Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:27])[N:14]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:15]=[N:16]2)=[CH:11][C:10]=1[O:28][CH3:29])C1C=CC=CC=1>[Pd].CC(N(C)C)=O>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:27])[N:14]([CH2:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH:15]=[N:16]2)=[CH:11][C:10]=1[O:28][CH3:29]
Reactant: COc1cc2c(=O)n(CC(=O)OC(C)(C)C)cnc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(=O)n(CC(=O)OC(C)(C)C)cnc2cc1O
Reaction time: 3 h
Yield: 43221.8 %

Procedure:
10% palladium on carbon (56 g, 53 mmol) was added to a solution of tert-butyl 2-[7-(benzyloxy)-6-methoxy-4-oxo-3(4H)-quinazolinyl]acetate (562 g, 1.42 mmol) in dimethylacetamide (3500 ml) at ambient temperature and stirred for 3 hours under an atmosphere of hydrogen (1 bar). The reaction was filtered through a pad of celite and the solvent evaporated in vacuo. The residual solid was dissolved in 20% methanol in dichloromethane and passed through a pad of silica gel. Evaporation of the solvent in vacuo followed by trituration with methanol yielded, tert-butyl 2-[7-hydroxy-6-methoxy-4-oxo-3(4H)-quinazolinyl]acetate (188 g, 43% yield):
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([NH:15][CH2:16][CH2:17][O:18][N+:19]([O-:21])=[O:20])=[O:14].[OH-].[K+].[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl>O.C(O)C>[O:28]1[CH2:27][CH:26]1[CH2:24][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([NH:15][CH2:16][CH2:17][O:18][N+:19]([O-:21])=[O:20])=[O:14]
Reactant: O=C(Cc1ccc2ccccc2c1O)NCCO[N+](=O)[O-]
Reactant: ClCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(Cc1ccc2ccccc2c1OCC1CO1)NCCO[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 22 h
Yield: 40 %

Procedure:
4.600 g (0.015 mole) of 1-hydroxy-N(2-nitroxyethyl)-2-naphthalene acetamide dissolved in a mixture of 4 ml of water, 1.436 g (0.021 mole) of 85% potassium hydroxide and 38 ml of ethanol were added slowly over a solution of 35.490 g (30 ml, 0.383 mole) of epichlorohydrin in 17 ml of ethanol, with temperature control. The mixture was stirred at room temperature for 22 hours. 150 ml of water were added and the mixture was concentrated at reduced pressure at 40° C. The mixture was extracted three times with 70 ml of ethyl acetate and dried over sodium sulphate. It was filtered and the solvent was removed at low pressure. The oil obtained was purified by column chromatography in silica gel (0.060-0.200 mm). 2.354 g (0.006 mole) of 1-(2,3-epoxy)propoxy-N-(2- nitroxyethyl)-2-naphthalene acetamide were obtained on eluting with a mixture of chloroform/methanol: 9/1 and removing the solvent at reduced pressure (m.p. 67°-71° C., Rf =0.41 TLC, silica gel Merck HPTLC-5629, chloroform 80/acetone 20). They were mixed with 8.88 g (12.8 ml, 0.150 mole) of isopropylamine in 80 ml of methanol and heated under reflux for 1 hour under anhydrous conditions. The product was concentrated at reduced pressure at 40° C. The oil obtained was redissolved in 80 ml of ethyl acetate and was extracted three times with 35 ml of 1N HCl. The acid extracts were pooled and were alkalized with the addition of powdered sodium carbonate and a solution of 1N NaOH to pH=12. The solution was treated twice with 50 ml of ethyl acetate. The organic extracts were pooled and washed twice with 25 ml of sodium chloride saturated water. It was dried over anhydrous sodium sulphate, was filtered and was concentrated at reduced pressure to give a residue which was purified by column chromatography on silica gel (0.060-0.200 mm). On eluting with a mixture of chloroform 90/methanol 20 and removing the solvent at reduced pressure until a constant weight, 1.113 g (17%) of an oil which solidified in amorphous form were obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][CH:15]=[CH:14]4)=[CH:9][N:8]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.[CH:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:31].C([O-])([O-])=O.[Na+].[Na+]>CC#N.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:35]5[CH:36]=[CH:37][C:32]([CH:30]=[O:31])=[CH:33][CH:34]=5)[CH:3]=4)[N:8]([S:20]([C:23]4[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=4)(=[O:21])=[O:22])[CH:9]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(-c4ccc(C=O)cc4)cnc32)cc1
Temperature: 150 °C

