Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1>C(Cl)Cl>[C:5]([O:16][C:13]1[CH:14]=[CH:15][C:10]([Br:9])=[CH:11][CH:12]=1)(=[O:7])[CH3:6]
Reactant: Oc1ccc(Br)cc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)Oc1ccc(Br)cc1
Temperature: 0 °C
Yield: 84.8 %

Procedure:
To the suspension of anhydrous aluminum chloride (84.0 g, 0.49 mol) in methylene chloride (1200 mL) was add acetyl chloride (49.2 g, 0.63 mol) while stirring and cooling on ice. The mixture was stirred for 20 minutes while cooling on ice followed by addition of 4-bromophenol (98 g, 0.57 mol). The reaction mixture was stirred at room temperature for 1 h and then ice water was added. The reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to yield 4-bromophenyl acetate (104.0 g, 85%). 1H-NMR (CDCl3): 2.28 (s, 3H), 6.98 (d, 2H), 7.48 (d, 2H).
Reaction SMILES: [CH:1]1([C:9]([O:11]CC)=[O:10])[C:3]2([CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH2:2]1.[OH-].[K+]>C(O)C.O>[CH:1]1([C:9]([OH:11])=[O:10])[C:3]2([CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH2:2]1
Reactant: CCOC(=O)C1CC12CCOCC2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CC12CCOCC2
Temperature: 60 °C

Procedure:
A solution of 120.50 g of ethyl 6-oxaspiro[2.5]-octane-1-carboxylate in 700 ml of ethanol/water 3.5:1 is mixed with 55.20 g of potassium hydroxide. The reaction mixture is heated at 60° C. for 4 hours, the ethanol is distilled off and the aqueous residue is diluted with water and extracted with tert-butyl methyl ether. The aqueous phase is adjusted to pH 2 with 4M hydrochloric acid and extracted with tert-butyl methyl ether. The combined organic extracts are washed with brine, dried with sodium sulphate and evaporated. The title compound is obtained as a yellowish oil and is employed without further purification for the next stage. Rt=2.13 (Gradient I).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[C:14]([N:26]([CH3:31])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:13]=2)[N:3]=1.C(O)(C(F)(F)F)=O.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[CH3:31][N:26]([S:27]([CH3:30])(=[O:29])=[O:28])[C:14]1[CH:13]=[C:12]([NH:11][C:4]2[N:3]=[C:2]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[CH:10]=[CH:9][C:5]=2[C:6]([NH2:8])=[O:7])[CH:17]=[CH:16][C:15]=1[C:18]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:19]
Reactant: C1COCCN1
Reactant: CN(c1cc(Nc2nc(Cl)ccc2C(N)=O)ccc1C(=O)N1CCOCC1)S(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: CN(c1cc(Nc2nc(N3CCOCC3)ccc2C(N)=O)ccc1C(=O)N1CCOCC1)S(C)(=O)=O
Yield: 38 %

