Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8]C)=[CH:6][CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].BrP(Br)Br.CO>C(Cl)Cl>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: COc1cccc(C(C)=O)c1Br
Agent: BrP(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1cccc(O)c1Br
Temperature: -40 °C
Reaction time: 17 h
Yield: 47 %

Procedure:
Under a nitrogen atmosphere, 1-(2-bromo-3-methoxy phenyl)ethanone (30.5 g, 229 mmol) which had been obtained in Reference example 1(1b) was dissolved in methylene chloride (500 mL), and added dropwise with a 1.0 M solution of tribromo phosphine in dichloromethane (293 mL, 293 mmol) at −80° C. over 5 hours. Upon the completion of the dropwise addition, the mixture was stirred for 17 hours at −40° C. Subsequently, the reaction solution was cooled to −80° C. and added dropwise with methanol (500 mL). Upon the completion of the dropwise addition, the temperature was raised to −40° C. followed by stirring for 3 hours. The temperature of the reaction solution was raised to room temperature. The solvent was distilled off under reduced pressure until the solution turned green. After adding ethanol, the mixture was extracted with ethyl acetate/hexane (1:1, V/V). After neutralization with a saturated aqueous solution of sodium hydrogen carbonate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate, 100:0-55:45, V/V) to give the title compound as a colorless oily substance (13.5 g, yield 47%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10](F)[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C-:14]#[N:15].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.CCOC(C)=O>[C:14]([C:10]1[C:9]([F:13])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=1)#[N:15]
Reactant: [C-]#N
Reactant: COC(=O)c1cc(F)c(F)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)c(C#N)cc1F
Temperature: 60 °C

Procedure:
Methyl 2,4,5-trifluorobenzoate (DSL Chemicals, 950 mg, 5 mmol), sodium cyanide (306 mg, 6.25 mmol) and tetrabutylammonium bromide (2.01 g, 6.25 mmol) were dissolved in DMF (10 mL) and the resulting mixture was heated at 60° C. overnight. Additional amount of sodium cyanide (306 mg, 6.25 mmol) was added and the mixture was stirred at 60° C. for 24 additional hours. The reaction mixture was diluted with EtOAc and washed with brine several times. The organic layer was dried over MgSO4 and concentrated under vacuum. The residue was purified by flash chromatography (silica, EtOAc/cHex) to give the title compound. 1H NMR (DMSO-d6, 300 MHz) δ 7.77 (dd, J=8.4, 5.5 Hz, 1H), 7.42 (dd, J=8.9, 5.0 Hz, 1H), 3.96 (s, 3H). LC/MS (Method B): 463.2 (M−H)−, 465.2 (M+H)+. HPLC (Method A) Rt 3.63 min (Purity: 99.9%).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].C(OC([N:36]1[C:40]([C:41]#[N:42])=[CH:39][CH:38]=[C:37]1B(O)O)=O)(C)(C)C>>[C:41]([C:40]1[NH:36][C:37]([C:2]2[C:3]([N:22]3[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]3)=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:19])([F:20])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:38][CH:39]=1)#[N:42]
Reactant: CC(C)(C)OC(=O)n1c(C#N)ccc1B(O)O
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Product: N#Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2C[C@H](O)[C@@H](O)C2)[nH]1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 29 using 5-bromo-6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 31.1) and (1-(tert-butoxycarbonyl)-5-cyano-1H-pyrrol-2-yl)boronic acid (Stage 29.1) to afford an off-white solid. UPLC-MS (Condition 3) tR=0.94 min, m/z=474.1 [M+H]+, m/z=472.1 [M−H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.02 (d, J=11.86 Hz, 2H) 3.46 (dd, J=11.86, 3.55 Hz, 2H) 3.89 (br. s, 2H) 5.09 (d, J=2.45 Hz, 2H) 6.29 (d, J=3.67 Hz, 1H) 7.03 (d, J=3.67 Hz, 1H) 7.35 (d, J=8.44 Hz, 2H) 7.82-7.90 (m, 2H) 8.07 (d, J=2.45 Hz, 1H) 8.75 (d, J=2.45 Hz, 1H) 10.18 (s, 1H) 12.65 (br. s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[C:11]1([NH:17][C:18]([N:20]2[C:28]3[C:23](=[CH:24][C:25]([NH2:29])=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.N1C=CC=CC=1.C(OCC)C>C(OC(O)C)C>[C:11]1([NH:17][C:18]([N:20]2[C:28]3[C:23](=[CH:24][C:25]([NH:29][C:6]4[C:5]([C:9]#[N:10])=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=4)=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)=[O:19])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc2c(ccn2C(=O)Nc2ccccc2)c1
Reactant: N#Cc1cnc(N)cc1Cl
Agent: CCOC(C)O
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: N#Cc1cnc(N)cc1Nc1ccc2c(ccn2C(=O)Nc2ccccc2)c1
Temperature: 130 °C
Reaction time: 4 h
Yield: 35.7 %

