Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([O:32][CH2:33][CH3:34])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH3:31].[Li+].[OH-]>>[CH2:33]([O:32][C@@H:4]([CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH3:31])[C:3]([OH:35])=[O:2])[CH3:34]
Reactant: CCO[C@@H](Cc1c(C)cc(OCc2nc(-c3ccc(OC(C)C)cc3)oc2C)cc1C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1c(C)cc(OCc2nc(-c3ccc(OC(C)C)cc3)oc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionic acid methyl ester was treated with LiOH to obtain (S)-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionic acid as colorless foam.
Reaction SMILES: [CH:1]([S:4][CH:5]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19](=[O:21])[CH3:20])[C:6]([Cl:9])([Cl:8])[Cl:7])([CH3:3])[CH3:2].C(O)(=[O:25])C.OO.O>C(OCC)(=O)C>[CH:1]([S:4]([CH:5]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19](=[O:21])[CH3:20])[C:6]([Cl:7])([Cl:9])[Cl:8])=[O:25])([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(=O)Oc1ccccc1C(=O)NC(SC(C)C)C(Cl)(Cl)Cl
Agent: OO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccccc1C(=O)NC(S(=O)C(C)C)C(Cl)(Cl)Cl
Reaction time: 3 h

Procedure:
To 15.0 g of N-(1-iso-propylthio-2,2,2-trichloroethyl)-2-acetoxybenzamide was added 80 ml of acetic acid and 3.8 g of 35% hydrogen peroxide solution was added dropwise thereto under stirring. Then the reaction was effected at 40°-50° C. for three hours and the reaction mixture was poured into water. 100 ml of ethyl acetate was added thereto and the solution was separated, dried, concentrated, washed and dried again to obtain 12.3 g of N-(1-iso-propylsulfinyl-2,2,2-trichloroethyl)-2-acetoxybenzamide.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([O:16]CC)=[O:15])[CH:13]=[C:8]2[CH:7]=[CH:6]1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O>[F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([OH:16])=[O:15])[CH:13]=[C:8]2[CH:7]=[CH:6]1
Reactant: CCOC(=O)c1cc2ccn(Cc3ccc(F)cc3F)c2cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2ccn(Cc3ccc(F)cc3F)c2cn1
Temperature: 100 °C
Yield: 32.9 %

Procedure:
To ethyl 1-(2,4-difluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (0.30 g, 1.58 mmol) in methanol (3 mL) was added sodium hydroxide (0.076 g, 3.16 mmol) in water (0.5 mL). The reaction was heated in a SmithCreator™ (microwave reactor from Personal Chemistry) to 100° C. for five minutes. The reaction solution was poured into water (30 mL) and the pH was adjusted to 2-3 by addition of citric acid. The precipitate that formed was collected by filtration and dried in vacuo to provide the title compound as a white powder (0.15 g, 55%). 1H NMR (DMSO-d6): δ ppm 8.97 (s, 1H), 8.35 (s, 1H), 7.82 (d, 1H, J=3.2 Hz), 7.28-7.38 (m, 2H), 7.09 (t, 1H, J=8.4 Hz), 6.76 (d, 1H, J=3.2 Hz), 5.67 (s, 2H). LCMS (API-ES, M+H+): 289.1
Reaction SMILES: B(Br)(Br)Br.C([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:17][N:18]=2)=[CH:10][CH:9]=1)C.O>ClCCl>[OH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[S:15][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:17][N:18]=2)=[CH:12][CH:13]=1
Reactant: CCCCCCCCc1cnc(-c2ccc(OCC)cc2)s1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCc1cnc(-c2ccc(O)cc2)s1
Reaction time: 8 h