Procedure:
A solution of 6-chloro-2-(3-(N-methylmethylsulfonamido)-4-(morpholine-4-carbonyl)phenylamino)nicotinamide (19 mg, 0.041 mmol) in morpholine (0.4 mL) in a sealed tube was stirred at 85° C. for 2 h. The morpholine was evaporated. The crude material was dissolved in 1 N aqueous HCl-MeOH (1:1, total 2 mL) and purified by reverse phase HPLC, using Shimadzu VP-ODS 20×100 mm column and eluting with 20% to 100% solvent B (10% MeOH-90% H2O-0.1% TFA) in solvent A (90% MeOH-10% H2O-0.1% TFA), to give the desired product as brown solid (11.7 mg, 38% yield) as bis-TFA salt. LCMS: (M+H)+=519.1. 1H NMR (400 MHz, methanol-d4) δ ppm 8.06 (1H, d, J=2.26 Hz), 7.90 (1H, d, J=8.78 Hz), 7.48 (1H, dd, J=8.41, 2.13 Hz), 7.26 (1H, d, J=8.53 Hz), 6.25 (1H, d, J=9.03 Hz), 3.70-3.93 (7H, m), 3.56-3.69 (7H, m), 3.41 (2H, t, J=4.64 Hz), 3.26 (3H, s), 3.06 (3H, s).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][C:9]=1[OH:10])=[N+:2]=[N-:3].[NH2:15][C:16]1([O:36][CH3:37])[C:23](=[O:24])[N:22]2[CH:17]1[S:18][CH2:19][C:20]([CH2:28][S:29][C:30]1[S:31][C:32]([CH3:35])=[N:33][N:34]=1)=[C:21]2[C:25]([OH:27])=[O:26]>>[N:1]([C:4]1[CH:5]=[C:6]([CH2:11][C:12]([NH:15][C:16]2([O:36][CH3:37])[C:23](=[O:24])[N:22]3[CH:17]2[S:18][CH2:19][C:20]([CH2:28][S:29][C:30]2[S:31][C:32]([CH3:35])=[N:33][N:34]=2)=[C:21]3[C:25]([OH:27])=[O:26])=[O:14])[CH:7]=[CH:8][C:9]=1[OH:10])=[N+:2]=[N-:3]
Reactant: COC1(N)C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CSC21
Reactant: [N-]=[N+]=Nc1cc(CC(=O)O)ccc1O
Product: COC1(NC(=O)Cc2ccc(O)c(N=[N+]=[N-])c2)C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CSC21

Procedure:
The title compound is prepared when 3-azido-4-hydroxybenzeneacetic acid is reacted with 7-amino-7-methoxy-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid according to Procedure V.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.BrC1C=C2C(=CC=1)C(N[C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=NC=C2>>[Br:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][N:3]=[C:2]2[NH:1][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:7][CH:8]=1
Reactant: O=C(Nc1nccc2cc(Br)ccc12)c1ccccc1
Reactant: Nc1nccc2ccc(Br)cc12
Product: O=C(Nc1nccc2ccc(Br)cc12)c1ccccc1

Procedure:
Compound 37e was prepared from 37d using the procedure described for 1e. 1H-NMR 200 MHz (CDCl3) δ: 6.98 (1H,d, J=6 Hz), 7.37-7.57 (6H, m), 8.41-8.48 (2H, m), 9.14 (1H, d, J=2 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[CH3:41][O:42][CH2:43][CH2:44][CH2:45][NH2:46].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.C(O)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:34]=[CH:35][C:36]([CH2:39][NH:46][CH2:45][CH2:44][CH2:43][O:42][CH3:41])=[CH:37][CH:38]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: COCCCN
Reactant: COc1cc(-c2nn(-c3ccc(C=O)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COCCCNCc1ccc(-n2nc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4F)c(OC)c3)c3c(N)ncnc32)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 10 %

Procedure:
A mixture of N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide (Intermediate 2) (0.075 g, 0.14 mmol), 3-methoxypropylamine (0.024 g, 0.27 mmol), and sodium triacetoxyborohydride (0.087 g, 0.41 mmol) in dichloroethane (1.4 mL) was shaken at room temperature for 3 days. Additional portions of 3-methoxypropylamine (0.1 mL, 1 mmol) and sodium triacetoxyborohydride (0.085 g, 0.40 mmol) were added and the mixture was shaken for 3 days. Acetic acid (0.1 mL) was added and the reaction mixture was shaken for 4 days. An additional portion of sodium triacetoxyborohydride (0.100 g, 0.470 mmol) was added and the reaction mixture was shaken for 16 h. 1N NaOH (1 mL) was added and the reaction mixture was concentrated, dissolved in DMF (2 mL), filtered through a syring-tip Acrodisc filter, and purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 20-80% acetonitrile—0.05 M ammonium acetate over 25 min, 21 mL/min); the fraction eluting from 18.0-19.7 min was collected, concentrated, and lyopholized to afford N1-{4-[4-amino-1-(4-{[(3-methoxypropyl)amino]methyl}phenyl)-1H-pyrazolo [3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide as a white solid (0.009 g, 0.014 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.93 (1H, s), 8.33-8.38 (2H, m), 8.18-8.20 (2H, m), 7.97-8.01 (1H, m), 7.87-7.91 (1H, m), 7.73-7.76 (1H, m), 7.54-7.64 (5H, m), 7.31-7.45 (2H, m), 3.95 (3H, s), 3.85-3.89 (2H, m), 3.38 (2H, s), 2.55-2.68 (2H, m), and 1.70-1.74 (2H, m); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile—0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 10.58 min. MS: MH+624.2.
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH2:3][CH2:4][N:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=2)=[CH:7][C:6]1=[O:24].[Cl:26]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:26][C:7]1[C:6](=[O:24])[N:5]([CH2:4][CH2:3][CH:2]([CH3:25])[CH3:1])[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:13][CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)CCn1ccc(-c2ccc(NC3CCOCC3)cc2)cc1=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCn1ccc(-c2ccc(NC3CCOCC3)cc2)c(Cl)c1=O
Yield: 27.9 %

