Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[N:8]=2)[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([CH2:13][NH2:14])[CH:10]=[C:9]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:19][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1cc(-c2ccc(OC(F)(F)F)cc2)nc(N2CCOCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCc1cc(-c2ccc(OC(F)(F)F)cc2)nc(N2CCOCC2)c1
Temperature: 0 °C
Yield: 64.5 %

Procedure:
The nitrile 26D (2 g, 5.7 mmol) dissolved in 50 ml of diethyl ether was added dropwise to a mixture of LiAlH4 (434 mg, 2 equiv.) in diethyl ether (60 mL) stirred at 0° C. Then the mixture was stirred at room temperature overnight. The excess of LiAlH4 was destroyed by water addition at 0° C., the solid formed was filtered, washed with Et2O and the filtrate was dried over Na2SO4 and evaporated to dryness to obtain 1.3 g of the amine 27D as a yellow oil. Yield=65% 1HNMR (DMSO, 400 MHz) δ 3.30 (2H, bs), 3.51 (4H, m), 3.76 (6H, m), 6.80 (1H, s), 7.29 (1H, s), 7.42 (2H, d, J=8 Hz), 8.18 (2H, dd)
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13]O)=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:17])#[N:2].C1C=CC(P([N:32]=[N+:33]=[N-:34])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[N:32]([CH2:13][C:12]1[N:8]([CH2:7][C:6]2[CH:15]=[CH:16][C:3]([C:1]#[N:2])=[C:4]([F:17])[CH:5]=2)[CH:9]=[N:10][CH:11]=1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(Cn2cncc2CO)cc1F
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1ccc(Cn2cncc2CN=[N+]=[N-])cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1-(4-cyano-3-fluorobenzyl)-5-(hydroxymethyl)imidazole, as described above in Example 4, Step F, (103 mg, 0.45 mmol) in dry THF (1 mL), at 0° C., under argon, were added DPPA (147 mg, 0.53 mmol) then DBU (75 mg, 0.49 mmol). The mixture was allowed to warm to ambient temperature and then stirred for 3 hrs. The mixture was then partitioned between H2O (10 mL) and CH2Cl2 (20 mL). The aqueous layer was extracted further with CH2Cl2 (2×15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of CHCl3-1% MeOH −0.1% NH4OH to CHCl3-5% MeOH −0.5% NH4OH, to yield the titled product.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][N:9]=1>C(NCC)C.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][N:9]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Clc1ccc(Cl)nc1
Reactant: C#CCCCC
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: CCCCC#Cc1ccc(Cl)cn1
Yield: 87.8 %

