Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:13]([C:14](=[O:30])[C:15]3[C:20]([F:21])=[CH:19][CH:18]=[C:17]([NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])[C:16]=3[F:29])=[CH:12][NH:11][C:8]2=[N:9][CH:10]=1)=[O:4].O.[OH-].[Li+].Cl>O1CCCC1>[F:29][C:16]1[C:17]([NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[C:14]([C:13]1[C:7]2[C:8](=[N:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[NH:11][CH:12]=1)=[O:30]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(C(=O)OC)cc23)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(C(=O)O)cc23)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester (P-1552, 80.0 mg, 0.18 mmol) in tetrahydrofuran (10.0 mL) were added water (3.0 mL) and lithium hydroxide (82 mg, 3.4 mmol). The reaction was stirred at room temperature overnight. The reaction was poured into water, acidified with 1 N HCl to pH around 1, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and washed with ethyl acetate to give an off-white solid (P-1559, 60 mg, 77%) MS (ESI) [M+H+]+=424.2.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:15][O:16][C:17]([C:19]1[C:23]([NH2:24])=[CH:22][NH:21][N:20]=1)=[O:18].[C:25]([C:29]1[CH:30]=[CH:31][C:32]([O:38][CH3:39])=[C:33]([CH:37]=1)[C:34](O)=[O:35])([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[CH3:15][O:16][C:17]([C:19]1[C:23]([NH:24][C:34](=[O:35])[C:33]2[CH:37]=[C:29]([C:25]([CH3:26])([CH3:27])[CH3:28])[CH:30]=[CH:31][C:32]=2[O:38][CH3:39])=[CH:22][NH:21][N:20]=1)=[O:18]
Reactant: COC(=O)c1n[nH]cc1N
Reactant: COc1ccc(C(C)(C)C)cc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)c1n[nH]cc1NC(=O)c1cc(C(C)(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
To a solution of EDC (11.59 g, 60.7 mmol), HOBt (8.19 g, 60.7 mmol) and 4-amino-1H-pyrazole-3-carboxylic acid methyl ester (7.84 g, 55.6 mmol) in DMF (100 ml) was added 5-tert-butyl-2-methoxy-benzoic acid (10.52 g, 50.6 mmol) and the mixture stirred at room temperature overnight. The mixture was reduced in vacuo and the residue partitioned between EtOAc (500 ml) and brine (200 ml), the organic portion was washed with saturated aqueous sodium hydrogen carbonate (200 ml), dried (MgSO4) and reduced in vacuo to yield 4-(5-tert-butyl-2-methoxy-benzoylamino)-1H-pyrazole-3-carboxylic acid methyl ester as a pale yellow solid (17.07 g, 93%). (LC/MS (acidic method): Rt 3.12 min, [M+H]+ 332).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[OH-].[Na+].CO.Cl>C1COCC1>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[CH:7]=[N:6][C:5]([C:3]([OH:4])=[O:2])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.7 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (40 mg, 0.13 mmol), 2M NaOH (2 mL), MeOH (2 mL) and THF (1 mL) was stirred at r.t. for 4 h. 1 M HCl was added until pH was about 2, and the resulting mixture was cooled in an ice bath for 30 min. The precipitate formed was collected by filtration and dried under high vacuum to afford 23 mg of the title compound as a yellow solid. MS: (+) m/z 297.00 (M+1).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]([SH:10])[CH:7]=[CH:8][CH:9]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH3:26])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>C1COCC1>[CH2:25]([O:24][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([S:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[NH2:3])=[N:13][CH:14]=[N:15]2)=[CH:20][C:19]=1[O:22][CH3:23])[CH3:26]
Reactant: Nc1cccc(S)c1
Reactant: CCOc1cc2ncnc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
To a stirred slurry of sodium hydride (350 mg of a 60% dispersion in mineral oil, 8.80 mmol) in anhydrous THF (50 mL) at rt, was added 3-aminobenzenethiol (1.00 g, 9.17 mmol). After stirring for 30 mins, 4-chloro-7-ethoxy-6-methoxyquinazoline (prepared as described in Example 6A Steps 1 through 5) (1.91 g, 8.03 mmol) was added and the reaction mixture was stirred at rt for a further 4 h. The mixture was concentrated under reduced pressure and the resulting solid was washed with water (three times) then ethyl acetate (three times) to afford 3-(7-ethoxy-6-methoxyquinazolin-4-ylthio)aniline (2.36 g, 90%) as yellow solid. 1H NMR (400 MHz; DMSO-d6) δ 8.69 (s, 1H), 7.30-7.31 (m, 2H), 7.13 (m, 1H), 6.80 (s, 1H), 6.72-6.74 (m, 2H), 5.31 (brs, 2H), 4.25 (q, J=7 Hz, 2H), 3.97 (s, 3H), 1.43 (t, J=7 Hz, 3H); LC-MS (ESI) m/z 328 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:44])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:43])[C:11]([C:41]#[N:42])=[C:12]([NH:24][C@H:25]2[CH2:31][CH2:30][CH2:29][CH2:28][N:27]([CH2:32][C:33](=[O:39])[N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[C:26]2=[O:40])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[O:21][C:20]([CH3:22])=[CH:19][C:18]=3[CH:23]=2)=[CH:6][CH:5]=1.C1COCC1>O>[C:41]([C:11](=[C:12]([NH:24][C@H:25]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]([CH2:32][C:33](=[O:39])[N:34]2[CH2:35][CH2:36][CH2:37][CH2:38]2)[C:26]1=[O:40])[NH:13][C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([CH3:22])=[CH:19][C:18]=2[CH:23]=1)[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:44])=[O:2])=[CH:5][CH:6]=1)=[O:43])#[N:42]
