Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:17][O:18][C:19](=[O:34])[C@H:20]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH2:21].[NH4+].[OH-]>>[CH3:17][O:18][C:19](=[O:34])[C@H:20]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[NH:21][C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](C)NC(=O)Cc1ccccc1

Procedure:
Following General Procedure A and using N-(phenylacetyl)-L-alanine (from Example B1 above) and Nε-(tert-butoxycarbonyl)-L-lysine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp=119-121° C.). The reaction was monitored by tlc (Rf=0.46 in 90:10:1 CH2Cl2MeOH\NH4OH).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:13][OH:14]>CO>[OH:14][N:13]=[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1)[C:9]([OH:11])=[O:10]
Reactant: NO
Reactant: O=C(O)C(=O)c1cccc(O)c1
Solvent: CO
Product: O=C(O)C(=NO)c1cccc(O)c1
Reaction time: 0.42 h

Procedure:
2-(3-Hydroxyphenyl)glyoxylic acid (3.32 g.) and 1N-methanol solution of hydroxylamine (45 ml.) were refluxed with stirring for 25 minutes. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 1N-aqueous solution of sodium hydroxide (70 ml.). An aqueous solution was washed with ether, acidified with dil. hydrochloric acid and then extracted with ethyl acetate. The extract was washed, dried and treated with an activated charcoal. The solvent was distilled off to give 2-hydroxyimino-2-(3-hydroxyphenyl)acetic acid (a mixture of syn and anti isomers) (2.9 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](O)[N:9]=2)[CH:3]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Oc1nccc(-c2cc(Cl)ccn2)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccnc(-c2ccnc(Cl)n2)c1
Reaction time: 3 h

Procedure:
A mixture of 10 g I.28 (4-(4-chloro-pyridin-2-yl)-pyrimidin-2-ol) in 100 ml phosphorus oxychloride was stirred for 3 h at reflux. The solvent was evaporated and the crude 8.1 was used in the next step without purification.
Reaction SMILES: [CH3:1][C@:2]1([C:18]([NH:20][C:21]2([C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=3)[CH2:23][CH2:22]2)=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.O[Li].O>>[CH3:1][C@:2]1([C:18]([NH:20][C:21]2([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)[CH2:22][CH2:23]2)=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@@]3(C)CCCN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Agent: [Li]O
Solvent: O
Product: C[C@]1(C(=O)NC2(c3ccc(C(=O)O)cc3)CC2)CCCN1Cc1ccc(C(F)(F)F)cc1
Yield: 88.9 %

Procedure:
The title compound (E43) (11.2 mg) was prepared according to the general procedure for esters hydrolysis (Method D) starting from (R)-methyl 4-(1-(2-methyl-1-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamido)cyclopropyl)benzoate (D159) (13 mg). (LiOH H2O: 4 eq; reaction time: 18 hrs).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20]([CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][NH:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:32]([O:34][C:35]([C:37]1[O:38][C:39]([CH2:42]Cl)=[CH:40][CH:41]=1)=[O:36])[CH3:33].C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:12]([O:19][C:20]([CH:22]1[CH2:31][C:26]2[C:25](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][N:23]1[CH2:42][C:39]1[O:38][C:37]([C:35]([O:34][CH2:32][CH3:33])=[O:36])=[CH:41][CH:40]=1)=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OCc1ccccc1)C1NCCc2ccccc21
Reactant: CCOC(=O)c1ccc(CCl)o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(CN2Cc3ccccc3CC2C(=O)OCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.8 %

