Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.CC1(C)C(C)(C)OB([C:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[NH:6]1[CH:5]=[CH:4][N:3]=[C:2]1[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Brc1ncc[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC=C(c2ncc[nH]2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 14.7 %

Procedure:
A mixture of 2-bromo-1H-imidazole (1.2 g, 8.16 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (3.0 g, 9.70 mmol), sodium carbonate (2.1 g, 19.8 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.120 g, 0.16 mmol) in 1,4-dioxane (30 mL) and water (10 mL) stirred overnight at 100° C. The reaction mixture was cooled to room temperature, poured into ethyl acetate (100 mL), washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 25% ethyl acetate-petroleum ether) to afford tert-butyl 4-(1H-imidazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.300 g, 15%) as a light yellow solid. MS (ESI, pos. ion) m/z 250 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH:17](I)([CH3:19])[CH3:18]>CC(C)=O.[Ag]=O>[CH:17]([N:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[CH2:10]1)([CH3:19])[CH3:18]
Reactant: CC(C)I
Reactant: FC(F)(F)c1cccc(C2CCCNC2)c1
Agent: O=[Ag]
Solvent: CC(C)=O
Product: CC(C)N1CCCC(c2cccc(C(F)(F)F)c2)C1
Reaction time: 24 h

Procedure:
3.4 g of silver oxide were added to a solution of 9.2 g of 3-(m-trifluoromethylphenyl)-piperidine in 45 ml of acetone and after 61/2 hours of stirring 1.1 g of silver oxide and 4.9 ml of isopropyl iodide were added. The mixture was stirred for 24 hours and was filtered. The filtrate was evaporated to dryness to obtain 10.4 g of N-isopropyl-3-(m-trifluoromethylphenyl)-piperidine.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:10][C:9]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[O:13][C:8]=2[CH:7]=1)=O)C.C(OC(=O)C(CC)CCN1C(=S)N2C3C=C(C4C=CC([N+]([O-])=O)=CC=4)OC=3C=C2C1=O)C.[N:55]([CH2:58][CH2:59][CH2:60][C:61]#[N:62])=[C:56]=[S:57].C([O-])([O-])=O.[K+].[K+]>C(O)C>[N+:20]([C:17]1[CH:16]=[CH:15][C:14]([C:12]2[O:13][C:8]3[CH:7]=[C:6]4[C:4](=[O:3])[N:55]([CH2:58][CH2:59][CH2:60][C:61]#[N:62])[C:56](=[S:57])[N:10]4[C:9]=3[CH:11]=2)=[CH:19][CH:18]=1)([O-:22])=[O:21]
Reactant: N#CCCCN=C=S
Reactant: CCOC(=O)c1cc2oc(-c3ccc([N+](=O)[O-])cc3)cc2[nH]1
Agent: CCOC(=O)C(CC)CCN1C(=O)c2cc3oc(-c4ccc([N+](=O)[O-])cc4)cc3n2C1=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N#CCCCN1C(=O)c2cc3oc(-c4ccc([N+](=O)[O-])cc4)cc3n2C1=S
Temperature: 110 °C

Procedure:
2-(4-nitro-phenyl)-4H-furo[3,2-b]pyrrole-5-carboxylic acid ethyl ester (60.97 mg, 0.21 mmol), prepared as described hereinabove (see, preparation of Compound 1), 4-isothiocyanato-butyronitrile (664 mg, 2.1 mmol) and a fine powder of anhydrous K2CO3 (27.6 mg, 0.2 mmol) are mixed together in a sealed tube, provided with a magnetic stirrer, and the mixture is heated at 110° C. for 2 hours. The mixture is cooled to room temperature, ethanol is added (2 ml), and the formed precipitate is filtered. The crude product is recrystallized from ethanol to give Compound 35.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:4]=2[N:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(O)CCC>[F:12][C:10]1[CH:9]=[CH:8][C:5]2[N:6]([CH3:7])[C:2]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:3][C:4]=2[CH:11]=1
Reactant: C1CNCCN1
Reactant: Cn1c(Cl)nc2cc(F)ccc21
Solvent: CCCCO
Product: Cn1c(N2CCNCC2)nc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
0.7 g 2-chloro-5-fluoro-1-methyl-1H-benzimidazole and 1.3 g piperazine are suspended in 10 ml n-butanol and stirred for 48 hours at ambient temperature. The reaction mixture is evaporated to dryness and the product is purified by chromatography (aluminium oxide, methylene chloride/methanol 10/1). 0.73 g (V-8) are obtained in the form of a solid. 1H NMR (400 MHz, DMSO): 6.9 (1H, t); 3.6 (3H, s).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](OCC2C=CC=CC=2)=[C:6]([N+]([O-])=O)[CH:5]=1)=[O:3].C(C1C=CC=CC=1)(=O)C.[Br:30]Br.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl.CO.CC#N>[Br:30][CH2:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: BrBr
Agent: [Br-]
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: CC(=O)c1ccccc1
Solvent: CC#N
Product: O=C(CBr)c1ccccc1