Procedure:
2-Amino-4-chloro-5-cyanopyridine (200 mg, 1.30 mmol, Production example 215-3) was dissolved in ethoxyethanol (13.0 ml); 5-aminoindole-1-carboxylic acid phenylamide (408 mg, 1.62 mmol, Production example 201-2) and pyridine hydrochloride (315 mg, 2.73 mmol) were added thereto; and the reaction mixture was heated and stirred at 130° C. for 4 hours. After cooling to room temperature, the reaction mixture was partitioned between a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate; the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia NH, hexane:ethyl acetate=2:3, ethyl acetate, ethyl acetate:methanol=95:5 in this order). The pale yellow oil obtained was solidified with diethyl ether; the crystals were suspended with diethyl ether, filtered off, washed with diethyl ether, and dried to yield the title compound (171 mg, 0.464 mmol, 35.7%) as colorless crystals.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]([OH:12])([CH3:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:13][C:14]([Cl:18])([Cl:17])[C:15]#[N:16].CO>C(OCC)C>[Cl:13][C:14]([Cl:18])([Cl:17])[C:15](=[NH:16])[O:12][C:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)([CH3:11])[CH3:10]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(C)(O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CC(C)(OC(=N)C(Cl)(Cl)Cl)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.7 %

Procedure:
A suspension of 60% sodium hydride in mineral oil (0.42 g, 10.50 mmol) in diethyl ether (10 mL) was treated with the dropwise addition of a solution of 2-phenylpropan-2-ol (12.02 mL, 86 mmol) in diethyl ether (30 mL). Upon completion of addition, the mixture was stirred for 30 minutes, during which time a nearly clear solution was observed. After this time, the mixture was cooled to 0° C. and then treated with the dropwise addition of trichloroacetonitrile (8.18 mL, 82 mmol), which caused the mixture to turn dark brown. The reaction was allowed to warm to room temperature over 1 hour, and then was concentrated in vacuo to yield a residue. The residue was dissolved in hexanes (10 mL) and treated with methanol (0.424 mL, 10.48 mmol), and the resulting mixture was stirred vigorously for 5 minutes. The resulting black suspension was filtered through glass fiberglass filter paper, and the collected solids were rinsed 3× with hexanes. The combined filtrates were concentrated in vacuo to yield 2-phenylpropan-2-yl 2,2,2-trichloroacetimidate (23.8 g, 85 mmol, 99% yield) as an amber oil which was used as-is in the next step.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:15])[C:9]=3[C:8](I)=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.[C:24]([O:28][C:29](=[O:38])[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([SH:37])[CH:32]=1)([CH3:27])([CH3:26])[CH3:25]>[Cu]I.CN(C=O)C>[C:24]([O:28][C:29](=[O:38])[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([S:37][C:8]2[C:9]3[C:14]([NH2:15])=[N:13][CH:12]=[N:11][C:10]=3[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:7]=2)[CH:32]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: Nc1ncnc2c1c(I)cn2C1CCCC1
Reactant: CC(C)(C)OC(=O)Nc1cccc(S)c1
Agent: [Cu]I
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(Sc2cn(C3CCCC3)c3ncnc(N)c23)c1
Temperature: 110 °C
Yield: 85 %