Procedure:
To a solution of 1,2,3,4-tetrahydroisoquinolinecarboxylic acid benzyl ester p-toluenesulfonate (2.1 g, 4.9 mmol) in acetonitrile (15 mL) were added 5-chloromethylfuran-2-carboxylic acid ethyl ester (0.50 mL, 3.3 mmol) and N,N-diisopropylethylamine (1.4 mL, 8.1 mmol), and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in ethyl acetate, and washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=92/8) to give the title compound (1.1 g, 2.6 mmol, 81%).
Reaction SMILES: [SH-].[Na+].[CH3:3][C:4]1([CH3:14])[O:8][N:7]=[C:6]([S:9]([CH2:12][CH3:13])(=O)=O)[CH2:5]1.C(=O)([O-])[O-].[K+].[K+].C(S([O-])=O)O.[Na+].BrC[C:29]1[CH:30]=[N:31][CH:32]=C[C:34]=1[C:35]([F:38])([F:37])[F:36]>CN(C)C=O.O>[CH3:3][C:4]1([CH3:14])[O:8][N:7]=[C:6]([S:9][CH2:12][C:13]2[CH:32]=[N:31][CH:30]=[CH:29][C:34]=2[C:35]([F:38])([F:37])[F:36])[CH2:5]1
Reactant: CCS(=O)(=O)C1=NOC(C)(C)C1
Reactant: FC(F)(F)c1ccncc1CBr
Agent: O=C([O-])[O-]
Agent: O=S([O-])CO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(SCc2cnccc2C(F)(F)F)=NO1
Reaction time: 1 h
Yield: 119.2 %

Procedure:
0.26 g of sodium hydrosulfide (purity: 70%, 4.6 mmoles) was added to a solution of 0.3 g (1.6 mmoles) of 5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline dissolved in 20 ml of N,N-dimethylformamide. The mixture was stirred for 1 hour. Thereto were added 0.22 g (1.6 mmoles) of anhydrous potassium carbonate and 0.25 g (1.6 mmoles) of Rongalit. The resulting mixture was stirred for 2 hours. Thereto was added, with ice-cooling, 0.3 g (1.3 mmoles) of 3-bromomethyl-4-trifluoromethyl-pyridine. The resulting mixture was stirred at room temperature for 2 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.45 g (yield: 98.9%) of 5,5-dimethyl-3-(4-trifluoromethyl-pyridin-3-ylmethylthio)-2-isoxazoline as a yellow oily substance.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH:5]=[CH:4][NH:3]1.[C:21]([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C=O)C>[CH3:21][N:3]1[CH:4]=[CH:5][C:6]([CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:7][C:2]1=[O:1]
Reactant: O=C([O-])[O-]
Reactant: O=C1c2ccccc2C(=O)N1CCc1cc[nH]c(=O)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1ccc(CCN2C(=O)c3ccccc3C2=O)cc1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 74.1 %

Procedure:
A mixture of 2-(2-(2-oxo-1,2-dihydropyridin-4-yl)ethyl)isoindoline-1,3-dione (300 mg, 1.1 mmol) CH3I (1.0 g, 7 mmol) and K2CO3 (700 mg, 5 mmol) in 30 mL of DCM and 10 mL of DMF was stirred at room temperature for 3 days. 30 mL of DCM was added. The mixture was washed with H2O (3×30 mL), dried over anhydrous sodium sulfate, concentrated under reduce pressure to give 2-(2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)isoindoline-1,3-dione (230 mg, 73%) as a white solid. LC-MS: 283 [M+H]+, tR=1.29 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:20][C:21]1[C:26]([C:27](Cl)=[O:28])=[C:25]([Cl:30])[N:24]=[CH:23][N:22]=1>O1CCCC1.ClCCl>[Cl:20][C:21]1[C:26]([C:27]([O:1][C:2]2[CH:7]=[CH:6][C:5]([S:8](=[O:10])(=[O:9])[NH:11][CH3:12])=[CH:4][CH:3]=2)=[O:28])=[C:25]([Cl:30])[N:24]=[CH:23][N:22]=1
Reactant: CNS(=O)(=O)c1ccc(O)cc1
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(OC(=O)c2c(Cl)ncnc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.4 %