Procedure:
9.0 ml (80 mmol) of 1-hexyne and 6.0 g (40 mmol) of 2,5-dichloropyridine in 80 ml of diethylamine are placed under argon, whereby a pale yellow solution results. Thereto there are added 0.40 g (1.5 mmol) of triphenylphosphine, 0.04 g (0.02 mmol) of copper-(I) iodide as well as 0.24 g (0.9 mmol) of palladium-dichloro-bis(triphenylphospine). The orange solution obtained is subsequently heated to reflux for 24 hours while stirring. Thereafter, the reaction mixture is cooled to 25° and evaporated at 40° under reduced pressure. The brown residue is then treated with 50 ml of ethanol and again evaporated. The crude product is filtered over 50 g of silica gel with 700 ml of hexane/toluene (1:1) and the eluate is evaporated at 50° under reduced pressure. The residue is subsequently distilled in a bulb tube at 190°/2600 Pa. There are obtained 6.8 g of 2-hexynyl-5-chloropyridine as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([NH2:51])[CH2:48][CH:49]=[CH2:50]>>[CH2:47]([NH:51][C:41](=[O:43])[CH2:40][CH:37]1[CH2:38][CH2:39][N:34]([C:32]([N:12]2[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[N:10][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][C:7]=2[O:44][CH2:45][CH3:46])=[O:33])[CH2:35][CH2:36]1)[CH2:48][CH:49]=[CH2:50]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: C=CCCN
Product: C=CCCNC(=O)CC1CCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with n-but-3-enylamine (Alfa) to give the title compound. LC-MS (ES+) 718 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][OH:7].[C:11]([Si:15](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:14])([CH3:13])[CH3:12].N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][O:7][Si:15]([C:11]([CH3:14])([CH3:13])[CH3:12])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCCc1cccc(Br)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCCc1cccc(Br)c1)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
3-Bromophenethyl alcohol was dissolved in 110 ml of N,N-dimethylformamide, and 16 ml of t-butyl chlorodiphenyl silane and 8.3 g of imidazole were added. After stirring was continued at room temperature overnight, the solution was diluted with ethyl acetate, and washed successively with 1N hydrochloric acid and saturated brine. After drying the organic layer over anhydrous magnesium sulfate, the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 22.1 g of [(3-bromophenethyl)oxy] (t-butyl)diphenyl silane in the 4:1 hexane-ethyl acetate fraction. Then, the obtained 22.1 g of [(3-bromophenethyl)oxy] (t-butyl) diphenyl silane was dissolved in 200 ml of tetrahydrofuran, and the mixture was cooled to −78° C. under nitrogen atmosphere. 37 ml of Butyl lithium (1.52 M solution in hexane) was added thereto, and the mixture was stirred for 30 minutes, and then 10 ml of 4-formylmorpholine was added. After stirring was continued at −78° C. for 1 hour, 1N-hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 17 g of the title compound in the 4:1 hexane-ethyl acetate fraction.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[C:12](\[C:15]2[CH:24]=[CH:23][C:18]3[N:19]([CH3:22])[CH:20]=[N:21][C:17]=3[CH:16]=2)/[CH2:13][CH3:14])=[CH:7][CH:6]=1.[CH3:32][NH2:33]>CO>[CH3:22][N:19]1[C:18]2[CH:23]=[CH:24][C:15](/[C:12](/[CH2:13][CH3:14])=[C:11](/[C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)\[C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:33][CH3:32])=[CH:6][CH:7]=3)=[CH:16][C:17]=2[N:21]=[CH:20]1
Reactant: CN
Reactant: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2c(c1)ncn2C
Solvent: CO
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCNC)cc1)c1ccc2c(c1)ncn2C
Temperature: 85 °C

Procedure:
To a stirred solution of (Z)-4-(1-(4-(2-chloroethoxy)phenyl)-2-(1-methyl-1H-benzo[d]imidazol-5-yl)but-1-enyl)phenol (20 mg, 1.0 eq) in 10 mL MeOH was added 5 mL CH3NH2 (aq) and heated at 85° C. for 72 h. The organic solvent was removed in vacuo, water was added to the residue, and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the desired (Z)-product. 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.60 (s, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 2H), 7.01 (d, J=9.2 Hz, 1H), 6.80 (d, J=8.4 Hz, 2H), 6.75 (d, J=8.8 Hz, 2H), 6.45 (d, J=8.4 Hz, 2H), 3.89 (t, J=5.2 Hz, 2H), 3.80 (s, 3H), 2.88 (t, J=5.2 Hz, 2H), 2.52 (q, J=7.2 Hz, 2H), 2.46 (s, 3H), 0.88 (t, J=7.2 Hz, 3H); m/z=428[M+1]+.
Reaction SMILES: [CH:1]([O-])([O-])OCC.[CH3:7][C:8]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=[N:23][O:24][CH3:25])[C:19]([NH:21][NH2:22])=[O:20]>O>[CH3:25][O:24][N:23]=[C:18]([C:19]1[O:20][CH:1]=[N:22][N:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][O:10][C:9]1[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:8]=1[CH3:7]
Reactant: CON=C(C(=O)NN)c1ccccc1COc1cc(C)ccc1C
Reactant: CCOC([O-])[O-]
Solvent: O
Product: CON=C(c1nnco1)c1ccccc1COc1cc(C)ccc1C
Yield: 19.8 %

