Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[Br:24][C:25]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:26]=1[CH2:27]Br>C1COCC1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:27][C:26]3[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:25]=3[Br:24])[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Fc1ccc(Br)c(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (2.0 g, 6.39 mmol) in THF (40 mL) at 0° C. was added NaH (285 mg, 60 w/w % in mineral oil, 7.13 mmol, 1.1 eq.) in one portion. The resulting foaming mixture was stirred in an ice bath. Additional THF (50 mL) was added into the reaction. The mixture was stirred at 0° C. for 30 min. A solution of 2-bromo-5-fluorobenzyl bromide (1.712 g, 6.39 mmol) in THF (20 mL) was added. The resulting mixture was stirred cold for 30 min and then allowed to warm to room temperature. The reaction was completed in 3 hours. The reaction was quenched with NH4Cl (aq., sat., 80 mL). Volatiles were removed in vacuo. The crude mixture was extracted with EtOAc and dried over Na2SO4. The residue was purified by flash chromatography on SiO2 (Biotage 40+M cartridge, EtOAc/hexane, gradient). (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-fluorobenzyl)-4-methyl-1,3-oxazolidin-2-one was obtained as a clear oil. LC-MS: 500.09 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.88 (s, 1H), 7.79 (s, 2H), 7.55 (dd, J=8.8, 5.2 Hz, 1H), 7.17 (dd, J=8.7, 4.5 Hz, 1H), 6.95 (m, 1H), 5.74 (d, J=8.0 Hz, 1H), 4.83 (d, J=15.8, 1H), 4.54 (d, J=16.0 Hz, 1H), 4.11 (m, 1H), 0.80 (d, J=6.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C@@H:7]2[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:16]12([N:26]=[C:27]=[O:28])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2.C(N(CC)CC)C.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C@@H:7]2[CH2:8][CH2:9][C@H:10]([NH:13][C:27]([NH:26][C:16]34[CH2:25][CH:20]5[CH2:19][CH:18]([CH2:24][CH:22]([CH2:21]5)[CH2:23]3)[CH2:17]4)=[O:28])[CH2:11][CH2:12]2)=[CH:14][CH:15]=1
Reactant: N[C@H]1CC[C@@H](Oc2ccc(F)cc2)CC1
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC12CC3CC(CC(C3)C1)C2)N[C@H]1CC[C@@H](Oc2ccc(F)cc2)CC1
Reaction time: 8 h

Procedure:
To a solution compound 10 in DMF was added 1-adamantyl isocyanate (0.16 g, 0.91 mmol) followed by triethylamine (0.10 g, 1.0 mmol) at 0° C. The reaction mixture was stirred overnight. The reaction mixture was poured into water, and the resulting precipitates were collected and washed with water. The crude product was recrystallized from DCM/hexanes. Yield: 0.31 g (88% of theory). M.P.: 207° C. 1H NMR (300 MHz, CDCl3): δ 6.98-6.91 (m, 2H), 6.84-6.78 (m, 2H), 4.34 (s, 1H), 4.30 (d, J=9.8 Hz, 1H), 4.20 (s, 1H), 3.71-3.56 (m, 1H), 2.13-1.44 (m, 23H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][C:29]1=[O:33]>>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([N:28]4[CH2:32][CH2:31][CH2:30][C:29]4=[O:33])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: O=C1CCCN1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(N2CCCC2=O)cc1

Procedure:
The title compound (E121) was prepared from 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]benzenesulfonamide (E106) and 2-pyrrolidinone using a similar method to that described for Example 23 (E23). MS (ES+) m/e 459 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]4[C:25]5[CH2:24][CH2:23][NH:22][CH2:21][C:20]=5[S:19][C:18]=4[CH3:26])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C(N(CC)CC)C.C(Cl)(Cl)Cl>[C:29]([N:22]1[CH2:23][CH2:24][C:25]2[C:17]([CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([C:6]4[C:5]5[CH:27]=[CH:28][C:2]([F:1])=[CH:3][C:4]=5[O:8][N:7]=4)[CH2:10][CH2:11]3)=[C:18]([CH3:26])[S:19][C:20]=2[CH2:21]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1sc2c(c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCNC2
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1sc2c(c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCN(C(=O)c1ccccc1)C2
Yield: 63.5 %

Procedure:
To a mixture of 0.5 g of 3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine in 0.5 ml of triethylamine and 10 ml of chloroform was added 0.18 g of benzoyl chloride under cooling and the mixture was stirred for an hour, and then poured into water. The organic layer was washed with water, dried and concentrated. The residue was purified by column chromatography to give 0.4 g of 6-benzoyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 192°-195° C. as oxalate 1/4 hydrate thereof.