Procedure:
A solution of intermediate D8 (0.65 g, 1.91 mmol) and N-chlorosuccinimide (0.25 g, 1.91 mmol) in DMF (10 ml) was stirred at 45° C. for 16 hours. After cooling to room temperature water was added and the solution was extracted with EtOAc, The organic layer was separated and washed with brine, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/EtOAc 8:2 as eluent). The desired fractions were collected and evaporated in vacuo to yield E1 (0.20 g, 28%) as a pale pink solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=O)[CH2:3]1.C(Cl)(=O)C(Cl)=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[NH2:22].N1C=CC=CC=1>ClCCl>[CH3:29][O:28][C:24]1[CH:23]=[C:21]([NH:22][C:8](=[O:10])[CH2:7][CH:4]2[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]2)[CH:20]=[C:19]([O:18][CH3:17])[C:25]=1[O:26][CH3:27]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C(O)CC1CCC(=O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(NC(=O)CC2CCC(=O)C2)cc(OC)c1OC
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 129.1 %

Procedure:
To a solution of 1.0 g (7 mmol) of 3-oxocyclopentyl acetic acid in dichloromethane (18 mL) and DMP (1 mL), was added 0.68 mL (7.7 mmol) oxalyl chloride. After 30 min, the solvent was removed in vacuo. The residue was dissolved in dichloromethane (20 mL), cooled to 0-5° C., and 1.29 g of 3,4,5-trimethoxyaniline (0.63 mmol) was added followed by 0.68 mL of pyridine (8.4 mmol). After 15 min, the reaction was allowed to warm to ambient temperature. After 2 h, the reaction was rinsed with 1N HCl, followed by aq. sodium bicarbonate, and water (3×). The organic layer was dried, the solvent removed in vacuo and the residue chromatographed on a silica gel with 2% methanol in methylene chloride to yield 0.25 g of the title compound. MS(ES+)m/z=308.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:18])[C:8](=[O:17])[N:9]2[CH2:12][C:13]([O:15]C)=[O:14])=[CH:4][C:3]=1[N:19]1[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]1[CH3:25].[OH-].[Li+]>O1CCCC1.O>[C:13]([CH2:12][N:9]1[C:10]2[C:5](=[CH:4][C:3]([N:19]3[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]3[CH3:25])=[C:2]([Cl:1])[CH:11]=2)[NH:6][C:7](=[O:18])[C:8]1=[O:17])([OH:15])=[O:14]
Reactant: COC(=O)Cn1c(=O)c(=O)[nH]c2cc(-n3c(C)ccc3C)c(Cl)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C)n1-c1cc2[nH]c(=O)c(=O)n(CC(=O)O)c2cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
4.0 g (10.6 mmol) of 7-chloro-6-(2,5-dimethyl-1-pyrrolyl)-1-(methoxycarbonylmethyl)-2,3(1H,4H)-quinoxalinedione (Example 44) were dissolved in 100 ml of tetrahydrofuran, and a solution of 0.76 g (31.9 mmol) of lithium hydroxide in 15 ml of water was added. The mixture was stirred at room temperature for 2 h and then the organic solvent was removed under reduced pressure, and the aqueous phase was acidified with 1M hydrochloric acid. The precipitate was filtered off with suction to yield 3.1 g (84%) of the product. Melting point>265° C.
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[F:13])([O-])=O>O.[Fe]>[Br:12][C:10]1[CH:9]=[CH:8][C:7]([F:13])=[C:6]([CH:11]=1)[NH2:3]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Nc1cc(Br)ccc1F
Temperature: 100 °C
Reaction time: 5 h
Yield: 52.9 %