Procedure:
Ethyl orthoformate (2 ml) was added to 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetohydrazide (0.49 g, 1.5 mmol), and the mixture was stirred under reflux for 4 hours. After completion of the reaction, water (100 ml) was added, and the mixture was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give 2-(2,5-dimethylphenoxymethyl)phenyl 1,3,4-oxadiazol-2-yl ketone O-methyloxime (0.10 g, 19.8%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=[O:13].[Br:14]Br.C(Cl)Cl>C(OCC)C>[Br:14][CH:7]1[C:6](=[O:13])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[O:9][CH2:8]1
Reactant: COc1ccc2c(c1)C(=O)CCO2
Reactant: BrBr
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc2c(c1)C(=O)C(Br)CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 6-methoxy-4-chromanone (35 g) in ethyl ether (1.6 liters) at 5°-10° C. was added dropwise over 30 minutes 10.6 ml of bromine. The mixture was stirred at 5°-10° C. for 30 minutes and then allowed to warm to room temperature. After 2 hours tlc (CH2Cl2) indicated formation of less polar products and only a trace of starting material remaining. The reaction mixture was washed with water (1 liter), saturated NaHCO3 (500 ml), and brine (500 ml), dried over MgSO4, and concentrated in vacuo to a yellow solid. The crude product was purified by silica gel flash column chromatography on 2.4 Kg fine silica gel, eluting with a gradient system consisting of 3:1 hexanes/dichloromethane followed by 2:1 hexanes/dichloromethane and finally 30% hexanes/dichloromethane. This afforded title product as a yellow solid in 80% yield.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:7]([CH3:8])[NH:6][CH2:5][CH2:4][NH:3]1.CS(O)(=O)=O.C([O-])(=O)C.[K+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O.C(O)C>[CH3:1][C@H:2]1[C@@H:7]([CH3:8])[NH:6][CH2:5][CH2:4][N:3]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@H]1NCCN[C@@H]1C
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C[C@H]1NCCN(C(=O)OCc2ccccc2)[C@H]1C
Temperature: 20 °C
Yield: 48.2 %

Procedure:
A 100 mL, three-necked round-bottom flask was charged with cis-2,3-dimethylpiperazine (Helvetica Chimica Acta, 1994, 77, 1057-64) (1.781 g, 15.6 mmol). The flask was cooled in an ice bath, and a solution of methanesulfonic acid (2.02 mL, 31.2 mmol) in 1.4 mL of water was added slowly, maintaining the temperature below 40° C. The solution was cooled to 20° C., and 2 mL of ethanol was added. The pH was adjusted to 4 with 60% aqueous potassium acetate, and then benzyl chloroformate (2.08 mL, 14.8 mmol in 1 mL of THF) and potassium acetate solutions were simultaneously added dropwise with adjustment of the rate to maintain the reaction solution at pH 4, with cooling to maintain the temperature at 25° C. After the mixture was stirred an additional hour, the organic solvents were removed and the remaining aqueous solution was washed with ethyl acetate. The ethyl acetate wash was extracted with 1 M HCl twice to recover the desired product. The acid extracts were combined with the original aqueous solution, and the pH was adjusted to 11 by the addition of 6 N NaOH, with cooling to maintain temperature below 40° C. The aqueous solution was extracted with ethyl acetate, and the combined extracts were dried over magnesium sulfate and concentrated in vacuo to provide phenylmethyl cis-2,3-dimethyl-1-piperazinecarboxylate (enantiomeric mixture) as a yellow oil (1.77 g, 46%). LCMS: (M+H)+: 249.1.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][CH2:19][C:18]=1[CH3:25])(=[O:3])[CH3:2].O.C([O:31]O)(C)(C)C>C1CCCCC1.O.[Ru](Cl)(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][C:19](=[O:31])[C:18]=1[CH3:25])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OO
Reactant: CC(=O)OCCCCCCCCCCCCC1=C(C)CCCC1(C)C
Agent: Cl[Ru](Cl)Cl
Solvent: O
Solvent: C1CCCCC1
Product: CC(=O)OCCCCCCCCCCCCC1=C(C)C(=O)CCC1(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1-(12-acetoxydodecyl)-2,6,6-trimethyl-1-cyclohexene (321 mg) in cyclohexane (6 ml) was added water (0.8 ml), ruthenium trichloride hydrate (1.3 mg) and 70% t-BuOOH (1.26 ml). The solution was stirred at room temperature for 6 hours, filtered through a pad of celite and poured into a solution of 10% Na2SO4. The solution was extracted with ethanol, washed with brine, dried with MgSO4 and distilled off under reduced pressure. The residue was purified by chromatography over silica gel to give 3-(12-acetoxydodecyl)-2,4,4-trimethyl-2-cyclohexen-1-one as a colorless oil (227 mg). TLC: (hexane-AcOEt: 3-7) Rf=0.68
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([C:17]3[NH:18][CH:19]=[CH:20][N:21]=3)[C:6]=2[C:22]=1[F:23].[CH3:24][O:25][C:26]1[CH:43]=[C:42]([CH3:44])[C:41](B2OC(C)(C)C(C)(C)O2)=[CH:40][C:27]=1[C:28]([NH:30][C:31]1([C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:33][CH2:32]1)=[O:29].C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:23][C:22]1[C:6]2[C:7]([C:17]3[NH:18][CH:19]=[CH:20][N:21]=3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[O:9][C:5]=2[CH:4]=[CH:3][C:2]=1[C:41]1[C:42]([CH3:44])=[CH:43][C:26]([O:25][CH3:24])=[C:27]([CH:40]=1)[C:28]([NH:30][C:31]1([C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:32][CH2:33]1)=[O:29]
Reactant: COc1cc(C)c(B2OC(C)(C)C(C)(C)O2)cc1C(=O)NC1(c2ncccn2)CC1
Reactant: Fc1ccc(-c2oc3ccc(Cl)c(F)c3c2-c2ncc[nH]2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C)c(-c2ccc3oc(-c4ccc(F)cc4)c(-c4ncc[nH]4)c3c2F)cc1C(=O)NC1(c2ncccn2)CC1
Temperature: 90 °C
Yield: 4.6 %