Reaction SMILES: C([O:5][C:6](=[O:51])[CH:7]([NH:16][C:17](=[O:50])[CH:18]([CH2:42][C:43]([O:45]C(C)(C)C)=[O:44])[CH2:19][CH2:20][CH2:21][S:22]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:8][C:9]([O:11]C(C)(C)C)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O.C(S)(S)C.C([SiH](C(C)C)C(C)C)(C)C>C(Cl)Cl>[C:43]([CH2:42][CH:18]([CH2:19][CH2:20][CH2:21][SH:22])[C:17]([NH:16][CH:7]([CH2:8][C:9]([OH:11])=[O:10])[C:6]([OH:51])=[O:5])=[O:50])([OH:45])=[O:44]
Reactant: CC(C)(C)OC(=O)CC(CCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CC(C)[SiH](C(C)C)C(C)C
Agent: CC(S)S
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC(CCCS)C(=O)NC(CC(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the protected thiolate of Example 119 in CH2Cl2 (1 mL) was added at 0° C. a solution of 60% TFA in CH2Cl2, containing 2% of ethanedithiol. Triisopropyl silane (1%) was then added and the reaction mixture was stirred at room temperature for 1 hour after which it was first concentrated using a stream of argon and then under vacuum. The obtained white solid was washed several times with a mixture of diethyl ether/hexanes (3:1). The obtained white solid was purified by semi-preparative HPLC to provide the desired compound.
Reaction SMILES: CN(C)C(N1CC=C(C2NC3N=CN=C(C4C=CC=C(NC(=O)C5C=CC(C(O)(C)C)=CC=5F)C=4C(C4C=CC=CC=4)(C4C=CC=CC=4)O[SiH2]C(C)(C)C)C=3C=2)CC1)=O.[CH3:60][N:61]([CH3:87])[C:62]([N:64]1[CH2:69][CH:68]=[C:67]([C:70]2[NH:86][C:73]3[N:74]=[CH:75][N:76]=[C:77]([C:78]4[CH:83]=[CH:82][C:81]([F:84])=[C:80]([NH2:85])[CH:79]=4)[C:72]=3[CH:71]=2)[CH2:66][CH2:65]1)=[O:63].FC1C=C(C(O)(C)C)C=CC=1C(O)=O.[OH:102][CH2:103][C:104]([C:107]1[CH:115]=[CH:114][C:110]([C:111](O)=[O:112])=[CH:109][CH:108]=1)([CH3:106])[CH3:105]>>[CH3:60][N:61]([CH3:87])[C:62]([N:64]1[CH2:65][CH:66]=[C:67]([C:70]2[NH:86][C:73]3[N:74]=[CH:75][N:76]=[C:77]([C:78]4[CH:83]=[CH:82][C:81]([F:84])=[C:80]([NH:85][C:111](=[O:112])[C:110]5[CH:114]=[CH:115][C:107]([C:104]([CH3:105])([CH3:106])[CH2:103][OH:102])=[CH:108][CH:109]=5)[CH:79]=4)[C:72]=3[CH:71]=2)[CH2:68][CH2:69]1)=[O:63]
Reactant: CC(C)(CO)c1ccc(C(=O)O)cc1
Reactant: CN(C)C(=O)N1CC=C(c2cc3c(-c4ccc(F)c(N)c4)ncnc3[nH]2)CC1
Agent: CC(C)(O)c1ccc(C(=O)O)c(F)c1
Agent: CN(C)C(=O)N1CC=C(c2cc3c(-c4cccc(NC(=O)c5ccc(C(C)(C)O)cc5F)c4C(O[SiH2]C(C)(C)C)(c4ccccc4)c4ccccc4)ncnc3[nH]2)CC1
Product: CN(C)C(=O)N1CC=C(c2cc3c(-c4ccc(F)c(NC(=O)c5ccc(C(C)(C)CO)cc5)c4)ncnc3[nH]2)CC1

Procedure:
Example 21 was prepared analogue to Intermediate 9 by replacing Intermediate 7 with Intermediate 10 and Intermediate 8 with 4-(2-hydroxy-1,1-dimethyl-ethyl)-benzoic acid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([CH3:21])=[CH:16][N:15]=1>O1CCCC1.BrCCBr.C[Si](Cl)(C)C.[Zn].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>[Cl:13][C:14]1[N:19]=[C:18]([CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=2)[C:17]([CH3:21])=[CH:16][N:15]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: Cc1cnc(Cl)nc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: Cc1cnc(Cl)nc1Cc1cccc(C(F)(F)F)c1
Yield: 41.9 %

Procedure:
To a suspension of zinc dust (2.5 g, 38 mmol) stirred in 25 mL of tetrahydrofuran were added 2 drops of 1,2-dibromoethane and the mixture was heated to reflux. The suspension was then cooled and 2 drops of trimethylsilyl chloride were added followed by portionwise addition of 3-(trifluoromethyl)benzyl bromide (6.0 g, 25 mmol) with heating. When the reaction temperature reached 55° C., a strong exotherm occurred and the reaction mixture was allowed to heat at reflux. The cooled reaction solution was decanted into a solution of 2,4dichloro-5-methylpyrimidine (3.3 g, 20 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.44 g, 0.63 mmol) stirring in 15 mL of tetrahydrofuran. Upon heating, the reaction mixture exothermed strongly again at 55° C. and was then heated to reflux. The reaction mixture was allowed to cool and partitioned between diethyl ether and water. The organic layer was separated, washed with 1 N aqueous hydrochloric acid and brine, dried over magnesium chloride and concentrated under reduced pressure to give a crude oil. Purification by flash chromatography on silica gel (15 to 25% ethyl acetate in hexane) yielded 2.4 g of the title compound of Step A as an oil. 1H NMR (CDCl3): δ8.35 (s, 1H), 7.60-7.35 (m, 4H), 4.15 (s, 2H), 2.25 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[NH:7][C:8](=[O:14])/[CH:9]=[C:10](\[O:12][CH3:13])/[CH3:11])([O-])=O.C(O)C>[Fe].O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[NH:7][C:8](=[O:14])/[CH:9]=[C:10](\[O:12][CH3:13])/[CH3:11]
Reactant: CO/C(C)=C\C(=O)Nc1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CCO
Solvent: O
Product: CO/C(C)=C\C(=O)Nc1cccc(N)c1
Temperature: 27 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
48 g of powdered iron were added over 15 minutes at 20° C. to a mixture of 18.9 g of m-nitro-3-methoxy-crotonanilide, 64 ml of 95% ethanol, 16 ml of water and 0.8 ml of 22° Be hydrochloric acid and the mixture was stirred for 11/2 hours at 27° C. The interior temperature was raised to 60° C. and the temperature was slowly lowered to 25° C. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure to obtain 13.6 g of m-amino-3-methoxy-crotonanilide. The product melted at 132° C. and after crystallization from ethanol still melted at 132° C.