Procedure:
To a round bottom flask with DMF (5 mL), was added 7-Cyclopentyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, CuI, N-methylmorphline and (3-Mercapto-phenyl)-carbamic acid tert-butyl ester. The reaction was heated at 110° C. overnight. After cooling to room temperature, the reaction mixture was extracted with EtOAc (80 mL) and saturated sodium bicarbonate solution (60 ml). The organic layer was washed with water, brine, dried over sodium sulfate and concentrated. Purification through flash column afforded the product as a light yellow solid (108 mg, 85%). MS: 426.1 (MH+); HPLC Rf: 6.332 min.; HPLC purity: 96%.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:50][CH2:51][CH3:52])[N:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:9]=1[C:10]([OH:12])=[O:11])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:62][C:63]1[O:64][C:65](=[O:69])[O:66][C:67]=1[CH3:68]>CC(C)=O.C1(C)C=CC=CC=1>[CH3:52][CH2:51][CH2:50][C:7]1[N:8]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:21]([C:26]4[N:30]([C:31]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)[N:29]=[N:28][N:27]=4)=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[C:9]([C:10]([O:12][CH2:68][C:67]2[O:66][C:65](=[O:69])[O:64][C:63]=2[CH3:62])=[O:11])=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[N:6]=1
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1oc(=O)oc1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
4-(1-Hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid dehydrate (100 g) was suspended in acetone (1 L) & heated to reflux; the solution obtained was added to suspension of potassium carbonate (15 g), potassium iodide (6 g) & 4-chloromethyl-5-methyl-1,3-dioxol-2-one (35 g) in acetone (500 mL) at reflux temperature. Reaction mass was refluxed for 2-6 hrs. After competition of reaction, the reaction mass was filtered & the acetone was distilled from combined mother liquor. The residue obtained was dissolved in toluene (1 L) toluene layer was washed with brine (3×250 mL). Toluene was removed under reduced pressure & residue thus obtained was recrystallized from methanol to give trityl Olmesartan
Reaction SMILES: C([Cl:4])(=[O:3])C.O.[O:6]=[C:7]([CH2:9][N:10]([C:12](=[NH:14])[NH2:13])[CH3:11])[OH:8]>C(O)C>[OH2:3].[O:6]=[C:7]([CH2:9][N:10]([C:12](=[NH:13])[NH2:14])[CH3:11])[OH:8].[ClH:4]
Reactant: CC(=O)Cl
Agent: CN(CC(=O)O)C(=N)N
Solvent: CCO
Solvent: O
Product: Cl
Temperature: 30 °C

Procedure:
Optimization experiments were performed by varying certain parameters of the reaction scheme in Example 1, as described below. A 1.5 mole equivalent of acetyl chloride was added dropwise to anhydrous ethanol to generate the acidified ethanol. Creatine monohydrate was added to the acidified ethanol at a ratio of 1 g:6 ml of ethanol and the reaction medium was heated to 37° C. for 20 hours. The reaction medium was then allowed to cool to 30° C. prior to filtration and the product (filter cake) was washed with ethanol chilled to 0° C. The amount of ethanol used in the wash was on a 1:1 w/v (g/ml) basis with the quantity of creatine monohydrate employed as the starting material. This reaction scheme yielded an 83 to 86% conversion of creatine monohydrate to CEE HCl.
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.Cl[C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]2[CH3:36])[N:27]=[C:26]([C:37]2[CH:42]=[CH:41][C:40]([NH:43][C:44]([NH:46][CH:47]3[CH2:49][CH2:48]3)=[O:45])=[CH:39][CH:38]=2)[CH:25]=1.[CH3:50][S:51][C:52]1[C:57](B2OC(C)(C)C(C)(C)O2)=[CH:56][CH:55]=[CH:54][N:53]=1>>[CH:47]1([NH:46][C:44]([NH:43][C:40]2[CH:41]=[CH:42][C:37]([C:26]3[CH:25]=[C:24]([C:57]4[C:52]([S:51][CH3:50])=[N:53][CH:54]=[CH:55][CH:56]=4)[N:29]=[C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]4[CH3:36])[N:27]=3)=[CH:38][CH:39]=2)=[O:45])[CH2:49][CH2:48]1
Reactant: C[C@H]1COCCN1c1nc(Cl)cc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Reactant: CSc1ncccc1B1OC(C)(C)C(C)(C)O1
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Product: CSc1ncccc1-c1cc(-c2ccc(NC(=O)NC3CC3)cc2)nc(N2CCOC[C@@H]2C)n1
Yield: 65 %

Procedure:
Method as described for intermediate 5 using (S)-1-(4-(6-chloro-2-(3-methylmorpholino)pyrimidin-4-yl)phenyl)-3-cyclopropylurea (intermediate 22) and 2-(methylsulfanyl)pyridine-3-boronic acid pinacol ester to afford a yellow solid (160 mg, 65%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[C:17](Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>C(Cl)Cl>[C:17]([NH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: COC(=O)c1sccc1N
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)Nc1ccsc1C(=O)OC
Temperature: 0 °C