Procedure:
The optically pure epoxide (FAE) is prepared from commercially available 4-benzyloxy-3-nitroacetophenone. Thus, the acetophenone may be brominated with bromine or pyridinium tribromide in an inert organic solvent such as CH3CN, MeOH or chloroform to give the α-bromoacetophenone. The bromoacetophenone is then reduced with a borane reducing agent, such as BH3THF, BH3.diethylaniline or BH3.Me2S, in the presence of a chiral oxazaborolidine catalyst, such as cis-(1R,2S)-aminoindanol-B-Me catalyst, to give the optically active bromohydrin after isolation by crystallization in >96% ee. The bromohydrin can be further enriched to >98% ee by recrystallization. The absolute configuration of the bromohydrin is determined by the chirality of the oxazaborolidine catalyst. The nitro group in the bromohydrin is selectively reduced to the amine group using a reducing agent known for selective nitro reduction, such as Sn, Fe with acid, SnCl2 or by heterogeneous catalytic hydrogenation in the presence of a noble metal catalyst such as PtO2 or Pt/C. Catalytic hydrogenation is cleaner if a noble metal catalyst such as platinum on carbon poisoned with dimethyl sulfide is used. The amine group is then formylated with a mixture of formic acid and acetic anhydride without racemization, and the resulting compound is converted to optically pure 4-benzyloxy-3-formamidostyrene oxide with a base such as aq. NaOH or K2CO3 in an alcohol solvent or solvent mixture such as MeOH/THF. The epoxide obtained can be purified by recrystallization from an inert organic solvent or solvent mixture, preferably from EtOAc/heptane or toluene/heptane.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[Cl:21][C:22]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:23]=1[CH:24]=[O:25]>>[CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH:24]([C:23]3[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:22]=3[Cl:21])[OH:25])[C:8]2=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CCCN1C1CCCCC1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: O=C1C(C(O)c2ccc(Cl)cc2Cl)CCN1C1CCCCC1
Yield: 51.6 %