Procedure:
A 1M solution of boron tribromide in dichloromethane (50 cm3) is added dropwise to a solution of 2-(4-ethoxyphenyl)-5-octylthiazole [J. prakt. Chem., (1979) Vol. 321, pp 643](2.0 g) and dichloromethane (50 cm3) at 0° C. under an atmosphere of nitrogen. The reaction solution is stirred overnight and water (100 cm3) added. The organic layer is separated off and the aqueous layer extracted with dichloromethane (2×100 cm3). The combined organic layers are washed with brine (2×100 cm3) and then dried (MgSO4), filtered and evaporated down. The residue is purified by column chromatography on silica gel using a 9:1 hexane/ethyl acetate mixture as eluent and recrystallisation from ethanol to yield 1.0 9 of g 2-(4-hydroxyphenyl)-5-octylthiazole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:6]=1.BrC[CH2:25][C:26]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[N:28]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[N:27]=1.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:22])[CH:4]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])[CH:6]=1)[CH2:25][C:26]1[CH:30]=[C:29]([C:31]2[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=2)[N:28]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[N:27]=1
Reactant: COC(=O)Cc1cn(COCC[Si](C)(C)C)c2ccccc12
Reactant: COc1ccc(-n2nc(CCBr)cc2-c2ccc(C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1cc(-c2ccc(C)cc2)n(-c2ccc(OC)cc2)n1)c1cn(COCC[Si](C)(C)C)c2ccccc12
Yield: 83.9 %

Procedure:
The title compound was synthesized via Method 2 from [1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-3yl]-acetic acid methyl ester (Step A, 0.17 g, 0.56 mmol), 3-bromoethyl-1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazole (Method 1 pyrazole bromide, 0.10 g, 0.28 mmol), sodium hydride (22 mg, 0.56 mmol) and DMF (4.0 mL), yielding 140 mg (84%) of 3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-3-yl]-propionic acid methyl ester. HPLC: Rt=3.91 (Method B). MS (ES+): mass calculated for C35H41N3O4Si, 595.29; m/z found 596.27 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 7.76 (d, J=7.8 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.61 (s, 1H), 7.30 (t, J=7.6 Hz, 1H), 7.27-7.19 (m, 5H), 7.15 (d, J=8.1 Hz, 2H), 7.05 (d, J=9.0 Hz, 2H), 6.44 (s, 1H), 5.64 (s, 2H), 4.47 (t, J=7.6 Hz, 1H), 3.89 (s, 3H), 3.71 (s, 3H), 3.62-3.52 (m, 3H), 3.25 (dd, J=6.6, 14.9 Hz ,1H), 2.40 (s, 3H), 0.87 (t, J=8.0 Hz, 2H), 0.0 (s, 9H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]([CH:20]([CH3:22])[CH3:21])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=2)[CH2:4][C@H:3]1[O:23][CH3:24].[Cl:25][C:26]1[N:27]=[C:28]([C:33](O)=[O:34])[NH:29][C:30]=1[CH2:31][CH3:32].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:25][C:26]1[N:27]=[C:28]([C:33]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[O:9][C:10]([CH:20]([CH3:21])[CH3:22])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=3)[CH2:4][C@H:3]2[O:23][CH3:24])=[O:34])[NH:29][C:30]=1[CH2:31][CH3:32]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OC)C2)oc1C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)oc1C(C)C
Yield: 80.6 %

Procedure:
The same operation as in Example (106d) was performed using butyl cis(±)-2-(4-amino-3-methoxypiperidin-1-yl)-5-isopropyl-1,3-oxazole-4-carboxylate obtained in Example (111c) (0.31 g, 0.91 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.11 g, 0.6 mmol), WSC hydrochloride (0.39 g, 2 mmol), HOBt (0.13 g, 1 mmol), DMA (3 mL) and dichloromethane (3 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 0.24 g of the title compound as a colorless solid (77%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].N1C=CC=CC=1.[C:19](Cl)(=[O:23])[O:20][CH2:21][CH3:22]>C(OCC)(=O)C>[C:19](=[O:23])([O:20][CH2:21][CH3:22])[O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:12]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)OCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of tert-butyl 3-hydroxypropylcarbamate (8.00 g) obtained in Reference Example 40 and ethyl acetate (50 mL) were added pyridine (4.06 mL) and ethyl chlorocarbonate (5.95 g) under ice-cooling, and the mixture was stirred at room temperature for 24 hrs. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL), an aqueous copper sulfate solution (30 mL), water (30 mL) and saturated brine (30 mL), and dried over anhydrous sodium sulfate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].[C:10](Cl)(=[O:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C(C)=CC=CC=1C.BrC1C=C(NC(=O)/C=C/C2C=CC=CC=2)C=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:10](=[O:19])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: O=C(/C=C/c1ccccc1)Nc1cccc(Br)c1
Solvent: Cc1cccc(C)n1
Product: O=C(/C=C/c1ccccc1)Nc1cc(F)cc(F)c1