Procedure:
To a solution of 5-bromo-3-(1H-indol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine [Intermediate B] (0.20 g, 0.43 mmole) in CH3CN (4 mL) in a Personal Chemistry microwave reaction vial was added 4-formylphenylboronic acid (64 mg, 0.43 mmol), bis(triphenylphosphine)-palladium(II)dichloride (40 mg, 0.057 mmol), and 1 M Na2CO3 (2 mL). The resulting mixture was de-gassed with Ar for 10 min, after which it was heated at 150° C. for 10 min in a Personal Chemistry Optimizer. The organic layer was separated, filtered, and partitioned between EtOAc and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give Intermediate AJ. HPLC retention time: 3.01 minutes. MS ESI (m/z): 492.4 (M+H)+, calc. 491.
Reaction SMILES: C(O[C:4]([C:6]1[S:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([C:17]([C:20]([C:23]4[CH:24]=[CH:25][C:26]5[O:30][CH:29]=[CH:28][C:27]=5[CH:31]=4)([F:22])[F:21])=[N:18][N:19]=3)[N:16]=2)=[CH:9][CH:10]=1)=[O:5])C.[OH-].[Na+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:77][N:78]1[CH2:83][CH2:82][NH:81][CH2:80][CH2:79]1>C1COCC1.CO.ClCCl.O>[O:30]1[C:26]2[CH:25]=[CH:24][C:23]([C:20]([F:21])([F:22])[C:17]3[N:15]4[N:16]=[C:11]([C:8]5[S:7][C:6]([C:4]([N:81]6[CH2:82][CH2:83][N:78]([CH3:77])[CH2:79][CH2:80]6)=[O:5])=[CH:10][CH:9]=5)[CH:12]=[CH:13][C:14]4=[N:19][N:18]=3)=[CH:31][C:27]=2[CH:28]=[CH:29]1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1ccc(-c2ccc3nnc(C(F)(F)c4ccc5occc5c4)n3n2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(C(=O)c2ccc(-c3ccc4nnc(C(F)(F)c5ccc6occc6c5)n4n3)s2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound prepared in step e was dissolved in a 2:1 THF/methanol (3 mL) mixture and treated with 2N NaOH (0.15 mL). The mixture was stirred for 3 hours at RT, evaporated in vacuo, diluted with water (10 mL), and acidified with 6 N HCl to pH 2. The white solid precipitates were collected, dried under reduced pressure, dissolved in DMF (2 mL) and treated with HATU (0.0.62 g, 0.16 mmol), HOBt (0.013 g, 0.09 mmol) and DIEA (0.06 mL, 0.32 mmol) respectively. The resulting mixture was stirred at RT for 30 minutes and N-Methylpiperazine (0.014 mL, 0.14 mmol) was added. Stirring was continued for an additional hour and water (20 mL) was added. Dichloromethane (20 mL) was added and layers separated. The CH2Cl2 layer was dried over MgSO4, evaporated in vacuo and chromatographed (CH2Cl2/0-10% MeOH) to yield a solid product. Recrystallization for EtOAc afforded the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J=9.8, 1H), 8.17-8.07 (m, 4H), 7.79 (d, J=9.1 Hz, 1H), 7.65 (dd, J=8.5, 2.1 Hz, 1H), 7.50 (d, J=3.9 Hz, 1H), 7.08 (s, 1H), 3.67 (m, 4H), 3.34 (m, 4H), 2.32 (s, 3H); MS (m/z): 495 (MH+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.CC(C)([O-])C.[K+].F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1.[OH-].[Na+]>CS(C)=O>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([O:12][C:9]2[CH:10]=[CH:11][C:6]([C:2]3[O:1][CH:5]=[CH:4][N:3]=3)=[CH:7][CH:8]=2)=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccc(-c2ncco2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(-c3ncco3)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 82.2 %