Procedure:
Using the procedure to synthesize Example 1 and using reagents 1-cyclohexyl-pyrrolidin-2-one (500 mg, 3.0 mmol), LDA (2.0 M, 1.8 mL, 3.6 mmol) and 2,4-dichlorobenzaldehyde (630 mg, 3.6 mmol) affords 530 mg (53%) of the title compound as a white solid. Separate the diastereomers over silica gel (30% ethyl acetate in hexanes) Isomer 1 (Example 78): (25%) Mass spectrum (apci) m/z=342.0 (M+H). HPLC (5 to 95) Rt (Purity at 220 mn)=3.77 min (98%). Isomer 2 (Example 79): (28%) Mass spectrum (apci) m/z=342.0 (M+H). HPLC (5 to 95) Rt (Purity at 220 nm)=3.52 min (100%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]=1.F[C:27]1[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=1)/[CH:30]=[CH:31]/B(O)O.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>C1COCC1.CCOC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:22]([O:21][C:4]1[CH:3]=[C:2](/[CH:31]=[CH:30]/[C:29]2[CH:35]=[CH:36][CH:37]=[CH:27][CH:28]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)Oc1cc(Br)c2cc(C(=O)c3ccc(Cl)cc3)ccc2n1
Reactant: OB(O)/C=C/c1cccc(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)Oc1cc(/C=C/c2ccccc2)c2cc(C(=O)c3ccc(Cl)cc3)ccc2n1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
A mixture of (4-bromo-2-(tert-butoxy)quinolin-6-yl)(4-chlorophenyl)methanone (157 mg, 0.375 mmol), (E)-(3-fluorostyryl)boronic acid (105.8 mg, 0.637 mmol), Pd(OAc)2 (8.42 mg, 0.0375 mmol), SPhos (30.79 mg, 0.0375 mmol), and K3PO4.H2O (159 mg, 0.75 mmol) in anhydrous THF (2.5 mL) was stirred at 30° C. overnight. The reaction was diluted with EtOAc and water. The organics were concentrated and purified by silica column chromatography (20% EtOAc/heptanes) to yield (E)-(2-(tert-butoxy)-4-styrylquinolin-6-yl)(4-chlorophenyl)methanone. (ES, m/z) [M-tBu]+ 404, 405, 407
Reaction SMILES: [OH:1][CH:2]([CH3:11])/[CH:3]=[C:4](\[CH3:10])/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:12]([O:14][P:15](Cl)([O:17][CH2:18][CH3:19])=[O:16])[CH3:13]>N1C=CC=CC=1>[CH2:12]([O:14][P:15]([O:17][CH2:18][CH3:19])([O:1][CH:2]([CH3:11])/[CH:3]=[C:4](\[CH3:10])/[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:16])[CH3:13]
Reactant: CCOC(=O)/C(C)=C/C(C)O
Reactant: CCOP(=O)(Cl)OCC
Solvent: c1ccncc1
Product: CCOC(=O)/C(C)=C/C(C)OP(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
29 (rac-Ethyl (2E)-4-hydroxy-2-methylpent-2-enoate) (0.99 g, 6.0 mmol) is dissolved in pyridine (1.6 ml) and cooled to 0° C. Diethylchlorophosphate (1.1 ml, 7.5 mmol) is added under stirring over 20 min at ≧3° C. After 4.5 hours of additional stirring at 0° C., the reaction mixture is quenched with 1 M H2SO4 (100 ml) and extracted with tBuOMe (300 ml) successively. The organic phase is washed with brine (50 ml), saturated NaHCO3 (50 ml) and brine (50 ml). The organic phase is dried with Na2SO4 and evaporated under reduced pressure at 40° C. The residue is purified by flash chromatography (AcOiPr:heptane fraction 50:50 to 60:40) to yield 17 (rac-Ethyl (2E)-4-(diethoxyphosphinyloxy)-2-methylpent-2-enoate) (1.56 g, 88%) as a yellowish oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([C:20]2[CH:21]=[CH:22][C:23]3[O:27][C:26]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[C:25]([C:35](=[O:38])[NH:36][CH3:37])[C:24]=3[CH:39]=2)[C:18]=1[CH3:19])[C:12]([O:14]C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([C:20]2[CH:21]=[CH:22][C:23]3[O:27][C:26]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)=[C:25]([C:35](=[O:38])[NH:36][CH3:37])[C:24]=3[CH:39]=2)[C:18]=1[CH3:19])[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)OC)cc(OCc4ccccc4)c3C)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)cc(OCc4ccccc4)c3C)cc12
Temperature: 60 °C