Procedure:
To a flame dried flask equipped with stir bar was added methyl 3-aminothiophene-2-carboxylate (2.06 g, 13.1 mmol) and anhydrous methylene chloride (10.0 mL). The resulting solution was cooled to 0° C., and treated successively with pyridine (1.11 mL, 13.7 mmol) and butyryl chloride (1.44 mL, 13.7 mmol) while stirring under N2. The ice bath was removed, and the reaction warmed to 25° C. and stirred 3 h. The reaction was then poured into 1N HCl and extracted with methylene chloride. The combined organics were dried over magnesium sulfate, filtered and concentrated to provide methyl 3-(butyrylamino)thiophene-2-carboxylate (1-2). MS 228 found, 227.3 required.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12]>O.CC(C)=O>[C:10]1([CH3:9])[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][C:5]1[C:4]([NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH3:9])=[N:3][C:2](=[O:1])[C:7](=[O:8])[CH:6]=1
Reactant: Cc1ccccc1N
Reactant: Oc1cccnc1O
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccccc1NC1=CC(=O)C(=O)N=C1Nc1ccccc1C
Reaction time: 2 h
Yield: 27 %

Procedure:
2,3-dihydroxypyridine (0.0027 mol), o-methylaniline (0.0054 mol), and NaIO3 (0.0009 mol) were dissolved in 160 ml of water/acetone (80:1, v/v) solvent. The reaction mixture was stirred for 2 hours, and maintained still overnight. It was then filtered and recrystallized with chloroform. The final product was 5,6-di(o-tolylamino)-2,3-pyridindione in a red powder. The yield was 27%-45%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10]Br)[CH:6]=[CH:7][CH:8]=1.[Mg].[CH3:13][C:14]1([CH3:31])[CH2:18][O:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[C:20]=2OC)=[N:15]1.O>O1CCCC1>[CH3:28][O:27][C:21]1[C:20]([CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[C:19]([C:16]2[O:17][CH2:18][C:14]([CH3:13])([CH3:31])[N:15]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COc1ccc(C2=NC(C)(C)CO2)c(OC)c1OC
Reactant: COc1cccc(CCBr)c1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(CCc2c(C3=NC(C)(C)CO3)ccc(OC)c2OC)c1
Reaction time: 16 h

Procedure:
A solution of 2-(3-methoxyphenyl)ethylbromide (12.2 g) in dry tetrahydrofuran (20 ml) was added dropwise to a suspension of magnesium (1.46 g) in dry tetrahydrofuran (20 ml), under an atmosphere of nitrogen, at a rate sufficient to maintain a state of reflux. After 1 hour the cooled solution was added to a stirred solution of 4,5-dihydro-4,4-dimethyl-2-(2,3,4-trimethoxyphenyl)oxazole (7.95 g) in dry tetrahydrofuran (50 ml) under an atmosphere of nitrogen. The mixture was stirred at 20° for 16 hours. Water (400 ml) was added and the aqueous phase thoroughly extracted with ethyl acetate (2×250 ml). The organic phase was dried over magnesium sulphate, filtered and the solvent removed in vacuo to yield a yellow oil which was purified by flash column chromatography on silica gel, using 10% ethyl acetate/90% petroleum ether as eluent, and by Kugelruhr distillation (air bath temperature 200°/1 mm Hg) 9.7 g of the title compound were obtained. MS m/e 369.
Reaction SMILES: [C:1]([C:4]([S:7]([CH2:10][CH:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:12]([OH:14])=O)(=[O:9])=[O:8])([CH3:6])[CH3:5])(=[O:3])[NH2:2].[NH2:22][C@@H:23]([CH2:42][C:43]1[N:44]=[CH:45][NH:46][CH:47]=1)[C:24]([NH:26][C@@H:27]([CH2:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C@@H:28]([OH:34])[C@H:29]([CH:31]1[CH2:33][CH2:32]1)[OH:30])=[O:25].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[C:1]([C:4]([S:7]([CH2:10][C@H:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:12]([NH:22][C@@H:23]([CH2:42][C:43]1[N:44]=[CH:45][NH:46][CH:47]=1)[C:24]([NH:26][C@@H:27]([CH2:35][CH:36]1[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1)[C@@H:28]([OH:34])[C@H:29]([CH:31]1[CH2:32][CH2:33]1)[OH:30])=[O:25])=[O:14])(=[O:8])=[O:9])([CH3:5])[CH3:6])(=[O:3])[NH2:2]
Reactant: CC(C)(C(N)=O)S(=O)(=O)CC(Cc1ccccc1)C(=O)O
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C(N)=O)S(=O)(=O)C[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 239 mg (0.76 mmol) of rac-α-[[(1-carbamoyl-1-methylethyl)sulfonyl]methyl]hydrocinnamic acid, 250 mg (0.69 mmol) of (S)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4-propionamide, 77 mg (0.76mmol) of triethylamine, 118 mg (0.76 mmol) of HOBT and 289 mg (0.76 mmol) of HBTU in 10 ml of dimethylformamide was stirred at room temperature overnight. Subsequently, the reaction solution was evaporated to dryness in a high vacuum, the residue was taken up in 75 ml of ethyl acetate and washed twice with 20 ml of saturated sodium hydrogen carbonate solution each time. The ethyl acetate solutions were dried over sodium sulphate and subsequently evaporated under reduced pressure. For purification and separation of the two epimeric products, the residue (450 mg) was chromatographed on 30 g of silica gel using a 97:3:0.1 o mixture of methylene chloride, methanol and ammonia as the eluent. After lyophilization from dioxan and water there were obtained the less polar epimer (S)-α-[(R)-α-[[(1-carbamoyl-1-methylethyl)sulfonyl]methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-imidazole-4-propionamide as a colourless amorphous powder, MS: 660 (M+H)+, and the more polar epimer (S)-α-[(S)-α-[[(1-carbamoyl-1-methylethyl)sulfonyl]methyl]hydrocinnamamido]-N-[(1S ,2R,3S)-1-(cyclohexylmethyl )-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4-propionamide, likewise as a colourless amorphous powder, MS: 660 (M+H)+.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]([F:25])([F:24])[C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[NH2:16]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:16][C:15]1[CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=[C:13]([C:12]([F:11])([F:24])[F:25])[CH:14]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: FC(F)(F)c1cc(Nc2nc3ccccc3[nH]2)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 3,5-bis(trifluoromethyl)aniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (white solid, mp 245-246° C.). MS(ES+) m/z 346 ([M+1]+, 100).
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3](=[O:18])[N:4]1[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:5]1=[N:6]2.[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([N:11]1[C:5]2=[N:6][C:7]3[C:2]([C:3](=[O:18])[N:4]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]1=2)=[CH:1][CH:10]=[CH:9][CH:8]=3)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCc1ccccc1
Reactant: O=c1c2ccccc2nc2[nH]c3ccccc3n12
Product: O=c1c2ccccc2nc2n(Cc3ccccc3)c3ccccc3n12