Procedure:
A solution of 4-(2-oxazolyl)phenol (10.8 g, 11.2 mmol) in DMSO (9 mL) was stirred as potassium tert-butoxide (1.5 g, 13.4 mmol) and 4-fluoro-nitrobenzene (1.3 mL, 12.3 mmol) were added sequentially. The reaction was stirred for 17 hours at ambient temperature. The reaction was poured into a cold aqueous sodium hydroxide solution (1 N). The solid was isolated by filtration to give 2.6 g of 2-[4-(4-nitrophenoxy)phenyl]oxazole.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6]C(C)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[OH-].[K+].CC[O:16][C:17]([CH3:19])=[O:18]>N1C=CC=CC=1.CO>[I:1][C:2]1[CH:7]=[CH:6][C:19]([C:17]([OH:16])=[O:18])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Cc1ccc(I)cc1[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: c1ccncc1
Product: O=C(O)c1ccc(I)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
In a 1 L three-neck round-bottom flask equipped with an internal thermometer, a reflux condenser, and an addition funnel, Bu4N+MnO4− (124 g, 343 mmol) was dissolved in pyridine (200 mL). The solution was heated to 60° C., and then the heating source was removed. A solution of 4-iodo-2-nitrotoluene (43.0 g, 163 mmol) in pyridine (60 mL) was added through the additional funnel over 2 h. The reaction temperature was maintained at 60° C. by adjusting the addition rate. When the addition was complete, the reaction mixture was cooled to rt. The solution was concentrated, diluted with EtOAc (300 mL) and water (200 mL), and stirred at rt for 30 min. The precipitated brown solid was filtered off and washed with EtOAc. The clear organic layer was washed with 5% aq. H2SO4 (200 mL) and brine (200 mL), dried (MgSO4), and concentrated to afford a thick, brown oil. The crude product was dissolved in EtOAc (200 mL) and then a solution of KOH (9.1 g, 163 mmol) in MeOH (ca. 30 mL) was added dropwise. The mixture was stirred at rt for 1 h, and the precipitated solid was collected by filtration and washed with EtOAc. The filtrate was concentrated and the precipitation was repeated with KOH in MeOH. The two crops were combined and dissolved in water (ca. 250 mL) and acidified with conc. HCl to pH<2. The precipitated white solid was collected by filtration and dried under vacuum to give the desired product (40 g, 136 mmol, 83%, >98% purity by HPLC). 1H NMR (400 MHz, CD3OD): 8.13 (d, J=1.6, 1H), 8.01 (dd, J=8.1, 1.6, 1H), 7.50 (d, J=8.1, 1H).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[Br-].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([Zn+])=[CH:23][C:22]=1[F:28]>O1CCCC1.[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>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[O:6][C:5]([C:7]3[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=3)=[N:4][C:3]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:23][C:22]=1[F:28]
Reactant: CCOC(=O)c1nc(-c2ccc(F)cc2)oc1Br
Reactant: Fc1cc([Zn+])ccc1Cl
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-c2ccc(F)cc2)oc1-c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 5-bromo-2-(4-fluorophenyl)oxazol-4-carboxylate (600 mg), 0.05M (4-chloro-3-fluorophenyl) zinc bromide (6 ml, tetrahydrofuran solution), and tetrakis-(triphenylphosphine) palladium (231 mg) in tetrahydrofuran (5 ml) was stirred under argon atmosphere at room temperature for 2 hours, followed by refluxing for 40 minutes. The reaction mixture was cooled and concentrated under reduced pressure, and water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was successively washed with 10% hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent: ethyl acetate:n-hexane=1:8) to obtain ethyl 5-(4-chloro-3-fluoro-phenyl)-2-(4-fluorophenyl)oxazol-4-carboxylate (580 mg) as pale reddish solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:25]=[CH:24][C:7]([NH:8][C:9]2[C:14]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][CH:5]=1.C([Si]([O:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][CH:52]2[CH2:54][O:53]2)=[CH:46][CH:45]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[OH:53][C@H:52]([CH2:51][O:50][C:47]1[CH:48]=[CH:49][C:44]([OH:43])=[CH:45][CH:46]=1)[CH2:54][NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:8][C:9]2[C:14]([NH:15][C:16](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:24][CH:25]=1
Reactant: NCCc1ccc(Nc2ncccc2NC(=O)c2ccccc2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(Nc1cccnc1Nc1ccc(CCNC[C@H](O)COc2ccc(O)cc2)cc1)c1ccccc1
Yield: 32.8 %