Procedure:
To a mixture of methyl 3-(benzyloxy)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoate (0.3 g, 0.57 mmol, 1 eq) in a 1:1 mixture of MeOH/THF at ambient temperature was added 5 eq. of NaOH, and the resulting mixture was heated to 60° C. for 5 h. The mixture was cooled to ambient temperature and then cooled in ice-water bath. The reaction mixture was acidified with 1.5 N HCl and then concentrated. The mixture with white precipitates was diluted with water and filtered to get the solid. It is further washed with water and dried in vacuum. Yield: 0.2 g (70%). 1H NMR (400 MHz, DMSO-d6): δ 2.19 (s, 3H), 2.82-2.83 (d, 3H, J=4.56 Hz), 5.27 (s, 2H), 7.34-7.46 (m, 6H), 7.50-7.55 (m, 4H), 7.60 (s, 1H), 7.75-7.77 (d, 1H, J=8.44 Hz), 7.99-8.03 (m, 2H), 8.49-8.50 (d, 1H), 13.0 (s, 1H). LCMS: (ES+) m/z=510 (M+H). Ascentis Express C18 (5.0×2.1-2.7 μm) Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH Mphase B: 98% MeCN-2% H2O-10 mM NH4COOH
Reaction SMILES: C(C1C=C(C2ON=C(C3C=C(C)C(OCC(O)CNC(=O)CO)=C(C)C=3)N=2)C=CC=1)=O.[CH2:32]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][C:42]=1[CH:43]=[O:44])[C:37]([OH:39])=O)[CH3:33].[CH2:45]([C:47]1[CH:62]=[C:61]([C:63](=[NH:66])[NH:64]O)[CH:60]=[C:59]([CH3:67])[C:48]=1[O:49][CH2:50][C@@H:51]([OH:58])[CH2:52][NH:53][C:54](=[O:57])[CH2:55][OH:56])[CH3:46]>>[CH2:45]([C:47]1[CH:62]=[C:61]([C:63]2[N:66]=[C:37]([C:36]3[CH:40]=[CH:41][C:42]([CH:43]=[O:44])=[C:34]([CH2:32][CH3:33])[CH:35]=3)[O:39][N:64]=2)[CH:60]=[C:59]([CH3:67])[C:48]=1[O:49][CH2:50][C@@H:51]([OH:58])[CH2:52][NH:53][C:54](=[O:57])[CH2:55][OH:56])[CH3:46]
Reactant: CCc1cc(C(=O)O)ccc1C=O
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Agent: Cc1cc(-c2noc(-c3cccc(C=O)c3)n2)cc(C)c1OCC(O)CNC(=O)CO
Product: CCc1cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)ccc1C=O
Yield: 49.8 %

Procedure:
The title compound (183 mg) is prepared in analogy to rac-N-(3-{4-[5-(3-formyl-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide starting from 3-ethyl-4-formyl-benzoic acid (140 mg, 0.786 mmol) and N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide (256 mg, 0.786 mmol). LC-MS**: tR=0.72 min; [M+1]+=468.25; 1H NMR (D6-DMSO): δ 1.23 (t, J=7.8 Hz, 3H), 1.28 (t, J=7.3 Hz, 3H), 2.36 (s, 3H), 2.70-2.78 (m, 3H), 3.19 (q, J=7.3 Hz, 2H), 3.23-3.29 (m, 1H), 3.40-3.48 (m, 1H), 3.71-3.81 (m, 2H), 3.84 (d, J=5.5 Hz, 2H), 3.94-4.00 (m, 1H), 5.31 (d, J=5.3 Hz, 1H), 5.56 (t, J=5.5 Hz, 1H), 7.71 (t, J=5.8 Hz, 1H), 7.82 (s, 2H), 8.09 (d, J=8.0 Hz, 1H), 8.19-8.24 (m, 2H), 10.38 (s, 1H).
Reaction SMILES: [O:1]=[C:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][O:9][C:10]2=[O:15])=[O:4].[H-].[Na+].Cl[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1.Cl>CN(C=O)C.C(OCC)(=O)C.O>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:5]([C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH2:8][O:9][C:10]3=[O:15])[C:3](=[O:4])[C:2](=[O:1])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:27][CH:28]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(Nc1cccc2c1COC2=O)C(=O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(C(=O)C(=O)c2ccccc2)c2cccc3c2COC3=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66 %