Procedure:
4-Hydroxy-N-methylbenzenesulfonamide (650 mg, 3.47 mmol) was dissolved in tetrahydrofuran (18 ml) and triethylamine (1.06 ml, 7.61 mmol) was added. Then a solution of 4,6-dichloropyrimidine-5-carbonyl chloride (808 mg, 3.82 mmol, prepared according to E. V. Tarasov et al. Synlett 2000, 5, 625-626) was dropwise added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with dichloromethane, washed with 4% sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated to give 1.4 g (91% yield) of the title compound, that was used in the next step without further purification. Purity 82%.
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]([NH:23][C:24]3[CH:33]=[CH:32][C:31]([C@@H:34]4[CH2:39][CH2:38][C@H:37]([C:40]([O:42]CC)=[O:41])[CH2:36][CH2:35]4)=[C:30]4[C:25]=3[C:26](=[O:46])[C:27]([CH3:45])=[CH:28][NH:29]4)[C:20]([C:47]([F:50])([F:49])[F:48])=[CH:19][N:18]=2)=[C:12]([O:51][CH3:52])[CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O.[OH-].[Li+]>C1COCC1.CO.O>[CH2:7]([O:6][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:33]=[CH:32][C:31]([C@@H:34]4[CH2:35][CH2:36][C@H:37]([C:40]([OH:42])=[O:41])[CH2:38][CH2:39]4)=[C:30]4[C:25]=3[C:26](=[O:46])[C:27]([CH3:45])=[CH:28][NH:29]4)[C:20]([C:47]([F:48])([F:50])[F:49])=[CH:19][N:18]=2)=[C:12]([O:51][CH3:52])[CH:11]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)[C@H]1CC[C@@H](c2ccc(Nc3nc(Nc4ccc(CP(=O)(OCC)OCC)cc4OC)ncc3C(F)(F)F)c3c(=O)c(C)c[nH]c32)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@@H](C(=O)O)CC4)c4[nH]cc(C)c(=O)c34)n2)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A solution of ethyl cis-4-(5-{[2-({4-[(diethoxyphosphoryl)methyl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-3-methyl-4-oxo-1,4-dihydroquinolin-8-yl)cyclohexanecarboxylate (Example 305, 61.7 mg, 0.083 mmol) in THF (0.11 mL) and MeOH (0.11 mL) was charged with a solution of lithium hydroxide, monohydrate (17.4 mg, 0.41 mmol) in H2O (0.11 mL) and allowed to stir at rt for 30 hrs. The reaction was concentrated under reduced pressure. The material was purified on an Isco combi-flash unit using DCM/MeOH (100:0→95:5) as eluent to afford 22.3 mg (38%) of the desired product. 1H NMR (400 MHz, MeOD) δ ppm 1.24-1.30 (m, 6H) 1.76-1.89 (m, 6H) 2.11-2.15 (m, 3H) 2.34 (d, J=4.80 Hz, 2H) 2.73 (br. s., 1H) 2.99 (s, 1H) 3.29 (br. s., 1H) 3.34 (s, 1H) 3.89-3.94 (m, 3H) 4.02-4.13 (m, 4H) 6.87 (dt, J=8.21, 2.34 Hz, 1H) 7.03 (t, J=2.02 Hz, 1H) 7.41 (d, J=8.59 Hz, 1H) 7.84 (d, J=0.76 Hz, 1H) 8.03 (d, J=8.34 Hz, 1H) 8.33 (s, 1H) 8.49 (d, J=6.32 Hz, 1H). MS (ES+): m/z 718.15/719.19 (100/98) [MH+]. HPLC: tR=1.47 min (Micromass TOF: polar—3 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:17][C:18](=[O:24])[C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=1.[H-].[Na+].Cl[CH2:28][C:29]1[N:34]=[C:33]([C:35]([O:37][CH3:38])=[O:36])[CH:32]=[CH:31][CH:30]=1.[Cl-].[NH4+]>CN(C)C=O.O>[C:12]([O:11][C:10]([NH:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[CH:17]([C:18](=[O:24])[C:19]1[CH:23]=[CH:22][S:21][CH:20]=1)[CH2:28][C:29]1[N:34]=[C:33]([C:35]([O:37][CH3:38])=[O:36])[CH:32]=[CH:31][CH:30]=1)=[O:16])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)c1cccc(CCl)n1
Reactant: COc1ccc(CC(=O)c2ccsc2)c(NC(=O)OC(C)(C)C)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CC(C(=O)c2ccsc2)c2ccc(OC)cc2NC(=O)OC(C)(C)C)n1
Yield: 78.6 %