Reactant: COC(=O)c1ccc(C(=O)C(C#N)=C(Nc2ccc3oc(C)cc3c2)N[C@H]2CCCCN(CC(=O)N3CCCC3)C2=O)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2cc(NC(N[C@H]3CCCCN(CC(=O)N4CCCC4)C3=O)=C(C#N)C(=O)c3ccc(C(=O)O)cc3)ccc2o1
Reaction time: 24 h
Yield: 83.4 %

Procedure:
The compound of Example 1 (0.442g, 0.740 mmol) was dissolved in 10 mL of 1:1 water:THF and the mixture was cooled to 0° C. To the solution was added LiOH monohydrate (0.31 g, 7.4 mmol). The reaction mixture was allowed to come to room temperature. After stirring for 24 h, the reaction mixture was concentrated by in vacuo and the residue was dissolved in methylene chloride. The mixture was extracted 2×25 mL with water. The combined aqueous layers were neutralized with 1 N HCl to pH 4 and were extracted 2×25 mL with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulfate and concentrated to give the title compound (360 mg, 83%) as yellow solid: MS (ESI, pos. ion) m/z 584 (M+H); HPLC (method B) tR=3.8 min, purity: >96%.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][C:3]=2[O:2]1.C([Mg]Br)C.Br[C:18]1[C:23](=[O:24])[NH:22][C:20](=[O:21])[C:19]=1[Br:25].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O1CCCC1>[Br:25][C:19]1[C:20]([NH:22][C:23](=[O:24])[C:18]=1[C:6]1[C:5]2[C:9](=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[NH:8][CH:7]=1)=[O:21]
Reactant: c1cc2cc3c(cc2[nH]1)OCO3
Reactant: O=C1NC(=O)C(Br)=C1Br
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2c[nH]c3cc4c(cc23)OCO4)=C1Br
Yield: 56.8 %

Procedure:
6.44 g (40 mmol) 5,6-methylenedioxyindole are dissolved in 300 ml anhydrous toluene and mixed dropwise at 60° C. with 20 ml of a 2M solution of ethyl magnesium bromide in tetrahydrofuran (Aldrich). After completion of the addition, there is added dropwise thereto a solution of 1.7 g (6.67 mmol) dibromomaleinimide in 50 ml toluene, with the addition of the minimum amount of tetrahydrofuran required for solution, and then heated under reflux for 18 hours. After cooling, the reaction mixture is mixed with a saturated aqueous solution of ammonium chloride, the organic phase is separated off and the aqueous phase is extracted three times with toluene and once with ethyl acetate. The combined organic phases are dried, rotary evaporated and chromatographed in silica gel (elution agent: dichloromethane/ethyl acetate 30:1 v/v). There is obtained 1.27 g (56% of theory) 2-bromo-3-(5,6-methylenedioxy-1H-indol-3-yl)-maleinimide; m.p. about 185° C. (decomp.); RF=0.50 (dichloromethane/ethyl acetate 3:1 v/v); and 0.63 g (22.5% of theory) 2,3-bis-(5,6-methylenedioxy-1H-indol-3-yl)-maleinimide in the form of red crystals; m.p, about 270° C. (decomp.), after recrystallisation from propanol; RF=0.36 (dichloromethane/ethyl acetate 3:1 v/v).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[C:18]([F:32])=[C:19]([CH:28]=[CH:29][C:30]=1[F:31])[O:20][CH2:21][C:22]([O:24]C(C)C)=[O:23].[Li+].[OH-].O>C1COCC1>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[C:18]([F:32])=[C:19]([CH:28]=[CH:29][C:30]=1[F:31])[O:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: Cc1cc(-c2ccccc2)cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2F)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2ccccc2)cc(CNc2c(F)ccc(OCC(=O)O)c2F)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a solution of isopropyl 2-[3-[(2,3-dimethyl-5-phenyl-phenyl)methylamino]-2,4-difluoro-phenoxy]acetate (110 mg, 0.25 mmol, 1.0 eq) in THF (4 mL) was added LiOH (52 mg, 1.2 mmol, 5 eq) and water (3 mL) and the reaction mixture stirred at room temperature for 1 h. The THF was removed under reduced pressure and the remaining aqueous solution was adjusted to pH 4-5 by addition of 1M HCl. The mixture was extracted with EtOAc and the combined organic extracts washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a yellow oil (80 mg, 80%).