Procedure:
To a solution of 2-oxo-N-(1-oxo-1,3-dihydroisobenzofuran-4-yl)-2-phenylacetamide (5 g, 11.7 mmol) in DMF (48 mL) was added NaH (0.78 g, 19.5 mmol). The solution was stirring at room temperature for 1.5 hr, followed by the addition of 1-(chloromethyl)-4-methoxy-benzene (2.8 mL). After stirred at 30° C. overnight, the resulting mixture was added water and adjusted to pH=3-4 with 0.5 N aq. HCl. Then ethyl acetate was added, concentrated and filtered, the filtrate was washed by ethyl acetate, the combine ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by flash chromatography on silica gel to obtain the desired compound (4.7 g, yield 66%). LC-MS (ESI) m/z: 402 (M+1)+. 1H-NMR (400 MHz, DMSO-d) δ (ppm): 3.73 (s, 3H), 4.83-5.17 (m, 4H), 6.89-6.91 (d, J=8.8 Hz, 2H), 7.18-7.20 (m, 2H), 7.24-7.26 (m, 1H), 7.38-7.42 (t, 1H), 7.52-7.56 (m, 2H), 7.69-7.71 (m, 1H), 7.75-7.81 (m, 3H).
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]([O:16][C:17]([NH:19][C@H:20]([C:28]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([OH:34])=O)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN1CCOCC1.[CH3:45][C:46]1[C:51]([C:52]([OH:54])=[O:53])=[C:50]([NH:55][C:56](=[O:62])[C@H:57]([CH:59]([CH3:61])[CH3:60])[NH2:58])[CH:49]=[CH:48][CH:47]=1>CN(C)C=O.O1CCCC1>[CH2:9]([O:16][C:17]([NH:19][C@H:20]([C:28]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([NH:58][C@H:57]([C:56]([NH:55][C:50]1[CH:49]=[CH:48][CH:47]=[C:46]([CH3:45])[C:51]=1[C:52]([OH:54])=[O:53])=[O:62])[CH:59]([CH3:61])[CH3:60])=[O:34])=[O:29])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccc(NC(=O)[C@@H](N)C(C)C)c1C(=O)O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)[C@@H](NC(=O)[C@@H]2CCCN2C(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)C(C)C)c1C(=O)O
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
Isobutyl chloroformate (0.17 ml) was added to a tetrahydrofuran solution (3.5 ml) containing N-benzyloxycarbonyl-L-phenylalanyl-L-proline (523 mg) and N-methylmorpholine (0.15 ml) at -15° C., and the mixture was stirred for 0.5 hour. An N,N-dimethylformamide solution (5.5 ml) containing 6-methyl-2-(L-valylamino)benzoic acid (220 mg) and N-methylmorpholine (0.12 ml) was added dropwise to the obtained reaction mixture at -15° C., and the mixture was stirred at this temperature for 0.5 hour and then at room temperature for two hours. The reaction mixture was treated by the same procedures as in item (c) of Example 1 to obtain 2-(N-benzyloxycarbonyl-L-phenylalanyl-L-prolyl-L-valyl)amino-6-methylbenzoic acid (317 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=[CH:14]O)[C:11](=O)[CH2:10][CH:9]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:24][NH2:25]>CO>[C:1]([O:5][C:6]([N:8]1[CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][C:11]2[NH:24][N:25]=[CH:14][C:12]=2[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CC(=CO)C(=O)CC1c1ccccc1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2cn[nH]c2CC1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 51 (310 mg, 1.02 mmol) from the previous step was dissolved in MeOH (3 ml). Hydrazine monohydrate (0.1 ml, 2.04 mmol) was added to the solution and then stirred at room temperature for 1 hour. Solvent was removed under reduced pressure to afford a yellow gel as the desired product. LCMS 300.2 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14]([O:20]C4C=CC=CC=4)=[N:15][CH:16]=[N:17]3)=[CH:12][C:11]=2[O:27][CH3:28])[CH:5]=[CH:4][N:3]=1.Cl.C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:20])[NH:15][CH:16]=[N:17]3)=[CH:12][C:11]=2[O:27][CH3:28])[CH:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1OCc1ccnc(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc2c(=O)[nH]cnc2cc1OCc1ccnc(Cl)c1
Temperature: 85 °C
Yield: 71.9 %