Reaction SMILES: [CH2:1]([SiH:5]([CH2:7][CH:8]([CH3:10])[CH3:9])Cl)[CH:2]([CH3:4])[CH3:3].[Cl-].[NH4+].CC[CH2:15][CH2:16][CH3:17].[CH2:18]1COCC1>>[C:16]([SiH:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:1][CH:2]([CH3:4])[CH3:3])([CH3:15])([CH3:17])[CH3:18]
Reactant: CC(C)C[SiH](Cl)CC(C)C
Reactant: C1CCOC1
Reactant: CCCCC
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)C[SiH](CC(C)C)C(C)(C)C
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
Diisobutylchlorosilane (18.0 mL, 100 mmol) was dissolved in THF (100 mL), and tert-butyl magnesium chloride THF solution (10M, 100 mL) was added dropwise thereto under nitrogen for 30 minutes. Cuprous bromide (286 mg, 2.00 mmol) was added to the resultant mixture, followed by stirring at 70° C. for 8 hours. The reaction mixture was left to cool, and saturated aqueous ammonium chloride and n-pentane were added thereto. The formed organic layer was washed three times with water and once with saturated brine, and the thus-washed layer was dried over sodium sulfate anhydrate. The solvent was removed, followed by purification through distillation under reduced pressure, whereby the Compound 36a was obtained as a colorless liquid (boiling point; 27 mmHg, 100° C. fraction, 13.6 g, 68%).
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][O:14]C2CCCCO2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.O1CCCC1.O.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.S(=O)(=O)(O)O>[C:1]1([O:11][CH2:12][CH2:13][OH:14])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1cc2c(c(OCCOC3CCCCO3)c1)CCCC2
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: OCCOc1cccc2c1CCCC2
Reaction time: 3.5 h
Yield: 44.2 %

Procedure:
A solution of 700 mg (2.54 mmol) of the title product of Example 58 in a mixture of 9 ml of acetic acid, 3 ml of tetrahydrofuran, and 3 ml of water was stirred at 85°-90° C. After 3.5 hours, 4 drops of concentrated sulfuric acid were added and stirring continued for an additional one-half hour. The mixture was permitted to cool, and 4 g of sodium carbonate monohydrate was added. The resulting mixture was partitioned between diethyl ether and water. The organic layer was washed repeatedly with saturated aqueous sodium bicarbonate, with water, and then with brine. The solution was dried over magnesium sulfate, the drying agent was removed by filtration, and the solvent was removed under reduced pressure. Chromatography of the residue on silica gel, using 15% ethyl acetate/toluene as eluent, gave 216 mg of the title compound.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:10](=[CH2:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[CH2:33](I)[CH3:34].C(OC(C)C)(=O)C>O.CN(C)C=O>[CH2:33]([O:12][C:11](=[O:13])[C:10](=[CH2:14])[CH2:9][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:6][CH:5]=1)[CH3:34].[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:10](=[CH2:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: CCI
Agent: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)C
Solvent: O
Product: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
30 g (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid (2-a, R1=Boc, R2=H, R3=CO2H), prepared according to Example 33 is added to 38.4 g caseium carbonate. Dimethylformamide (50 ml) is then added. Ethyl iodide (8.26 ml) is then added and the mixture is stirred for 16 h at room temperature. Water (1200 ml) and isopropyl acetate (120 ml) are added. The phases are separated. The aqueous phase is washed with isopropyl acetate (2×120 ml). The combined organic phases are washed with 20% aqueous sodium chloride solution (180 ml) and then dried (MgSO4). The mixture is concentrated under reduced pressure to afford (R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid ethyl ester (2-a, R1=Boc, R2=H, R3=CO2Et). 1H NMR (CDCl3): 1.31 (3H), 1.40 (9H), 2.37 (1H), 2.59 (1H), 2.84 (1H), 2.93 (1H), 4.06 (1H), 4.24 (2H), 4.56 (1H), 5.62 (1H), 6.25 (1H), 7.29 (2H), 7.35 (1H), 7.45 (2H), 7.54 (2H), 7.59 (2H).