Procedure:
Iron powder (9.3 g, 0.166 mM) and ammonium chloride (1.7 g, 0.032 mM) were stirred in water (42 ml) at 100° C. for 30 minutes. Commercially available 2-nitro 4-bromo fluorobenzene (9.2 g, 0.42 mM) was added drop wise to the above solution over a period of 45 minutes. The reaction was stirred at 100° C. for an additional five hours. Water was removed in vacuo. The resultant crude solution was stirred in ethyl acetate (100 mL) for 20 minutes and the organic solution was decanted off. This wash was repeated two more times. The organic layers were combined, dried (MgSO4), passed through a plug of SiO2, and concentrated to afford 4.2 g (53% yield) of the desired product as a red oil. The product was used without further purification. NMR (CHCl3) δ 3.78 (bs, 2H); 6.65-7.07(m, 3H).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][C@H:6]([NH:23][C:24](=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])=[CH:10][CH:9]=1)C.[OH-].[Na+]>CO>[C:4]([CH2:5][C@H:6]([NH:23][C:24](=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])=[CH:10][CH:9]=1)([OH:31])=[O:3]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(F)ccc2OC)cc1)NC(=O)CCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(F)cc1-c1ccc(C[C@H](CC(=O)O)NC(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
To a solution of (R)-4-(4-ethoxy-1-(5′-fluoro-2′-methoxybiphenyl-4-yl)-4-oxobutan-2-ylamino)-4-oxobutanoic acid (83 mg, 0.192 mmol) in MeOH (2 mL) is added 1N NaOH (4 mL, 4 mmol) After stirring at room temperature for 2 hours, the crude is concentrated under reduced pressure to remove MeOH and is diluted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN), and then lyophilized to give (R)-4-(1-carboxy-3-(5′-fluoro-2′-methoxybiphenyl-4-yl)propan-2-ylamino)-4-oxobutanoic acid (58 mg). HPLC retention time=1.46 minutes (condition D); MS (m+1)=404.2; 1H NMR (400 MHz, CD3OD) δ ppm 2.36-2.59 (m, 6H) 2.84 (dd, J=13.4, 6.3 Hz, 1H) 2.91 (dd, J=13.4, 6.3 Hz, 1H) 3.75 (s, 3H) 4.34-4.56 (m, 1H) 6.95-7.08 (m, 3H) 7.26 (d, J=8.1 Hz, 2H) 7.42 (d, J=8.3 Hz, 2H)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[O:29]1[C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=[N:30]1>C(Cl)Cl.C1COCC1>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[C:3]([CH2:2][NH:1][C:34]([C:33]4[O:29][N:30]=[CH:31][CH:32]=4)=[O:35])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: O=C(O)c1ccno1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CNC(=O)c1ccno1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 4 %

Procedure:
To a solution of (S)-3-(aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3, 0.08 g, 0.21 mmol) in DCM-THF mixture (1:1, 4 ml) at 0° C. was added 1.0 eq. of isoxazole-5-carboxylic acid loaded TFP resin. The resulting mixture was stirred vigorously for 1 hour at 0° C., and then filtered. The remaining resin was then washed with DCM-THF (1:1, 2×10 ml portions) for 30 min, and then filtered. The combined filtrates were concentrated, and the resulting oil was purified by column chromatography to give the title compound (3.4 mg, 4%). MS: Calcd.: 479. Found: [M+H]+ 480.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:18][OH:19])([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[CH:27]([N:30]=[C:31]=[O:32])([CH3:29])[CH3:28]>ClCCl.CN(C)C1C=CN=CC=1>[CH:27]([NH:30][C:31](=[O:32])[O:19][CH2:18][C:4]1([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:12]=[C:3]1[O:2][CH3:1])([CH3:29])[CH3:28]
Reactant: COC1=CCc2ccccc2C1(CO)CCC(C)C
Reactant: CC(C)N=C=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=CCc2ccccc2C1(CCC(C)C)COC(=O)NC(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.4 %