Procedure:
To a mixture of 2-(5-chloro-4-fluoro-2-(4-fluorophenyl)benzofuran-3-yl)-1H-imidazole (0.1 g, 0.302 mmol) and 2-methoxy-4-methyl-N-(1-(pyrimidin-2-yl)cyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.186 g, 0.454 mmol) in dioxane (2 ml) in a sealed tube was added water (0.1 ml) and sodium carbonate (0.080 g, 0.756 mmol). The resulting mixture was degassed for 10 min, added with palladium (II) acetate (6.79 mg, 0.030 mmol) followed by 2-(dicyclohexyl-phosphino)-2′,4′,6′-triisopropylbiphenyl (0.144 g, 0.302 mmol) under a N2 atmosphere. The resulting mixture was again degassed for 5 minutes. The reaction mixture was then heated at 90° C. The reaction mixture was diluted with ethyl acetate, washed with water, dried over Na2SO4, filtered and concentrated. The crude product was purified by using 40 g combiflash silica column with 6% methanol in chloroform as an eluent. The desired fractions were collected and concentrated to give the titled product (8 mg, Yield: 4.6%). 1H NMR (400 MHz, CD3OD): δ 8.65 (d, J=4.8, 2H), 7.88 (s, 1H), 7.69-7.65 (m, 2H), 7.56 (d, J=8.4, 1H), 7.31-7.27 (m, 3H), 7.24-7.16 (m, 4H), 4.08 (s, 3H), 2.28 (s, 3H), 1.81-1.78 (m, 2H), 1.52-1.49 (m, 2H). 19F NMR (376.6 MHz, DMSO-d6) −113.33, −124.62. LCMS: (ES+) m/z=578.2 (M+H)+; Column—Ascentis Express C8 (5×2.1 mm-2.7 μm); Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH; Mphase B: 98% MeCN-2% H20-10 mM NH4COOH; Flow=1 ML/MIN;
Reaction SMILES: C(O[C:9]([NH:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15])=[O:10])C1C=CC=CC=1.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:34]C(=O)[C:32]3[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=3[N:30]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>>[NH2:15][C:14]1[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:32]2[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=2[NH:30][C:29](=[O:34])[C:26]2[CH:25]=[CH:24][C:23]([C:19]([CH3:21])([CH3:20])[CH3:22])=[CH:28][CH:27]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)c1ccc(-c2nc3ccccc3c(=O)o2)cc1
Reactant: Nc1cccc(NC(=O)OCc2ccccc2)c1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2cccc(N)c2)cc1
Yield: 6.9 %