Reaction SMILES: [NH2:1][C:2]1[C:9]([Cl:10])=[CH:8][C:7]([Br:11])=[CH:6][C:3]=1[CH:4]=O.[NH2:12][C:13](N)=[O:14]>O>[Br:11][C:7]1[CH:6]=[C:3]2[C:2](=[C:9]([Cl:10])[CH:8]=1)[N:1]=[C:13]([OH:14])[N:12]=[CH:4]2
Reactant: Nc1c(Cl)cc(Br)cc1C=O
Reactant: NC(N)=O
Solvent: O
Product: Oc1ncc2cc(Br)cc(Cl)c2n1
Temperature: 180 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
A mixture of 2-amino-5-bromo-3-chlorobenzaldehyde (9.0 g, 38.6 mmol) and urea (34.7 g, 579 mmol) was heated to 180° C. and stirred for 2 hours. The reaction mixture was cooled to room temperature, and the resulting precipitate was diluted with water (1 L) and stirred for 2 hours. The resulting precipitate was filtered, and the moisture trapped was completely removed by the co-evaporation with toluene three times. The title compound (9.0 g, 90%) was obtained as a yellow solid. MS (ES+) C8H4BrClN2O requires: 257, 259, found: 258, 260 [M+H]+.
Reaction SMILES: Cl.Cl[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[CH:5]1.[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:10][C:9]([F:12])([F:11])[C:7]1[N:6]=[CH:5][N:4]([CH2:3][C:17]([CH2:16][CH2:15][C:14]([F:13])([F:22])[F:23])([C:18]#[N:19])[C:20]#[N:21])[CH:8]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: FC(F)(F)c1cn(CCl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cnc(C(F)(F)F)c1
Yield: 27.7 %

Procedure:
2.90 g of 1-(chloromethyl)-4-(trifluoromethyl)-1H-imidazole hydrochloride and 2.11 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 39 ml of N,N-dimethylformamide. 3.59 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.12 g of {[4-(trifluoromethyl)-1H-imidazole-1-yl]methyl}(3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (38), hereinafter) shown by below formula.
Reaction SMILES: [N:1]1([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]3[CH:18]=[N:19][C:20]([C:21]([OH:23])=[O:22])=[C:10]3[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]1(O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(P(=O)(OCC)OCC)#N.C(=O)(O)[O-].[Na+]>ClCCl.C(N(CC)CC)C>[N:1]1([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]3[CH:18]=[N:19][C:20]([C:21]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:22])=[C:10]3[CH2:9]2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1ncn2c1CN(C(=O)N1CCCC1)c1ccccc1-2
Reactant: Oc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccccc1)c1ncn2c1CN(C(=O)N1CCCC1)c1ccccc1-2
Reaction time: 8 h

Procedure:
To a mixture of 4,5-dihydro-5-[(pyrrolidino)carbonyl]imidazo[1,5-a]quinoxaline-3-carboxylic acid (I, EXAMPLE 323, 0.543 g), 0.245 g of phenol, 0.48 ml of triethylamine, and 6 ml of dichloromethane are added 0.42 ml of diethyl cyanophosphonate. After stirring for 1 hr an additional 0.11 g of phenol are added. When the reaction had stirred another 2.5 hr an additional 0.11 g of phenol and 0.26 ml of diethyl cyanophosphonate are added. The reaction is stored overnight in the refrigerator and then stirred with 1 ml of aqueous sodium bicarbonate for about 30 min. The mixture is then partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layers are dried over sodium sulfate, concentrated, and the residue chromatographed on silica gel (300 ml) eluting with methanol/methylene chloride (2/98), the appropriate fractions are pooled and concentrated to give the title compound, which is crystallized from dichloromethane/hexane, mp 196.5°-199°; MS (m/z) at 388; IR (mineral oil) 1648, 1199, 1723, 1502, 1410 cm-1 ; 1H NMR (CDCl3) 1.81, 3.31, 5.09, 7.15-7.33, 7.42, 7.55, 8.11 δ.