Reaction SMILES: [Na:1].COC1OCC(CO[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:13]=2[CH3:30])CO1.[CH2:31]([C:33]1([CH2:41][CH3:42])[O:38][CH2:37][CH:36]([CH2:39][OH:40])[CH2:35][O:34]1)[CH3:32]>>[Na:1].[CH2:41]([C:33]1([CH2:31][CH3:32])[O:34][CH2:35][CH:36]([CH2:39][O:40][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:13]=2[CH3:30])[CH2:37][O:38]1)[CH3:42]
Reactant: COC1OCC(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)CO1
Reactant: CCC1(CC)OCC(CO)CO1
Agent: [Na]
Product: CCC1(CC)OCC(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)CO1
Yield: 9.7 %

Procedure:
The same procedure as in the steps (6b) to (6f) of Example 6 was repeated using (2,2-diethyl-1,3-dioxan-5-yl)methanol obtained in the step (23a) to obtain the title compound (164 mg, total yield: 9.7%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[NH:3]1.[I-].[K+].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24]>CN1CCCC1=O>[CH2:24]([N:3]1[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH2:7][C:2]1([CH3:10])[CH3:1])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=[CH2:14]
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: C=CCCCCCCCCCBr
Agent: [I-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: C=CCCCCCCCCCN1C(C)(C)CCCC1(C)C
Temperature: 120 °C
Yield: 86.4 %

Procedure:
2459 g of N-methylpyrrolidinone and 1013 g 2,2,6,6-tetramethylpiperidine were stirred and heated under inert atmosphere at atmospheric pressure. Granular potassium iodide (527 g) was added gradually over 45 minutes. At a slurry temperature of 112° C., 11-bromo-1-undecene (647 g) was added. The temperature was raised to 120° C. within 15 minutes, maintained at 120-135° C. for three hours and 100-120° C. for four hours. The slurry was cooled to room temperature and partitioned between aqueous NaOH and hexane to give two homogeneous liquid layers. The upper organic layer was separated and distilled below atmospheric pressure to remove a volatile mixture including hexane and tetramethylpiperidine (TMP). The portion remaining after hexane and TMP removal was distilled at 155-164° C./3 mmHg to give 704 g of 1-(10-undecenyl)-2,2,6,6-tetramethylpiperidine (98% purity by GC) as a colorless liquid. The structure was identified by NMR, GC-MS, and High Resolution MS.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][N:26]([CH3:39])[C:27](=[O:38])[O:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[CH2:36][NH2:37]>>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:20])([CH3:21])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:37][CH2:36][C:30]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=1[O:28][C:27](=[O:38])[N:26]([CH3:25])[CH3:39])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)Oc1cc(F)ccc1CN
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: CN(C)C(=O)Oc1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and intermediate 133, 2-(aminomethyl)-5-fluorophenyl dimethylcarbamate. 1H NMR (CDCl3, 500 MHz) δ ppm: 1.58 (6H, s, gem-Me), 2.92, 3.05 (2s, NMe), 3.96 (2H, m, NCH2), 4.00 (2H, m, OCH2), 4.48 (2H, d, J=5.5 Hz, NCH2), 5.26 (2H, s, OCH2), 6.84 (1H, dd, J=2.5 Hz, 9 Hz, Ar—H), 6.87 (1H, dt, J=2.5 Hz, 8 Hz, Ar—H), 7.25–7.33 (4H, m, Ar—Hs), 7.53 (2H, d, J=˜7 Hz, Ar—Hs), 7.78 (1H, brt, J=5 Hz, NH); 13C NMR (CDCl3, 125.77 Hz) δ ppm: 27.68, 36.61, 36.89, 37.97, 42.97, 58.06, 74.73, 76.23, 110.58, 110.77, 113.06, 113.23, 126.55, 126.58, 128.31, 128.45, 128.91, 131.23, 131.31, 136.76, 140.70, 142.00, 150.60, 150.69, 154.50, 156.30, 159.79, 161.40, 163.37, 162.43. HRMS (ESI) calcd for C27H30N4O6F (M+H) 525.2149. Found 525.2163.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][N:3]=1.[N+:10]([N:13]=[C:14]1[NH:18][CH2:17][CH2:16][NH:15]1)([O-:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:15]2[CH2:16][CH2:17][NH:18][C:14]2=[N:13][N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])N=C1NCCN1