Procedure:
Under an argon atmosphere, to a solution of tert-butyl [5-methoxy-2-(2-oxo-2-thiophen-3-ylethyl)phenyl]carbamate (1.87 g) in N,N-dimethylformamide (27 mL) was added sodium hydride (min. 55% in oil, 247 mg) in five divided portions under ice-cooling with stirring. This mixture was stirred for 70 minutes under ice-cooling. Then, methyl 6-chloromethylpyridine-2-carboxylate (999 mg) was added thereto in one portion, followed by stirring at 35° C. for 16 hours. To the reaction mixture were added a saturated aqueous ammonium chloride solution and water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (2.10 g). 1H-NMR (CDCl3) δ ppm: 1.60 (9H, s), 3.54 (1H, dd, J=10.2, 15.8 Hz), 3.61-3.75 (4H, m), 4.05 (3H, s), 5.40 (1H, dd, J=4.9, 10.2 Hz), 6.55 (1H, dd, J=2.8, 8.5 Hz), 7.00-7.12 (2H, m), 7.15-7.25 (2H, m), 7.50 (1H, dd, J=1.3, 5.0 Hz), 7.63 (1H, t, J=7.8 Hz), 7.89-7.95 (1H, m), 8.00-8.11 (2H, m).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]([NH2:13])=[CH:11][CH:10]=[N:9]2)=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17](=[O:28])[C:18](=[CH:24]OCC)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:15]>>[CH2:14]([O:16][C:17](=[O:28])[C:18](=[CH:24][NH:13][C:12]1[N:8]([CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[N:9]=[CH:10][CH:11]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:15]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccnn1Cc1ccncc1
Product: CCOC(=O)C(=CNc1ccnn1Cc1ccncc1)C(=O)OCC
Yield: 64 %

Procedure:
174 g of 1-(4-picolyl)-5-aminopyrazole and 216 g of ethoxymethylene malonic acid diethyl ester are heated with stirring at 140°, until the theoretical amount of alcohol has distilled off. The reaction mixture crystallizes on cooling. Recrystallization from ethyl acetate yields 220 g of [[[1-(4-picolyl)-5-pyrazolyl]amino]methylene]malonic acid diethyl ester (65%), m.p. 95°-97°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[NH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2>C(O)C>[NH:23]1[C:24]2[C:20](=[CH:19][C:18]([NH:17][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=4)[N:5]=[CH:4][C:3]=3[C:15]#[N:16])=[CH:26][CH:25]=2)[CH:21]=[CH:22]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc2[nH]ccc2c1

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-3-quinolinecarbonitrile, 200 ml ethanol, and 3.40 g (25.8 mmol) 5-aminoindole was heated to reflux under N2 for 3.5 hours. Removed heat, made basic with saturated sodium bicarbonate and stripped solvents, azeotroping with ethanol. Collected solids and washed with hexane, then water. Dissolved solids in 200 ml ethyl acetate, added Darco and filtered. Stripped solvent and dried in vacuo overnight (50° C.). Washed twice more with ether to removed starting material aminoindole. 4.372 g of red-brown solid: mass spectrum (m/e electrospray): M+H=330.2.
Reaction SMILES: C([O:5][C:6](=[O:44])[CH2:7][N:8]1[C:12](=[O:13])[CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][CH:24]([NH:27][CH2:28][C@H:29]([OH:42])[C:30]4[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:31]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[S:10][C:9]1=[O:43])(C)(C)C.ClCCl.FC(F)(F)C(O)=O>C(OCC)C>[OH:42][C@H:29]([C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([NH:37][S:38]([CH3:41])(=[O:39])=[O:40])[CH:31]=1)[CH2:28][NH:27][CH:24]1[CH2:25][CH2:26][N:21]([C:18]2[CH:17]=[CH:16][C:15]([CH2:14][CH:11]3[S:10][C:9](=[O:43])[N:8]([CH2:7][C:6]([OH:44])=[O:5])[C:12]3=[O:13])=[CH:20][CH:19]=2)[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)CN1C(=O)SC(Cc2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(CC4SC(=O)N(CC(=O)O)C4=O)cc3)CC2)ccc1O
Temperature: 25 °C
Reaction time: 10 h
Yield: 69.3 %

