Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([Br:26])[CH:17]=3)[C:11]=1[C:12]([NH:14]O)=[NH:13])=[CH:8][CH:7]=[C:6]1[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=21.C(N(CC)CC)C.[Cl:38][CH2:39][C:40](Cl)=[O:41].[O:43]1CCCC1>O>[NH2:1][C:2]1[O:3][C:4]2[C:9]([C:10]([OH:43])([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([Br:26])[CH:17]=3)[C:11]=1[C:12]([NH:14][C:40](=[O:41])[CH2:39][Cl:38])=[NH:13])=[CH:8][CH:7]=[C:6]1[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=21
Reactant: C1CCOC1
Reactant: O=C(Cl)CCl
Reactant: COc1cc(C2C(C(=N)NO)=C(N)Oc3c2ccc2ccccc32)cc(Br)c1OC
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(C2(O)C(C(=N)NC(=O)CCl)=C(N)Oc3c2ccc2ccccc32)cc(Br)c1OC

Procedure:
2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-N-hydroxy-4H-benzo[h]chromene-3-carboxamidine (21) (118 mg, 0.25 mmol) and triethylamine (35 ml, 0.25 mmol) are taken in 10 ml tetrahydrofuran at −5° C. and is charged with chloroacetyl chloride (23 mg, 0.25 mmol) by drop wise addition under strong stirring. The reaction mixture is then stirred allowing to come to room temperature under LC-MS control and is stirred further at room temperature till the reaction is complete. The reaction mixture is diluted with water to about 50 ml and stirred for 2 h at room temperature. Thus resulting precipitates are separated by filtration, washed well with water and is dried under high vacuum to get solids of the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][C:11]1[C:17](Cl)=[CH:16][C:14]([NH2:15])=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=1.[C:22](=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:10][C:11]1[C:17]([O:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[CH3:22])=[CH:16][C:14]([NH2:15])=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: Oc1ccc(F)cc1F
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1Oc1cc(N)c([N+](=O)[O-])cc1Cl
Temperature: 90 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
To a solution of 2,4-difluorophenol (1.9 g, 14.61 mmol) in DMSO (20 ml) was added 4,5-dichloro-2-nitroaniline (3 g, 14.49 mmol) and potassium carbonate (4 g, 28.94 mmol) with stirring overnight at 90° C. Then the reaction was quenched with water (200 ml) and extracted with ethyl acetate (3×100 ml) and the organic layers combined and dried over anhydrous magnesium sulfate. The organic layers were concentrated under vacuum to give a residue, which was purified by a silica gel column with 2%˜5% ethyl acetate in petroleum ether to produce 4-chloro-5-(4-fluoro-2-methylphenoxy)-2-nitroaniline as a yellow solid (1.3 g, 30%). Next, to a solution of 4-chloro-5-(2,4-difluorophenoxy)-2-nitroaniline (1.3 g, 4.32 mmol) in ethanol (20 ml) was added hydrogen chloride (conc. 1 ml) followed by the addition of Zn powder (1.7 g, 25.92 mmol) in portions at room temperature. The resulting solution was stirred for 4 h at 85° C. The resulting mixture was concentrated under vacuum and dissolved in water (150 ml), adjusted pH to 8 with aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (3×100 ml), dried and concentrated under reduced pressure to give a residue, which was purified by a silica gel column with 10%˜20% ethyl acetate in petroleum ether to produce 4-chloro-5-(2,4-difluorophenoxy)benzene-1,2-diamine as a light yellow solid (600 mg, 51%). Finally, a solution of 4-chloro-5-(2,4-difluorophenoxy)benzene-1,2-diamine (100 mg, 0.37 mmol) in hydrogen chloride (conc. 2 ml) and TFA (10 ml) was stirred overnight at 80° C. The solution was