Procedure:
By methods substantially equivalent to those described in Example 96, the title compound (40 mg, 9% for two steps) was prepared from m-(benzyloxycarbonylamino)aniline 1.5 mmol) and 2-(4-tert-butylphenyl)-4H-3,1-benzoxazin-4-one (1.5 mmol).
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45](Cl)=[O:46]>>[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45]([O:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:29][CH2:30]4)(=[O:26])=[O:27])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1)=[O:46]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)NC1CCCOCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: COc1cccc(C(=O)OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCOCCCC(NC(=O)OC(C)(C)C)C(=O)N3C2)c1
Yield: 45.4 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-10-oxatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 3-methoxybenzoyl chloride (74 μL, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 56 mg (45%) of 18-(3-methoxybenzoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-10-oxatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 98.7% pure (HPLC), MS m/z 703 (M−H)−, HRMS: calcd. 705.2806 and found 705.2782 (M+H)+, mp 149-151° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][CH:6]=1)=[O:4].[N-:15]=[N+:16]=[N-:17].[Na+].[Na+].[Cl-]>CC(C)=O>[N:15]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][CH:6]=1)=[O:4])=[N+:16]=[N-:17]
Reactant: CC(C)(C)c1ccc(C(=O)CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)c1ccc(C(=O)CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a solution of the product of Example 1A (985 mg, 3.86 mmol) in 45 mL acetone was added NaN3 (0.505 g, 7.07 mmol), and the mixture stirred overnight at room temperature. The reaction mixture was poured into saturated NaCl solution and extracted with dichloromethane. The extracts were washed with saturated NaCl solution, dried over Na2SO4, and concentrated in vacuo to afford the title compound as a yellow oil (715 mg, 85%). 1H NMR (DMSO-d6) δ 7.88 (d, 2H, J=8.5 Hz), 7.57 (d, 2H, J=8.5 Hz), 4.86 (s, 2H), 1.31 (s, 9H); MS (ESI+) m/z 218 (M+H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:12])=[CH:7][CH:8]=[C:9]([F:11])[CH:10]=2)[CH2:3][CH2:2]1.[C:13]([O:17][C:18]([NH:20][C@@H:21]([CH3:25])[C:22](O)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:13]([O:17][C:18](=[O:19])[NH:20][C@H:21]([C:22](=[O:23])[NH:12][C:6]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:5]=1[NH:4][CH:1]1[CH2:3][CH2:2]1)[CH3:25])([CH3:14])([CH3:15])[CH3:16]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(F)cc1NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1NC1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.1 %

Procedure:
A mixture of N2-cyclopropyl-4-fluorobenzene-1,2-diamine (0.724 g, 4.4 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (0.91 g, 4.8 mmol), HOAt (0.65 g, 4.8 mmol), 4-methylmorpholine (1.1 mL, 9.7 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.92 g, 4.8 mmol) in DCM (15 mL) was stirred at RT for 18 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic fraction was washed with brine, dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) to afford [(S)-1-(2-cyclopropylamino-4-fluorophenylcarbamoyl)ethyl]carbamic acid tert-butyl ester as a brown oil (1.07 g, 72%). LCMS (Method B): RT 3.40 min [M+H]+ 338.2. 110180243
Reaction SMILES: [C:1]([C:3]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:4]=1[NH2:5])#[N:2].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>CCCCCC>[Br:10][C:8]1[CH:7]=[CH:6][C:4]([N:5]=[CH:13][N:14]([CH3:16])[CH3:15])=[C:3]([C:1]#[N:2])[CH:9]=1
Reactant: N#Cc1cc(Br)ccc1N
Reactant: COC(OC)N(C)C
Solvent: CCCCCC
Product: CN(C)C=Nc1ccc(Br)cc1C#N
Yield: 85.3 %

Procedure:
59 g (300 mmol) of 2-cyano-4-bromoaniline are suspended in 35 ml of dimethylformamide dimethyl acetal (780 mmol) and heated under reflux for 1.5 h. The resulting mixture is cooled and then 300 ml of hexane are added. The resulting solid is filtered off and washed with hexane. 64.5 g (85%) of the desired product are obtained.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[CH:41]=[C:42]([CH:48]=[CH:49][CH:50]=1)[CH2:43][NH:44][C:45](=[O:47])[CH3:46]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:49]2[CH:50]=[CH:40][CH:41]=[C:42]([CH2:43][NH:44][C:45](=[O:47])[CH3:46])[CH:48]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(=O)NCc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)NCc1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Yield: 44.5 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (3.30 g), N-(3-bromobenzyl)acetamide (1.05 g) and tetrakis(triphenylphosphine)palladium(0) (0.18 g), the title compound (1.24 g) was obtained as a pale-yellow amorphous powder.