Procedure:
A mixture of 7-((2-chloro-4-pyridyl)methoxy)-6-methoxy-4-phenoxyquinazoline (260 mg, 0.7 mmol) and 2M hydrochloric acid (15 ml) was heated at 85° C. for 2 hours. The mixture was allowed to cool and adjusted to pH6-7 with sodium hydrogen carbonate solution. The resulting precipitate was collected by filtration and dried to give 7-((2-chloro-4-pyridyl)methoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (160 mg, 76%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=2)[C:5]2[N:15]([CH2:27][C@H:28]3[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]3)[C:16]([CH:18]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=3)[OH:19])=[N:17][C:4]=2[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[N:17]=[C:16]([C:18]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=3)=[O:19])[N:15]([CH2:27][C@H:28]3[CH2:29][CH2:30][C@H:31]([CH3:34])[CH2:32][CH2:33]3)[C:5]2=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=2)[N:7]=1
Reactant: C[C@H]1CC[C@H](Cn2c(C(O)c3ncccc3F)nc3cc(Cl)nc(-c4cncc(Cl)c4)c32)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: C[C@H]1CC[C@H](Cn2c(C(=O)c3ncccc3F)nc3cc(Cl)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of {6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-2-yl}(3-fluoropyridin-2-yl)methanol (807 mg, 1.61 mmol) in dichloromethane (15 mL) was added Dess-Martin periodinane (2.7 g, 6.45 mmoL) at 0° C. Then reaction was gradually warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with dichloromethane (15 mL), quenched with aqueous saturated NaHCO3 solution (40 mL), and extracted with dichloromethane (2×30 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. Purification of the residue on a silica gel column (0 to 100% EtOAc/hexanes) afforded {6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-d]pyridin-2-yl}(3-fluoropyridin-2-yl)methanone. MS APCl calcd. for C25H22Cl2FN5O [M+H]+ 498. found 498.
Reaction SMILES: C([O:5][C:6](=[O:47])[C@H:7]([N:23]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]2[O:44][CH2:45][O:46][C:40]=2[CH:39]=1)[S:24]([C:27]1[C:32]([CH3:33])=[CH:31][C:30]([O:34][CH3:35])=[CH:29][C:28]=1[CH3:36])(=[O:26])=[O:25])[CH2:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>FC(F)(F)C(O)=O.C(Cl)Cl>[CH2:45]1[O:44][C:41]2[CH:42]=[CH:43][C:38]([CH2:37][N:23]([S:24]([C:27]3[C:32]([CH3:33])=[CH:31][C:30]([O:34][CH3:35])=[CH:29][C:28]=3[CH3:36])(=[O:25])=[O:26])[C@H:7]([CH2:8][NH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]3[CH:19]=[CH:20][CH:21]=[CH:22]3)=[O:11])[C:6]([OH:47])=[O:5])=[CH:39][C:40]=2[O:46]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CNC(=O)c2ccccc2-n2cccc2)C(=O)OC(C)(C)C)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CNC(=O)c2ccccc2-n2cccc2)C(=O)O)c(C)c1
Reaction time: 1.5 h
Yield: 113.8 %

Procedure:
A solution of tert-butyl-2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-[(2-pyrrol-1-yl)phenylcarbonylamino]-propionate (915 mg, 1.3 mmol) in 20% trifluoracetic acid-methylene chloride (15 ml) was stirred for 1 hour. Extra trifluoroacetic acid (0.5 ml) was added and stirring continued for 1.5 hours. The material was then condensed on the rotary evaporator and the residue was taken up in toluene (40 ml) and again condensed. This procedure was repeated twice (2×40 ml toluene, to remove traces of trifluoracetic acid) to provide 2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-[(2-pyrrol-1-yl)phenylcarbonylamino]-propionic acid as a golden tan solid (896 mg).
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:25]=[CH:24][C:11]2[NH:12][C:13]([C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][N:16]=3)=[N:14][C:10]=2[CH:9]=1)=[O:7])#[N:2].[N:26]([Sn](CCCC)(CCCC)CCCC)=[N+:27]=[N-:28].C(#N)C.O1CCCC1>C(O)(=O)C>[N:2]1[NH:26][N:27]=[N:28][C:1]=1[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:25]=[CH:24][C:11]2[NH:12][C:13]([C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][N:16]=3)=[N:14][C:10]=2[CH:9]=1)=[O:7]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#CCCNC(=O)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CC#N
Product: O=C(NCCc1nn[nH]n1)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Temperature: 25 °C

Procedure:
A stirred solution of 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2-cyano-ethyl)-amide [150 mg, Example 246(s)] and azidotributyltin (2 ml) was heated at 95° C. for 24 hours. The reaction was cooled to ambient temperature and stirred for 2 hours with acetonitrile (20 ml), tetrahydrofuran (10 ml) and acetic acid (20 ml). The reaction mixture was washed with iso-hexane (6×80 ml) and concentrated in vacuo. The residue was subjected to preparative HPLC to give 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid [2-(2H-tetrazol-5-yl)-ethyl]-amide (35.9 mg) as a brown solid.