC(C(F)(F)F)=CN=1)(=O)=O.[CH3:26][S:27]([NH2:30])(=[O:29])=[O:28].[H-].[Na+].Cl[C:34]1[C:39]([N+:40]([O-:42])=[O:41])=[CH:38][C:37]([C:43]([F:46])([F:45])[F:44])=[CH:36][N:35]=1>O1CCCC1.O>[N+:40]([C:39]1[C:34]([NH:30][S:27]([CH3:26])(=[O:29])=[O:28])=[N:35][CH:36]=[C:37]([C:43]([F:46])([F:44])[F:45])[CH:38]=1)([O-:42])=[O:41]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Reactant: CS(N)(=O)=O
Agent: CS(=O)(=O)Nc1ncc(C(F)(F)F)cc1NC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 65.8 %

Procedure:
Preparation of N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-4-fluorobenzamide (Compound No. 10) (1) 4.4 g of methanesulfonamide was dissolved in 70 ml of dry tetrahydrofuran, and 1.9 g of 60% sodium hydride was added thereto under cooling with ice. After completion of the addition, the mixture was reacted for one hour under reflux. After cooling, 7.0 g of 2-chloro-3-nitro-5-trifluoromethylpyridine was added thereto, and the mixture was reacted for 6 hours under reflux. After completion of the reaction, the reaction product was poured into 300 ml of water and washed with ethyl ether. Then, the aqueous layer was weakly acidified with dilute hydrochloric acid. Precipitated crystals were collected by filtration and dried to obtain 5.8 g of N-(3-nitro-5-trifluoromethyl-2-pyridyl)methanesulfonamide having a melting point of from 138° to 139° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH3:38][S:39]([N:42]1[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]1)(=[O:41])=[O:40]>>[CH3:38][S:39]([N:42]1[CH2:43][CH2:44][CH:45]([NH:48][C:21]([N:11]2[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([CH3:37])[N:9]=[C:10]2[C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][C:25]=2[O:34][CH2:35][CH3:36])=[O:22])[CH2:46][CH2:47]1)(=[O:41])=[O:40]
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)N1CCC(N)CC1
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)NC1CCN(S(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-methanesulfonyl-piperidin-4-ylamine (prepared as described by Bartkovitz, D. J. et al. WO2004069139) to give the title compound. HR-MS (ES, m/z) calculated for C33H36N4O4SF3Cl2 [(M+H)+] 711.1781, observed 711.1778.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.Cl>C1COCC1>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([B:15]([OH:20])[OH:16])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCCOc1ccc(Br)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(B(O)O)cc1
Temperature: 25 °C

Procedure:
A solution of the Grignard Reagent prepared from 1A (72 g) and Mg (7.75 g) in dry THF 250 ml) is added dropwise to a stirred, cooled (-78° C.) solution of tri-isopropyl borate (109.1 g) in dry THF 40 ml) under dry N2. The stirred mixture is allowed to warm to room temperature overnight and stirred with 10% HCl (320 ml) at room temperature for 1 hr. The product is extracted into ether twice, and the combined etheral extracts are washed with water and dried (MgSO4). Solvent is removed in vacuo to yield a colourless solid, mp =80°-85° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH2:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([CH:19]([C:25](OCC)=[O:26])[C:20](OCC)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C[O-].[Na+]>CO>[CH2:1]([N:8]1[C:25](=[O:26])[CH:19]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:20](=[O:21])[NH:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Reactant: NC(=O)NCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1NC(=O)N(Cc2ccccc2)C(=O)C1Cc1ccccc1

Procedure:
To a suspension of 22.53 g (150 mmol) of benzylurea and 37.5 g (150 mmol) of diethyl benzylmalonate in 77 ml of methanol, 36.6 ml (150 mmol) of a 4.1M sodium methylate solution was added at room temperature, followed by refluxing for 16 hours. After the reaction mixture was cooled, the solvent was distilled off. After the residue was dissolved in water and insoluble substances were filtered out, the filtrate was adjusted to pH 3-4 by adding concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and n-hexane-diethyl ether and dried to yield 48.35 g (quant., white crystal) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[C:10]=2[CH:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:25][CH:24]=2)O)=[CH:5][CH:4]=1.[ClH:39]>C(OCC)(=O)C>[ClH:39].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[C:10]=2[CH2:21][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:25][CH:24]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2=C(C(O)c3ccc(OCCCN4CCCCC4)cc3)c3ccc(OC)cc3CC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2Cc2ccc(OCCCN3CCCCC3)cc2)cc1
Yield: 97 %