quenched with water (100 ml), adjusted pH value of the solution to 7 with aqueous sodium bicarbonate and extracted with ethyl acetate (3×50 ml) and the organic layers combined and dried over anhydrous magnesium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 5%˜10% ethyl acetate in petroleum ether to produce 5-chloro-6-(2,4-difluorophenoxy)-2-(trifluoromethyl)-1H-1,3-benzodiazole as a white solid (73.5 mg, 57%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=O)[C:11]([CH3:15])([CH3:14])[CH2:10][C@H:9]1[C:16]([O:18]C(C)(C)C)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([BH-](CC)CC)C.[Li+].C([SiH](CC)CC)C.B(F)(F)F.O1[CH2:46][CH2:45][CH2:44]C1>>[C:45]([C@@:9]1([C:16]([OH:18])=[O:17])[CH2:10][C:11]([CH3:14])([CH3:15])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([CH3:44])([CH3:46])[CH3:23]
Reactant: CC(C)(C)OC(=O)[C@@H]1CC(C)(C)C(=O)N1C(=O)OC(C)(C)C
Reactant: CC[BH-](CC)CC
Reactant: C1CCOC1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: [Li+]
Product: CC1(C)CN(C(=O)OC(C)(C)C)[C@@](C(=O)O)(C(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl N-tert-butoxycarbonyl-4,4-dimethylpyroglutamate (2.0 mmol) in tetrahydrofuran (5 mL) stirring at −78° C., was added a 1M solution of lithium triethylborohydride in tetrahydrofuran (2.4 mL, 2.4 mmol) dropwise over 5 minutes. After 30 minutes, the cooling bath was removed and saturated aqueous sodium bicarbonate (5 mL) was added. The reaction mixture was immersed in an ice/water bath and 30% aqueous hydrogen peroxide (10 drops) was added. The solution was stirred for 20 minutes at 0° C., then the reaction mixture was concentrated in vacuo to remove the tetrahydrofuran. The aqueous solution was diluted with water (10 mL) and extracted with dichloromethane (3×40 mL). The organic layers were dried (Na2SO4), filtered and concentrated. The residue was dissolved in dichloromethane (20 mL) and triethylsilane (310 μL, 2.0 mmol), then cooled to −78° C. and boron trifluoride diethyletherate (270 μL, 2.13 mmol) was added dropwise. Stirring was continued for 30 minutes, at which time additional triethylsilane (310 μL, 2.0 mmol) and boron trifluoride diethyletherate (270 μL, 2.13 mmol) were added. After stirring at −78° C. for an additional two hours, the cooling bath was removed and saturated aqueous sodium bicarbonate (4 mL) was added. After 5 minutes the mixture was extracted with dichloromethane (3×40 mL). The organic layers were dried (Na2SO4), filtered and concentrated to give Boc-Pro(4,4-dimethyl)-OtBu.
Reaction SMILES: C[O:2][C:3](=[O:58])[CH2:4][NH:5][C:6](=[O:57])[C@H:7]([NH:11][C:12](=[O:56])[C@H:13]([NH:21][C:22](=[O:55])[C@H:23]([NH:25][C:26](=[O:54])[CH2:27][C@@H:28]([OH:53])/[CH:29]=[CH:30]/[CH2:31][CH2:32][S:33][C:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH3:24])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:8]([CH3:10])[CH3:9].[Li+].[OH-].C(Cl)(Cl)Cl.Cl>C1COCC1.O>[OH:53][C@@H:28](/[CH:29]=[CH:30]/[CH2:31][CH2:32][S:33][C:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:27][C:26]([NH:25][C@H:23]([CH3:24])[C:22]([NH:21][C@H:13]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:12]([NH:11][C@H:7]([CH:8]([CH3:9])[CH3:10])[C:6]([NH:5][CH2:4][C:3]([OH:58])=[O:2])=[O:57])=[O:56])=[O:55])=[O:54]
Reactant: COC(=O)CNC(=O)[C@H](NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)C[C@@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)[C@@H](NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)C[C@@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCC(=O)O
Yield: 42.4 %