Procedure:
N-{2-[4-(2-Aminoethyl)anilino]-3-pyridinyl}benzamide (0.1 g, 0.30 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.107 g, 0.265 mmol) according to Procedure G (eluant: 20:1 going to 10:1 chloroform-methanol) to give the title compound (0.064 g, 0.087 mmol).
Reaction SMILES: Cl[C:2]1[N:11]([CH3:12])[CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:19])[CH:8]=2)[N:3]=1.[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23][NH2:24]>>[Cl:19][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:24][CH2:23][CH:22]([O:25][CH3:26])[O:21][CH3:20])[N:11]([CH3:12])[CH:10]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN1C(Cl)=Nc2ccc(Cl)cc2C1c1ccccc1
Reactant: COC(CN)OC
Product: COC(CNC1=Nc2ccc(Cl)cc2C(c2ccccc2)N1C)OC
Temperature: 0 °C

Procedure:
The starting material may be prepared as follows: A mixture of 3.0 g of 2,6-dichloro-3,4-dihydro-3-methyl-4-phenylquinazoline and 15 ml of 2,2-dimethoxyethylamine was heated at 100°-110° C. for 1 hour. The mixture was poured into ice-water and the resulting mixture was extracted with ether. The ether layer was washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness. The residual oil was crystallized from isopropyl ether-hexane to give 2.0 g of 6-chloro-3,4-dihydro-2-(2,2-dimethoxyethylamino)-3-methyl-4-phenylquinazoline as colorless needles, m.p. 104.5°-105° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][C:9]=2[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:24]=[CH:25][C:26]([C:49](=[O:71])[NH:50][S:51]([C:54]4[CH:59]=[CH:58][C:57]([NH:60][CH2:61][CH:62]5[CH2:67][CH2:66][O:65][CH2:64][CH2:63]5)=[C:56]([N+:68]([O-:70])=[O:69])[CH:55]=4)(=[O:53])=[O:52])=[C:27]([CH:48]=3)[O:28][C:29]3[CH:30]=[C:31]4[C:35](=[CH:36][CH:37]=3)[NH:34][CH:33]=[C:32]4[CH2:38][CH2:39][NH:40]C(=O)OC(C)(C)C)[CH2:19][CH2:18]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:40][CH2:39][CH2:38][C:32]1[C:31]2[C:35](=[CH:36][CH:37]=[C:29]([O:28][C:27]3[CH:48]=[C:23]([N:20]4[CH2:21][CH2:22][N:17]([CH2:16][C:9]5[CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13][C:8]=5[C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)[CH2:18][CH2:19]4)[CH:24]=[CH:25][C:26]=3[C:49]([NH:50][S:51]([C:54]3[CH:59]=[CH:58][C:57]([NH:60][CH2:61][CH:62]4[CH2:63][CH2:64][O:65][CH2:66][CH2:67]4)=[C:56]([N+:68]([O-:70])=[O:69])[CH:55]=3)(=[O:53])=[O:52])=[O:71])[CH:30]=2)[NH:34][CH:33]=1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CCOCC5)c([N+](=O)[O-])c4)c(Oc4ccc5[nH]cc(CCNC(=O)OC(C)(C)C)c5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CCOCC5)c([N+](=O)[O-])c4)c(Oc4ccc5[nH]cc(CCN)c5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reaction time: 0.25 h