Procedure:
Reaction of the product of Example 21 (1.5 g, 2.9 mmol) with hydrochloric acid (50 mL of a saturated ethyl acetate solution) in ethyl acetate (50 mL) according to the procedure in Example 18 gave a 97% yield of the desired product: 1H-NMR (300 MHz, CDCl3) δ7.70-7.80 (m, 2H), 7.42 (d, J=8.4 Hz, 1H), 7.15-7.30 (m, 3H), 7.05 (m, 1H), 6.85-6.95 (m, 4H), 6.69 (d, J=8.6 Hz, 2H), 4.34 (s, 2H), 3.97-4.03 (m, 2H), 3.92 (s, 3H), 3.82 (s, 3H), 3.50-3.60 (m, 2H), 3.05-3.20 (m, 2H), 2.57-2.70 (m, 2H), 2.20-2.50 (m, 4H), 1.80-2.00 (m, 4H); MS (FD) m/e 495 (Mhu+-hydrochloric acid); Anal. Calc'd. for: C, 74.49; H, 7.20; N, 2.63. Found: C, 74.74; H, 7.36; N, 2.75.
Reaction SMILES: [CH3:1][CH:2]([CH2:14][CH2:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][CH2:4][O:5][C:6]1[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][CH:7]=1.[CH2:25](OC1OC(C(O)=O)=CC=1)CCCCCCCCC/C=C\CC>>[CH3:1][CH:2]([CH2:14][CH2:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][CH2:4][O:5][C:6]1[O:10][C:9]([C:11]([CH3:25])=[O:13])=[CH:8][CH:7]=1
Reactant: CC/C=C\CCCCCCCCCCOc1ccc(C(=O)O)o1
Reactant: CC(C)CCCC(C)CCCC(C)CCOc1ccc(C(=O)O)o1
Product: CC(=O)c1ccc(OCCC(C)CCCC(C)CCCC(C)C)o1

Procedure:
In the procedure of Example 4(B), 5-(3,7,11-trimethyldodecyloxy)-2-furancarboxylic acid was substituted for cis-5-(11-tetradecenyloxy)furancarboxylic acid, to yield as a pale yellow oil, methyl 5-(3,7,11-trimethyldodecyloxy)-2-furyl ketone, B.P. 165° C. (0.25 mm Hg.).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9](=[O:40])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[CH2:26][CH2:25]3)[N:20]=[C:19]([O:34][CH2:35][C:36]([F:39])([F:38])[F:37])[N:18]=2)=[CH:12][CH:11]=1)(=[O:7])=[O:6].Br[CH2:42][CH2:43][CH2:44][CH2:45]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2([NH:23][C:21]3[N:20]=[C:19]([O:34][CH2:35][C:36]([F:37])([F:38])[F:39])[N:18]=[C:17]([NH:16][C:13]4[CH:12]=[CH:11][C:10]([C:9]([NH:8][S:5]([CH2:4][CH2:3][N:2]5[CH2:45][CH2:44][CH2:43][CH2:42]5)(=[O:7])=[O:6])=[O:40])=[CH:15][CH:14]=4)[N:22]=3)[CH2:26][CH2:25]2)=[CH:28][CH:29]=1
Reactant: BrCCCCBr
Reactant: NCCS(=O)(=O)NC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(NS(=O)(=O)CCN1CCCC1)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Temperature: 65 °C
Yield: 15.1 %

Procedure:
To a solution of N-(2-aminoethylsulfonyl)-4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamide HCl salt (20 mg, 0.031 mmol) in Acetonitrile (Volume: 2 mL) was added 1,4-dibromobutane (6.96 mg, 0.032 mmol) and POTASSIUM CARBONATE (21.23 mg, 0.154 mmol). The mixture was heated to 65° C. for 16 h. After cooling to rt, the mixture was diluted with EtOAc, washed with water, and brine. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by rev. phase preparative HPLC (Column: Sunfire prep C18 OBO 5 uM, 30×100 mm by Waters Corp) using a gradient of 20-100% ACN/water w/0.1% TFA modifier to give 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-N-(2-(pyrrolidin-1-yl)ethylsulfonyl)benzamide (3 mg) as the TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17-1.48 (m, 4H), 1.80-2.12 (m, 4H), 3.37-4.41 (m, 8H), 5.00 (q, J=9.0 Hz, 2H), 7.15-7.44 (m, 4H), 7.67-7.86 (m, 3H), 7.93 (s, 1H), 8.86 (br. s., 1H), 9.71 (br. s., 1H), 10.13 (br. s., 1H); LC-MS (Condition A), MS m/z (M++H) 640.0.