Procedure:
6-Benzylbenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with benzimidazo[2,1-b]quinazolin-12(6H)one and benzyl chloride.
Reaction SMILES: [CH:1](=[CH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>CO>[C:2]1([C:1]2[CH2:8][CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:19][N:18]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CO
Product: c1ccc(C2=NNC(c3ccccc3)C2)cc1

Procedure:
Benzalacetophenone (12.5 parts) is reacted with hydrazine hydrate (3.1 parts by volume) in methanol to form 3,5-diphenyl-2-pyrazoline. Panasol AN-2 (30 ml), nitrobenzene (7.4 parts) and 5% palladium on carbon catalyst (2 parts) are then added and the mixture heated. Following the distillation of methanol and water from the reaction mixture, the temperature is raised to 200°C. and held at that temperature for 24 hours. The mixture is then cooled to 50°C., filtered, and the catalyst bearing cake of 3,5-diphenylpyrazole is 79.5%, m.p. 194°C. to 199°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:23]([CH3:22])(=[O:25])=[O:24])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1ccc(NCc2cccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1cccnc1)c1ccc(Cl)cc1

Procedure:
A 5.5 g. portion of 3-(4-chlorophenylaminomethyl)pyridine was dissolved in 50 ml. of dichloromethane and 3.8 g. of potassium carbonate was added. To it was added, dropwise with stirring, 2.4 ml. of methanesulfonyl chloride. The mixture was stirred at ambient temperature for several days, and it was then washed twice with water, dried and concentrated to a solid. It was triturated with petroleum ether and dried to obtain 7.1 g. of the desired product, m.p. 137.5°-140.5°. It was further triturated with diethyl ether and dried to obtain 7.0 g. of purified product, m.p. 137°-141°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[CH2:21](O)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OCCc1ccccc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride dispersion in mineral oil (0. 175 g) and stirred for 15 minutes. The mesylate of phenethyl alcohol (1.28 g) was added and the mixture was stirred and heated under argon at 60° C. overnight. The cooled mixture was treated with glacial acetic acid (3 drops) and the volatiles were removed under vacuum. The residue was mixed with water, the product was extracted with diethyl ether (3×50 mL) and the organic layers were washed in turn with water. The combined organic layers were dried (Na2SO4), filtered, and evaporated to give crude product. The material was purified by HPLC (dichloromethane-hexane; 3: 1) to provide 0.4 g of 4-[(2-phenylethyl)oxy]-alpha-oxobenzeneacetic acid methyl ester as a colorless oil.