Procedure:
To a solution of Example 179A (50 mg, 0.2 mmol) in dichloromethane (1 mL) was added triethylamine (0.13 mL, 1 mmol), 4-dimethylaminopyridine (9 mg, 0.08 mmol), and isopropyl isocyanate (0.1 mL, 1 mmol). The solution was stirred at room temperature for 18 h. After which, additional 5.0 equivalents (0.1 mL) of isopropyl isocyanate were added, and the solution was stirred for another 18 h. The solution was diluted with dichloromethane (2 mL), washed with water (2×1 mL), dried (Na2SO4), and concentrated in vacuo. Column chromatography on silica (0-5% ethyl acetate/hexane) afforded product (39 mg, 59%). 1H NMR (300 MHz, CDCl3) δ ppm 0.70 (m, 7 H), 0.91 (m, 8 H), 1.37 (m, 1 H), 1.60 (m, 1 H), 1.93 (m, 1 H), 3.49 (d, J=3.68 Hz, 2 H), 3.58 (s, 3 H), 4.21 (d, J=10.30 Hz, 1 H), 4.45 (d, J=10.30 Hz, 1 H), 5.00 (t, J=3.68 Hz, 1 H), 7.17 (m, 3 H), 7.30 (m, 1 H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21](Cl)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([OH:41])[CH2:36]2.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>>[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43].[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:30][C:31]3[CH:32]=[CH:33][CH:34]=[C:35]4[C:39]=3[C:38](=[O:40])[N:37]([OH:41])[CH2:36]4)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: Nc1cccc2c1C(=O)N(O)C2
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4c3C(=O)N(O)C4)n2)c(OC)c1)OCC
Yield: 7 %

Procedure:
The title product was prepared according to the procedure for Example 102 using diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (50.0 mg, 0.11 mmol) and 7-amino-2-hydroxy-2,3-dihydro-1H-isoindol-1-one (Compound 186A, 21.70 mg, 0.13 mmol). The reaction mixture purified by MDP to isolate the desired product (4.6 mg, yield: 7%) as a TFA salt. 1H NMR (CD3OD, 400 MHz): δ=1.29 (t, J=7.2 Hz, 6H), 3.33 (d, J=21.2 Hz, 2H), 3.89 (s, 3H), 4.06-4.13 (m, 4H), 4.63 (s, 2H), 4.96 (dt, J=2.8, 8.4 Hz, 1H), 7.10 (t, J=2.0 Hz, 1H), 7.24 (d, J=7.6 Hz, 1H), 7.36 (dd, J=0.8, 8.0 Hz, 0.5H), 7.52 (m, 1H), 7.66 (d, J=8.0 Hz, 1H), 8.32 (d, J=8.0 Hz, 0.5H), 8.37 (s, 1H). MS (ES+): m/z 582.17 [MH+]. HPLC: tR=3.64 min (OpenLynx, polar—5 min).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([C:23]([F:34])([F:33])[F:22])[CH:29]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Product: COc1ccc(-c2nc3cc(-c4cccc(C(F)(F)F)c4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 3-trifluoromethylphenylboronic acid (163 mg, 0.86 mmol) the subtitle compound was obtained, (120 mg, 51%). 1H NMR (DMSO) δ 8.70(s, 1H), 8.52(d, 1H), 8.24(s, 1H), 8.11(s, 1H), 7.97(d, 1H), 7.86(d, 1H), 7.81(s, 2H), 7.68(d, 1H), 4.11(s, 3H). MS 415 m/z (M+H)+.