Procedure:
A mixture of 5-[[4-[4-[[(R)-2-hydroxy-2-[4-hydroxy-3-[(methylsulfonyl)amino]-phenyl]ethyl]amino]-1-piperidinyl]phenyl]methyl]-2,4-dioxo-3-thiazolidineacetic acid tert-butyl-ester (300 mg, 0.46 mmol) (which was obtained in Example 64), dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) was stirred at room temperature for 10 hours. The mixture was then poured into ethyl ether (50 mL), and the precipitated solid was filtered and dried to give an off-white solid (189 mg, 58% yield); mp 158–160° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.58–1.66 (m, 2H), 2.02–2.10 (m, 2H), 2.60–2.64 (m, 2H), 2.85–3.04 (m, 4H), 3.16–3.40 (m, 4H), 3.80 (m, 2H), 4.20 (s, 2H), 4.80 (m, 1H), 5.06 (m, 1H), 6.17 (brs, 1H), 6.87–6.91 (m, 3H), 7.05–7.1 (m, 3H), 7.23 (m, 1H), 8.60 (brs, 1H), 8.80 (s, 1H), 9.94 (s, 1H), 13.3 (brs, 1H); MS (ES) m/z: 649 (MH+).
Reaction SMILES: CC(C)(C)[C@H](NC(C1N=C(C2C=CC=CC=2)N2CCNCC=12)=O)C(NC)=O.[CH3:28][NH:29][C:30](=[O:37])[C@H:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH2:32].[Br:38][C:39]1[N:43]2[CH2:44][CH2:45][N:46]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:47][C:42]2=[C:41]([C:55](O)=[O:56])[N:40]=1>>[Br:38][C:39]1[N:43]2[CH2:44][CH2:45][N:46]([C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH2:47][C:42]2=[C:41]([C:55](=[O:56])[NH:32][C@@H:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:30]([NH:29][CH3:28])=[O:37])[N:40]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(Br)nc(C(=O)O)c2C1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Agent: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CNCC2)C(C)(C)C
Product: CNC(=O)[C@@H](NC(=O)c1nc(Br)n2c1CN(C(=O)OC(C)(C)C)CC2)C(C)(C)C

Procedure:
Additional compounds 22-29 were synthesized by the same procedure as described above (Examples 1 and 2) for Compound 2 except that in Example 1, alternative amines were used in place of L-tert-Leucine methylamide in the reaction with intermediate Intermediate 1I to form intermediate Intermediate 1J. For example, Compound 22 was synthesized in the same manner as Compound 2 except that (S)-2-amino-3,3-dimethylbutan-1-ol was used in place of L-tert-Leucine methylamide. Compound 23 was synthesized in the same manner as Compound 2 except that (R)-2-amino-3,3-dimethylbutan-1-ol was used in place of L-tert-Leucine methylamide. These resulting intermediates were deprotected with TFA, as described in Example 2, to form additional Compounds 22-29.
Reaction SMILES: C(OC(N1CCC(C2C=CC(Cl)=CC=2)(C#N)CC1)=O)(C)(C)C.C(OC([N:30]1[CH2:35][CH2:34][C:33]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)([C:36]([OH:39])([CH3:38])[CH3:37])[CH2:32][CH2:31]1)=O)(C)(C)C>>[Cl:46][C:43]1[CH:44]=[CH:45][C:40]([C:33]2([C:36]([OH:39])([CH3:37])[CH3:38])[CH2:34][CH2:35][NH:30][CH2:31][CH2:32]2)=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Cl)cc2)(C(C)(C)O)CC1
Agent: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)cc2)CC1
Product: CC(C)(O)C1(c2ccc(Cl)cc2)CCNCC1