Procedure:
A solution of EXAMPLE 299E (146.6 mg) in dichloromethane (10 mL) was cooled in an ice bath and 2,2,2-trifluoroacetic acid (5 mL) was added dropwise over 5 minutes. The reaction mixture was stirred 15 minutes under nitrogen, the ice bath was removed and the reaction was allowed to come to ambient temperature. The reaction was stirred 1.5 hours and then concentrated. The crude material was purified by reverse phase chromatography with ammonium acetate buffer in acetonitrile to give the title compound. 1H NMR (300 MHz, dimethyosulfoxide-d6) δ 10.86 (d, 1H), 8.39 (d, 1H), 8.33 (t, 1H), 8.06 (br s, 1H), 7.71 (dd, 1H), 7.53 (d, 1H), 7.34 (d, 2H), 7.26 (d, 1H), 7.19 (d, 1H), 7.05 (m, 3H), 6.89 (d, 1H), 6.70 (dd, 1H), 6.52 (dd, 1H), 6.15 (d, 1H), 3.83 (dd, 2H), 3.22 (m, 3H), 2.82-3.00 (m, 8H), 2.72 (s, 2H), 2.16 (m, 6H), 1.96 (s, 2H), 1.88 (m, 4H), 1.60 (d, 2H), 1.38 (m, 2H), 1.24 (m, 2H), 0.93 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[CH:22]1([NH2:25])[CH2:24][CH2:23]1>>[CH:22]1([NH:25][C:2]2[C:10]3[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=3[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=2[C:18]([F:21])([F:20])[F:19])[CH2:24][CH2:23]1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c2[nH]c(C(F)(F)F)nc12
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(NC2CC2)c2[nH]c(C(F)(F)F)nc12

Procedure:
4-Chloro-7-nitro-2,5-bis(trifluoromethyl)benzimidazole is reacted with cyclopropylamine to obtain the corresponding 4-(cyclopropylamino)-7-nitro-2,5-bis(trifluoromethyl)-benzimidazole, m.w., 354.2.
Reaction SMILES: [CH:1]([C:3]1[C:4]([NH:11][C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[CH:16][CH:17]=2)=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1)=[O:2].NC1C=C(NC(=O)OC(C)(C)C)C=CC=1[F:33]>>[F:33][C:17]1[CH:16]=[CH:15][C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[CH:13][C:12]=1[NH:11][C:4]1[C:3]([CH:1]=[O:2])=[CH:8][N:7]=[C:6]([S:9][CH3:10])[N:5]=1
Reactant: CSc1ncc(C=O)c(Nc2cccc(NC(=O)OC(C)(C)C)c2)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)c(N)c1
Product: CSc1ncc(C=O)c(Nc2cc(NC(=O)OC(C)(C)C)ccc2F)n1

Procedure:
The title compound was prepared according to the procedures described for Intermediate 50, starting from tert-butyl (3-amino-4-fluorophenyl)carbamate (58a; prepared according to the reported protocol in Kuramoto, Y. et al. J. Med. Chem. 2003, 46, 1905-1917).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:22]([F:23])=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15]OS(C)(=O)=O)=[CH:10][C:9]=2[F:24])[C:6](=[O:25])[CH:5]=[CH:4][C:3]=1[C:26](=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34].[C:36]([O:40][C:41](=[O:48])[C@@H:42]([CH2:44][CH:45]([CH3:47])[CH3:46])[NH2:43])([CH3:39])([CH3:38])[CH3:37]>>[NH2:1][C:2]1[N:7]([C:8]2[C:22]([F:23])=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15][NH:43][C@@H:42]([C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:48])[CH2:44][CH:45]([CH3:46])[CH3:47])=[CH:10][C:9]=2[F:24])[C:6](=[O:25])[CH:5]=[CH:4][C:3]=1[C:26](=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34]
Reactant: CS(=O)(=O)OCCCOc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)c(F)c1
Reactant: CC(C)C[C@@H](N)C(=O)OC(C)(C)C
Product: CC(C)C[C@@H](NCCCOc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)c(F)c1)C(=O)OC(C)(C)C