Procedure:
To a solution of 13 (190 mg, 0.236 mmol) in THF (4 mL) was added a solution of LiOH (8.48 mg, 0.354 mmol) in H2O (1 mL) at 0° C. After stirring for 1 h CHCl3 (60 mL) was added to the solution followed by 1M HCl (10 mL). The layers were separated and the aqueous phase washed with CHCl3 (2×10 mL). The organic layers were combined, washed with brine, dried with MgSO4 and concentrated in vacuo. The crude material was then purified by flash column chromatography on silica gel (eluent 2% MeOH/CH2Cl2) to give 14 (80 mg, 0.1 mmol, 43%) as a pale yellow solid: Rf 0.21 AcOH/MeOH/CH2Cl2/(1:4:95).
Reaction SMILES: [C:1]([O:16]CC1C=CC=CC=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O-:14])=[O:13].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:46][CH2:47][C@@H:48]([C@H:50]([C@@H:52]([C@@H:54]([CH2:56][OH:57])[OH:55])[OH:53])[OH:51])[OH:49]>CN(C=O)C.O>[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([NH:46][CH2:47][C@@H:48]([C@H:50]([C@@H:52]([C@@H:54]([CH2:56][OH:57])[OH:55])[OH:53])[OH:51])[OH:49])=[O:16])([OH:14])=[O:13]
Reactant: NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C([O-])CCCCCCCCCCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCCCCCCCCCC(=O)NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Monobenzyl dodecanedioate (530 mg, 1.7 mmol) was dissolved in 10 mL of DMF, to which EDC (N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride) (325 mg, 1.7 mmol) and HOBt (1-hydroxybenzotriazole) (230 mg, 1.7 mmol) were added. The mixture was stirred at room temperature for one hour and then D-glucamine (380 mg, 1.9 mmol) was added. The mixture was stirred at room temperature overnight, poured into 50 mL water, agitated and filtered to give the desired amide, of formula IIa in 95% yield. NMR (DMSO-D-6)7.70(brm, 1H), 7.30(m, 5H), 5.07(s, 2H), 4.73(d, 1H, J=4.5 Hz), 4.44(d, 1H, J=5.4 Hz), 4.36(d, 1H, J=6.0 Hz), 4.32 (t, 1H, J=5.7 Hz), 4.24(d, 1H, J=6.6 Hz), 3.58–3.52(m, 3H), 3.50–3.40(m, 3H), 3.21(m, 1H), 3.00(m, 1H), 2.33(t, 2H, J=7.2 Hz), 2.05(t, 2H, J=7.2 Hz), 1.50(m, 4H), 1.22(m, 12H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CCN(C(C)C)C(C)C.CN(C(O[N:28]1[N:36]=N[C:30]2C=CC=C[C:29]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C[O:45]CC1>>[C:29]([NH:28][NH:36][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=1)(=[O:45])[CH3:30]
Reactant: O=C(O)c1cccc(I)c1
Reactant: C1CCOC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NNC(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 3-iodobenzoic acid (2.0 g, 8.06 mmol) in 60 ml of THF there are added, in succession, DIPEA (1.83 ml, 10.48 mmol) and TBTU (2.59 g, 8.06 mmol). The reaction mixture is stirred overnight at ambient temperature. 1.19 g (16.12 mmol) of acetyl hydrazide are added and the reaction mixture is heated at reflux for 30 hours. After evaporation to dryness, the residue is taken up in water with a small amount of CH2Cl2; a thick precipitate forms, which is filtered off to yield the expected product.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:9]=2)[N:4]([CH3:30])[C:3]=1[C:31](O)=[O:32].Cl.[CH:35]([NH:38][C:39](=[O:48])[C@H:40]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH2:41])([CH3:37])[CH3:36].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:35]([NH:38][C:39](=[O:48])[CH:40]([NH:41][C:31]([C:3]1[N:4]([CH3:30])[C:5]2[C:10]([C:2]=1[Cl:1])=[CH:9][C:8]([NH:11][C:12]([C:14]1[C:15]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=3)=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:13])=[CH:7][CH:6]=2)=[O:32])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:37])[CH3:36]
Reactant: Cn1c(C(=O)O)c(Cl)c2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Reactant: CC(C)NC(=O)[C@@H](N)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)NC(=O)C(NC(=O)c1c(Cl)c2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2n1C)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 86.3 %