Procedure:
The title compound was prepared by following the procedure of Example 456, step 3, but replacing 4-(4-chloro-phenyl)-4-cyano-piperidine-1-carboxylic acid tert-butyl ester with: 4-(4-chloro-phenyl)-4-(1-hydroxy-1-methyl-ethyl)-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: S1C2C=CC=CC=2N=C1COC1C2C=C(F)C=CC=2SC=1C(NC(C)(C)C(O)=O)=O.C[O:32][C:33](=[O:62])[C:34]([NH:37][C:38]([C:40]1[S:44][C:43]2[CH:45]=[CH:46][C:47]([F:49])=[CH:48][C:42]=2[C:41]=1[O:50][CH2:51][C:52]1[CH:53]=[N:54][C:55]([C:58]([F:61])([F:60])[F:59])=[CH:56][CH:57]=1)=[O:39])([CH3:36])[CH3:35]>>[F:49][C:47]1[CH:46]=[CH:45][C:43]2[S:44][C:40]([C:38]([NH:37][C:34]([CH3:35])([CH3:36])[C:33]([OH:62])=[O:32])=[O:39])=[C:41]([O:50][CH2:51][C:52]3[CH:53]=[N:54][C:55]([C:58]([F:60])([F:59])[F:61])=[CH:56][CH:57]=3)[C:42]=2[CH:48]=1
Reactant: COC(=O)C(C)(C)NC(=O)c1sc2ccc(F)cc2c1OCc1ccc(C(F)(F)F)nc1
Agent: CC(C)(NC(=O)c1sc2ccc(F)cc2c1OCc1nc2ccccc2s1)C(=O)O
Product: CC(C)(NC(=O)c1sc2ccc(F)cc2c1OCc1ccc(C(F)(F)F)nc1)C(=O)O

Procedure:
2-{[5-Fluoro-3-(6-trifluoromethyl-pyridin-3-ylmethoxy)-benzo[b]thio-phene-2-carbonyl]-amino}-2-methyl-propionic acid was prepared in similar manner as 2-{[3-(benzothiazol-2-ylmethoxy)-5-fluoro-benzo[b]thiophene-2-carbonyl]-amino}-2-methyl-propionic acid (example 158) via 2-{[5-fluoro-3-(6-trifluoromethyl-pyridin-3-ylmethoxy)-benzo[b]thio-phene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester (C21H18F4N2O4S (470.45), LCMS (ESI): 471.10 (MH+)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11](N3CCC4C=CNC=4C3C)=[O:12])[CH:10]=2)[CH:7]=1.[CH3:23][O:24][C:25]1[O:26][C:27]2[CH2:32][CH2:31][NH:30][CH:29]([CH3:33])[C:28]=2[N:34]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:30]3[CH2:31][CH2:32][C:27]4[O:26][C:25]([O:24][CH3:23])=[N:34][C:28]=4[CH:29]3[CH3:33])=[O:12])[CH:10]=2)[CH:7]=1
Reactant: COc1nc2c(o1)CCNC2C
Reactant: CC1c2[nH]ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Product: COc1nc2c(o1)CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-methyl-1,4,5,7-tetrahydro-pyrrolo[2,3-c]pyridin-6-yl)-methanone is reacted with 2-methoxy-4-methyl-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine to provide the title compound.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)O1.I[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][C@@H:26]([CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:25][CH2:24]2>C1(C)C=CC=CC=1.O1CCOCC1.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]>[C:35]([O:34][C:33]([NH:32][CH2:31][C@H:26]1[CH2:25][CH2:24][C:23]2[C:28](=[CH:29][CH:30]=[C:21]([C:9]3[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=3)[CH:22]=2)[O:27]1)=[O:39])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCc2cc(I)ccc2O1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@H](CNC(=O)OC(C)(C)C)O3)cc1
Temperature: 85 °C
Reaction time: 16 h
Yield: 83.1 %

Procedure:
A solution of methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (Example 15, 1.67 g, 6.36 mmol) in 130 mL toluene and 27 mL 1,4-dioxane was degassed with argon for 10 minutes. tert-Butyl [(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methylcarbamate (Example 12, 1.65 g) and 265 mg (3 mol %) Pd(dppf)Cl2 were then added, and the solution was degassed with argon for an additional 5 minutes. Finally, 26.5 mL of 2M aqueous sodium carbonate was added and the solution was stirred at 85° C. for 16 hours. This mixture was then cooled to ambient temperature, filtered through a pad of Celite®, and concentrated in vacuo. The product was then purified by Biotage (100% methylene chloride to 3% MeOH: methylene chloride) to obtain 1.40 g of product. m/z=397.9 [M+].