Procedure:
From Intermediate 4F and D-Leucine tert-butyl ester, LCMS purity 95%, m/z 606 [M+H]+, 1H NMR (300 MHz, DMSO), δ: 9.30-9.00 (2H, m), 7.62-7.52 (1H, m), 7.47-7.32 (2H, m), 7.28-7.12 (1H, m), 7.06 (2H, d, J=10.2 Hz), 5.73 (1H, d, J=9.6 Hz), 4.20 (2H, t, J=5.7 Hz), 3.99 (1H, br s), 3.25-2.95 (2H, m), 2.20-2.05 (2H, m), 1.80-1.60 (3H, m), 1.49 (9H, s), 0.95 (6H, d, J=4.8 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=O)[N:3]=[CH:2]1.[CH2:10]([C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]([F:34])[F:33])[CH:24]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:18][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]([F:34])[F:33])[CH:24]=2)[CH2:20][CH2:21][N:22]1[C:7](=[O:9])[CH2:6][C:4]1[N:3]=[CH:2][NH:1][CH:5]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC(F)F
Product: COc1ccc(N2CCN(C(=O)Cc3c[nH]cn3)[C@@H](Cc3ccccc3)C2)cc1OC(F)F

Procedure:
Prepared by the method outlined for Example 189 using (1H-imidazol-4-yl)-acetic acid and (S)3-benzyl-1-(3-difluoromethoxy-4-methoxy-phenyl)-piperazine (Example 69, Compound 157) as starting materials. Product as an oil. LC/MS (Method B) 3.14 min, [M+1]+ 457. Potency class C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:7]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13](OC)=[O:14])[C:6](=[O:17])[N:5]([CH3:18])[N:4]=1.[H-].C([Al+]CC(C)C)C(C)C.CC(C)=O>C(Cl)Cl>[OH:14][CH2:13][C:9]1[S:10][CH:11]=[CH:12][C:8]=1[N:7]1[C:3]([O:2][CH3:1])=[N:4][N:5]([CH3:18])[C:6]1=[O:17]
Reactant: COC(=O)c1sccc1-n1c(OC)nn(C)c1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1nn(C)c(=O)n1-c1ccsc1CO
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
To a solution of the title compound of Step D (1.8 g) in methylene chloride (23 mL) under N2 at -78° C. was added a solution of diisobutylaluminum hydride (18.3 mL, 1 M) in methylene chloride. The resulting solution was allowed to stir at -78° C. for 15 min, warmed to room temperature and then stirred for 1.5 h. After cooling the reaction mixture to -78° C., acetone was added and after about 10 min, the reaction mixture was quenched with 1N HCl. The reaction mixture was allowed to warm to room temperature, was diluted further with methylene chloride, and was then washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to yield 1.3 g of the title compound of Step E as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:19])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>C(O)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:11]2[O:10][C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]2=[O:19])=[CH:21]1
Reactant: CCOC(=O)C1=C(Nc2ccc(Br)cc2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(Br)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 35.9 %

Procedure:
To a solution of ethyl 2-[(4-bromophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.15 g, 0.46 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.067 g, 0.46 mmol) in ethanol (5.0 mL), piperidine (0.85 mL, 0.92 mmol) was added at ambient temperature. The mixture was refluxed for 24 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound (0.075 g, y. 36%).