Procedure:
The product from step (e) (292.5 mg, 0.619 mmol), (S)-N-isopropyl-2-phenylglycinamide hydrochloride salt (182.1 mg, 0.797 mmol), PyBroP (415.8 mg, 0.865 mmol) were suspended in anhydrous CH2Cl2 (6 ml), followed by the addition of DIEA (0.36 ml, 2.07 mol). The reaction mixture was stirred at room temperature for 3.5 h. The product was purified by flash chromatography using 30:70 of hexane:EtOAc to afford 345.5 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10](OCl)(=[O:14])[CH2:11][CH2:12][CH3:13]>>[C:10]([O:9][C:3]1[C:2]([Cl:1])=[CH:7][NH:6][C:5](=[O:8])[CH:4]=1)(=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC(=O)OCl
Reactant: O=c1cc(O)c(Cl)c[nH]1
Product: CCCC(=O)Oc1cc(=O)[nH]cc1Cl
Yield: 12.8 %

Procedure:
The general procedure of Example 3 was followed using 2.00 g of 5-chloro-4-hydroxy-2-pyridone and 2.20 g of butanoyloxy chloride, thereby producing 0.38 g of the title compound in a yield of 13%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][C:13]1[C:14]([NH2:18])=[N:15][NH:16][CH:17]=1.O=[C:20]([C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)[CH2:21][C:22](OCC)=[O:23]>C(O)(=O)C>[CH3:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][C:13]1[CH:17]=[N:16][N:15]2[C:22]([OH:23])=[CH:21][C:20]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[N:18][C:14]=12
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: Cc1c(Cc2c[nH]nc2N)cccc1C(F)(F)F
Solvent: CC(=O)O
Product: Cc1c(Cc2cnn3c(O)cc(-c4ccncc4)nc23)cccc1C(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of 4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-amine (115 mg, 0.45 mmol) in acetic acid (2.0 mL) was added ethyl 3-oxo-3-(4-pyridinyl)propanoate (87 mg, 0.45 mmol) in a microwave reaction vessel. It was sealed and irradiated (microwave) at 140° C. for 60 minutes. The reaction mixture was cooled and stood for 2 hours. Precipitate was observed, filtered. Solid was washed with acetic acid (1 mL), then ethanol (1 mL×2). Solid was dried. The titled compound was obtained. (87 mg, 50%); LC/MS: MS (ES+) m/e 385 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.44 (s, 3H) 4.12 (s, 2H) 6.14 (s, 1H) 7.34 (s, 2H) 7.56 (d, J=9.09 Hz, 1H) 7.67 (s, 1H) 7.81 (br. s., 2H) 8.78 (br. s., 2H) 12.37 (br. s., 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([O-:11])=[O:10].[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([O:18][C:15]2[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 55.3 %

Procedure:
After adding 4,6-dichloropyrimidine (750 mg) to a suspension of 4-nitrophenol (700 mg) and sodium hydride (60%) (200 mg) in dimethylformamide (13 ml) at 0° C., the mixture was heated and stirred at 80° C. for 1.5 hours. The reaction solution was poured into saturated brine and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated. The obtained residue was passed through an NH silica gel column (Fuji Silysia Chemical), eluted with a solvent (ethyl acetate-hexane=1-4) and concentrated to obtain 700 mg of the title compound.
Reaction SMILES: C([O:8][C:9](=[O:33])[C@H:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:11][C@H:12]([P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C1C=CC=CC=1.[H][H]>C(O)C>[CH2:27]([O:26][P:21]([C@@H:12]([NH:11][C@H:10]([C:9]([OH:33])=[O:8])[CH2:29][CH:30]([CH3:31])[CH3:32])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([O:23][CH2:24][CH3:25])=[O:22])[CH3:28]
Reactant: [H][H]
Reactant: CCOP(=O)(OCC)[C@H](CCc1ccccc1)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Solvent: CCO
Product: CCOP(=O)(OCC)[C@H](CCc1ccccc1)N[C@@H](CC(C)C)C(=O)O
Yield: 101.9 %

Procedure:
To a solution of 230 mg of N-[1-(R)-diethoxyphosphoryl-3-phenylpropyl]-L-leucine benzyl ester in 5 ml of 95% ethanol was added 50 mg of 10% Pd--C, and the mixture was stirred under an atmospheric pressure of hydrogen at room temperature for 3 hours. The Pd--C was filtered off, and the solvent was distilled off under reduced pressure to yield the title compound as a colorless oil (190 mg).
Reaction SMILES: [Br:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)=[O:6].[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[C@@H:15]([O:21][C:22]([C:24]1([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23])[CH2:14]2>C(#N)C>[Br-:1].[C:31]1([C:24]2([C:22]([O:21][C@@H:15]3[CH:16]4[CH2:19][CH2:20][N+:13]([CH2:2][CH2:3][NH:4][C:5]([C:7]5[CH:12]=[N:11][CH:10]=[CH:9][N:8]=5)=[O:6])([CH2:18][CH2:17]4)[CH2:14]3)=[O:23])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(NCCBr)c1cnccn1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Solvent: CC#N
Product: O=C(NCC[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3ccccc3)CCCCCC1)C2)c1cnccn1
Product: [Br-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.9 %