Reactant: Fc1ccc(CBr)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])N=C1NCCN1Cc1ccc(F)nc1
Temperature: 25 °C
Yield: 50.2 %

Procedure:
A mixture of 2-fluoro-5-pyridylmethyl bromide (9.5 g), 2-(nitroimino)imidazolidine (6.5 g), potassium carbonate (7.6 g) and acetonitrile (100 ml) was refluxed for 2 hours with stirring. After the reaction, the reaction mixture was cooled to room temperature, and cold water (100 ml) was added. The resulting crystals were collected by filtration and washed with ether to give slightly colored 1-(2-fluoro-5-pyridylmethyl)-2-(nitroimino)imidazolidine (6.0 g) as the desired compound.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[CH3:18][O:17][C:15](=[O:16])[CH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: COC(=O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
Cesium carbonate (5.35 g, 16.4 mmol, 3.00 equivalents) was added to a solution of methyl 4-hydroxyphenylacetate (1.00 g, 6.02 mmol, 1.10 equivalents) and benzyl bromide (0.65 mL, 5.47 mmol, 1.00 equivalents) in dichloromethane (40 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred vigorously overnight. The reaction was extracted with 1N hydrochloric acid (2×100 mL) and brine (100 mL). The organic portion was dried over sodium sulfate and the solvent removed in vacuo. The resulting oily solid was chromatographed on a 40S Biotage column (20% ethyl acetate/Hexanes) to give the title ester as a clear colorless oil (1.35 g, 96%). 1H NMR (400 MHz, CDCl3) δ 3.56 (s, 2H), 3.67 (s, 3H), 5.04 (s, 2H), 6.91-6.94 (d, 2H), 7.17-7.19 (d, 2H), 7.3-7.4 (m, 5H). F. 2-Acetylamino-3-[3-(1-tert-butoxycarbonylamino-3-methyl-butyl)-isoxazol-5-yl]-propionic acid ethyl ester
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:19]([O-])([O-])=O.[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:19])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Br)cc(NC2CCCC2)c1C
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Br)cc(N(C)C2CCCC2)c1C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a stirred solution of methyl 5-bromo-3-(cyclopentylamino)-2-methylbenzoate (0.5 g, 1.75 mmol) in acetonitrile (10 mL), Cs2CO3 (1.02 g, 2.63 mmol) and methyl iodide (1.45 g, 3.5 mmol) were added to it. The resulting reaction mixture was stirred at 80° C. for 4 h. Upon completion, the solvent was removed under reduced pressure and residue dissolved in water and extracted with ethyl acetate. Crude material obtained was purified by column chromatography over silica gel affording the desired compound product without further purification (0.39 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:42])[C:15]([O:17][CH2:18][CH2:19][C:20]2([CH3:41])[O:25][C:24]3[C:26]([CH3:40])=[C:27]([CH3:39])[C:28]([O:31]CC4C=CC=CC=4)=[C:29]([CH3:30])[C:23]=3[CH2:22][CH2:21]2)=[O:16])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCCCCC>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:42])[C:15]([O:17][CH2:18][CH2:19][C:20]2([CH3:41])[O:25][C:24]3[C:26]([CH3:40])=[C:27]([CH3:39])[C:28]([OH:31])=[C:29]([CH3:30])[C:23]=3[CH2:22][CH2:21]2)=[O:16])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CCOC(=O)C(C)c1ccc(-c3ccccc3)c(F)c1)O2
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCOC(=O)C(C)c1ccc(-c3ccccc3)c(F)c1)O2
Reaction time: 18 h
Yield: 36 %

Procedure:
A solution of 2-(6-benzyloxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[1,2-b]pyran-2yl)ethyl 2-(3-fluoro4-phenyl-phenyl)propionate in ethyl acetate was treated with 10% palladium on charcoal (Aldrich, 0.5 g). The resulting mixture was hydrogenated on a Parr Apparatus [initial pressure 60 pounds/inch2 (psi)]. After 18 hours, the reaction mixture was filtered, and the resulting solution concentrated in vacuo. The residue was subjected to flash chromatography (silica gel, 2:8, v:v, ethyl acetate:hexane). Concentration of the appropriate fractions afforded a clear oil. Hexane was added to the oil and a white solid formed upon standing. The white solid was collected by filtration to afford 0.91 g (36% yield) of 2-(6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[1,2-b]pyran-2yl)ethyl 2-(3-fluoro4-phenyl-phenyl)propionate as a mixture of stereoisomers.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1)([O-:23])=[O:22].C(O)(C(F)(F)F)=O>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1-c1ccccc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(-c2ccccc2)c2ccccc2n1Cc1ccc([N+](=O)[O-])cc1

Procedure:
1-(4-Nitro-benzyl)-3-phenyl-1H-indolecarboxylic acid ethyl ester was prepared from of 3-phenyl-1H-indolecarboxylic acid ethyl ester and 4-nitrobenzyl bromide followed the procedure of Example 3 Step 1 as a yellow powder: 1H NMR (DMSO-d6) δ 1H NMR (DMSO-d6) δ 0.91 (t, J=7.2 Hz, 3H), 4.05 (q, J=7.2 Hz, 2H), 5.97 (s, 2H), 7.17-7.23 (m, 1H), 7.32 (d, J=8.8 Hz, 2H), 7.36-7.42 (m, 1H), 7.38-7.42 (m, 1H), 7.45-7.48 (m, 4H), 7.52 (d, J=8.2 Hz, 1H), 7.62 (d, J=8.2 Hz, 1H), 8.19 (d, J=8.8 Hz, 2H); MS (ESI) m/z 401 (MH+); 399 ([M−H]−); HRMS calcd for C24H21N2O4: 401.1490; found (ESI+): 401.1494; Anal. calcd for C24H20N2O4.0.05 TFA C, 71.99; H, 5.03; N, 7.00 Found: C, 71.27; H, 4.98; N, 6.90.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:15][CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([OH:14])=O)[S:10][CH:11]=1.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:15][CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:14])[S:10][CH:11]=1
Reactant: CCn1ncc(Cl)c1-c1csc(C(=O)O)c1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1ncc(Cl)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of 4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (0.26 g, 1.0 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (0.35 g, 1.1 mmol) and DIPEA (0.5 mL, 2.86 mmol) in DCM (5 mL) at 25° C. was added PyBrOP (0.6 g, 1.2 mmol) in one portion. After 2 h, the solution was concentrated and purified via column chromatography (silica, 20-50% EtOAc/hexane) affording the title compound (0.54 g, 91%) as a white solid: LC-MS (ES) m/z=588 (M+H)+.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][C:21]([N:23]([CH3:29])[CH:24]([CH3:28])[C:25]([OH:27])=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].[Br:30][C:31]1[CH:36]=[C:35]([NH2:37])[N:34]=[C:33]([NH2:38])[CH:32]=1.CN1C(=O)CCC1>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[N:23]([CH:24]([C:25](=[O:27])[NH:38][C:33]1[CH:32]=[C:31]([Br:30])[CH:36]=[C:35]([NH2:37])[N:34]=1)[CH3:28])[CH3:29])([CH3:17])([CH3:18])[CH3:19]
Reactant: Nc1cc(Br)cc(N)n1
Reactant: CC(C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CC(C(=O)Nc1cc(Br)cc(N)n1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
N,N′-dicyclohexylcarbodiimide (24.7 g, 120 mmol) is added slowly to a mixture of 2-{[(tert-butoxy)carbonyl](methyl)amino}propanoic acid (39 g, 192 mmol) in DCM (60 ml) with ice bath cooling. Stirring is continued and the mixture warmed to RT. The mixture is stirred at RT for 30 minutes before 4-bromopyridine-2,6-diamine A (15 g, 80 mmol) in 60 ml DCM and 10 ml NMP is added dropwise. After stirring for 3 days at RT the reaction mixture is diluted with DCM, filtered and extracted with a saturated aqueous sodium hydrogencarbonate solution. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 19.8 g (67%). HPLC-MS: M+H=373/375; tR=0.93 min (Method—2).