Reaction SMILES: [O:1]1[CH2:5][CH2:4]CC1.[CH2:6]([NH:10][S:11]([CH2:14][CH:15]([OH:34])[CH:16]([OH:33])[CH:17]([NH:25][C:26](=O)[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)(=[O:13])=[O:12])[CH2:7][CH2:8][CH3:9].CO>C(Cl)(Cl)Cl>[C:5]([OH:1])(=[O:12])[CH3:4].[CH2:6]([NH:10][S:11]([CH2:14][CH:15]([OH:34])[CH:16]([OH:33])[CH:17]([NH:25][CH2:26][CH2:27][CH2:28][CH:29]([CH3:30])[CH3:31])[CH2:18][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)(=[O:12])=[O:13])[CH2:7][CH2:8][CH3:9]
Reactant: C1CCOC1
Reactant: CCCCNS(=O)(=O)CC(O)C(O)C(CC1CCCCC1)NC(=O)CCC(C)C
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(=O)O
Product: CCCCNS(=O)(=O)CC(O)C(O)C(CC1CCCCC1)NCCCC(C)C
Reaction time: 1 h

Procedure:
Borane dimethylsulfide complex (10 molar, 0.9 ml., 9 mmole) was added dropwise to a tetrahydrofuran solution (3 ml.) of [1S-(1R*,2S*,3S*)]-N-[4-[(butylamino)sulfonyl]-1-(cyclohexylmethyl)-2,3-dihydroxybutyl]-4-methylpentanamide (100 mg., 0.23 mmole, product of Example 38). The reaction mixture is stirred at 50° for one hour, quenched with 1N HCl (10 ml.), and after 30 minutes, saturated sodium bicarbonate was added (pH 8). The product was extracted with ethyl acetate (2×150 ml.) and this solution was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by chromatography through silica gel (20 g., Merck) using (2.5:0.1:100) methanol:acetic acid:chloroform. The appropriate fractions were combined and concentrated to yield 63 mg. of glassy, very hygroscopic white solid [βR-(βR*,γR*,δS*)]-N-butyl-β, γ-dihydroxy-δ-[(4-methylpentyl)amino]cyclohexanepentanesulfonamide, monoacetate salt; m.p. 68°-82°, [α]D =+14° (c=0 5, methanol). TLC (silica gel, methanol:chloroform, 1:9) Rf =0.46.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[N:11]1([CH2:16][C:17]([N:19]2[CH2:23][C@H:22]([OH:24])[CH2:21][C@H:20]2[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)=[O:26])=[O:18])[CH:15]=[N:14][CH:13]=[N:12]1.C(N(CC)CC)C.[Cl-].[NH4+]>C(Cl)Cl>[N:11]1([CH2:16][C:17]([N:19]2[CH2:23][C:22](=[O:24])[CH2:21][C@H:20]2[C:25]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)=[CH:32][CH:33]=2)=[O:26])=[O:18])[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](O)CN1C(=O)Cn1cncn1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1
Reaction time: 0.25 h
Yield: 53.2 %

Procedure:
DMSO (3.78 mmol, 0.268 mL) was added drop-wise to a flask charged with oxalyl chloride (0.165 mL, 1.89 mmol) and methylene chloride (4 mL) at −78° C. The mixture was stirred for 15 minutes and then (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-hydroxypyrrolidine-2-carboxamide (0.20 g, 0.47 mmol), prepared as in Reference 11, in methylene chloride (1 mL) was added via syringe. The reaction mixture then was stirred at 0° C. for 30 minutes and then quenched with triethylamine (2.0 mL, 15 mmol). The mixture was stirred for an additional 5 minutes and then saturated ammonium chloride (aq., 20 mL) was added. Product was purified from the organic layer by chromatography (EtOAc to EtOAc/MeOH (9:1)+1% NEt3) to give (S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-oxopyrrolidine-2-carboxamide (0.11 g, 0.25 mmol, 53% yield) as an oil.