Procedure:
Pyrazine-2-carboxylic acid (2-bromo-ethyl)-amide (Example 55a) (87 mg) was added to a solution of 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester (Example 14e) (113 mg) in acetonitrile (2 mL). The reaction mixture was allowed to stir at room temperature for 16 h. A solid precipitated out and was filtered off, washed with cold acetonitrile and dried under vacuum at 40° C. to give the title compound (96 mg) as a white solid.
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Br:31][C:32]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:33]=1[CH2:34]Br.Cl>CC(N(C)C)=O>[Br:31][C:32]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:33]=1[CH2:34][N:9]1[C:10](=[O:23])[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:12]([OH:13])[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]1=[O:24]
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Reactant: Fc1ccc(Br)c(CBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(Cc2cc(F)ccc2Br)c1=O
Reaction time: 8 h
Yield: 32.1 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles) and 2-bromo-5-fluorobenzyl bromide (375 uL, 2.0 mmoles) in dimethylacetamide (6 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (3.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from acetic acid-water gave the title compound (160 mg, 31%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (bras., 1 H), 10.10 (br. s., 1 H), 7.69 (dd, J=8.59, 5.31 Hz, 1 H), 7.11 (ddd, J=8.53, 3.16 Hz, 1 H), 7.05 (dd, J=9.60, 2.78 Hz, 1 H), 4.95 (s, 2H), 4.63 (t, J=12.38 Hz, 1 H), 4.13 (d, J=5.81 Hz, 2 H), 2.24 (q, 2 H), 1.79 (d, J=13.14 Hz, 2 H), 1.52-1.74 (m, J=27.54, 11.62 Hz, 3 H), 1.28 (q, J=12.88 Hz, 2 H), 1.10 (q, J=12.97 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])[O:3]1.C(=O)([O-])[O-].[K+].[K+].F[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1>CN(C=O)C>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[O:5]1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccccc2Oc2ccc([N+](=O)[O-])cc2)OC1(C)C
Reaction time: 18 h

Procedure:
To a solution of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.00 g, 9.09 mmol) in DMF was added Potassium carbonate (2.51 g, 18.2 mmol) and 1-fluoro-4-nitrobenzene (0.964 ml, 9.09 mmol). The reaction was flushed with nitrogen, sealed, and heated to 120 deg. C. After 18 h, water was added and the mixture extracted twice with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purify by silica gel chromatography, eluting with 0-15% EtOAc/hexanes to give 4,4,5,5-tetramethyl-2-(2-(4-nitrophenoxy)phenyl)-1,3,2-dioxaborolane as a white solid. MS m/z=342 [M+1]+. Calc'd for C18H20BNO5: 341.17.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:4]=1[OH:11].N[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[SH:19].C([N:22](CC)CC)C>C1COCC1>[NH2:22][S:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:4]=1[OH:11]
Reactant: CCN(CC)CC
Reactant: Nc1ccccc1S
Reactant: Oc1c(Cl)cc(Cl)cc1CBr
Solvent: C1CCOC1
Product: NSc1ccccc1Cc1cc(Cl)cc(Cl)c1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 2-(bromomethyl)-4,6-dichlorophenol (1.24 g, 4.8 mmol) in THF (20 mL) was added dropwise to a solution of 2-Aminothiophenol (0.60 g, 4.8 mmol) and triethylamine (0.70 mL) in THF (20 mL) and stirred at room temperature for 12 hours. A solid had formed and was filtered out followed by removal of the solvent in vacuum. The crude product was dissolved in dichloromethane, washed with saturated NaCl solution and dried over MgSO4. The product was obtained as a yellow oil in a quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C:19](Cl)=[O:20].O>CN(C=O)C>[Br:8][C:6]1[C:5]([F:9])=[CH:4][C:3]2[O:10][CH2:18][C:19](=[O:20])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Br)c(F)cc1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COc2cc(F)c(Br)cc2N1
Temperature: 80 °C
Yield: 90.3 %

Procedure:
To a 0° C. mixture of 2-amino-4-bromo-5-fluorophenol (38.0 g, crude from previous step) and K2CO3 (76.0 g, 553 mmol) in DMF (100 mL) was added 2-chloroacetyl chloride (23.0 g, 15.3 mL, 203 mmol) drop-wise. The reaction mixture was heated at 80° C. overnight then cooled to ambient temperature and poured into water (300 mL). The precipitate was collected by filtration, washed with water and dried to give 6-bromo-7-fluoro-4H-benzo[1,4]oxazin-3-one (41.0 g, 90%). 1H NMR (DMSO-d6, 400 MHz): δ 7.13 (m, 2H), 4.62 (s, 2H). The amide proton was not observed.