Procedure:
The compound was prepared from 3,5-difluoroaniline (5 g, 38.7 mmol) and cinnamoylchloride (6.45 g, 38.7 mmol) in the presence of 2,6-lutidine (6.8 mL, 58 mmol) as described for Intermediate 18 to give a colorless solid, 8.1 g (81%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:18]([CH3:20])[CH3:19])[C:10](=O)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].N12CCN(CC1)CC2.C[N:36](/[CH:38]=[C:39](\[Cl:44])/[CH:40]=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])(=O)C.[NH4+]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:10]1[N:36]=[CH:38][C:39]([Cl:44])=[CH:40][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:18]([CH3:20])[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Reactant: CN(C)/C=C(\Cl)C=[N+](C)C
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Cl)cnc1[C@@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.6 %

Procedure:
To a mixture of ethyl(S)-4-((tert-butoxycarbonyl)amino)-5-methyl-3-oxohexanoate (9.68 g, 33.7 mmol) from above in THF (100 mL) at 0° C. was added potassium tert-butoxide (3.78 g, 35.4 mmol). The mixture was warmed to rt and stirred for 45 min, at which point 1,4-diazabicyclo[2.2.2]octane (3.78 g, 33.7 mmol) and 2-chloro-1,3-bis(dimethylamino)trimethinium hexaflurophosphate (15.5 g, 50.5 mmol) were added successively. The mixture was heated to 45° C. and stirred for 3 h, at which point ammonium acetate (5.19 g, 67.4 mmol) was added. The mixture was then heated to reflux and stirred for 15 h. It was then cooled to rt and concentrated under reduced pressure. The residue was dry-loaded onto a silica gel column and purified (eluting with 5% EtOAc in hexanes, gradient to 15%) to yield 6.09 g of ethyl(S)-2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloronicotinate (51%). LC-MS tR=1.14 min in 1 min chromatography, MS (ESI) m/z 357.3 [M+H]+. 1H NMR (CDCl3, 400 MHz): δ 8.61 (d, J=2.4 Hz, 1H), 8.18 (d, J=2.8 Hz, 1H), 5.71 (d, J=9.6 Hz, 1H), 5.62 (dd, J=5.2 Hz, 9.6 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 2.08-2.00 (m, 1H), 1.42 (s, 9H), 1.42 (t, J=7.2 Hz, 3H), 0.93 (d, J=6.4 Hz, 3H), 0.83 (d, J=6.4 Hz, 3H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:5]([Cl:16])=[N:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:23][C:24]1[C:25](B(O)O)=[CH:26][C:27]([F:30])=[N:28][CH:29]=1.C(Cl)Cl>COCCOC.CCOC(C)=O.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]>[Cl:16][C:5]1[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:7][C:2]([C:25]2[C:24]([Cl:23])=[CH:29][N:28]=[C:27]([F:30])[CH:26]=2)=[CH:3][N:4]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: Clc1ncc(Br)nc1NCC1CCOCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Fc1cc(-c2cnc(Cl)c(NCC3CCOCC3)n2)c(Cl)cn1
Temperature: 100 °C
Yield: 38.4 %

Procedure:
To a degassed suspension of 6-bromo-3-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (358 mg, 1.168 mmol), Na2CO3 (1.518 ml, 3.04 mmol) and 5-chloro-2-fluoropyridin-4-ylboronic acid (307 mg, 1.752 mmol) in DME (5 ml) was added PdCl2(dppf).CH2Cl2 adduct (76 mg, 0.093 mmol). The reaction mixture was capped in a flask and heated to 100° C. for 4 hr an oil bath. The reaction mixture was diluted with EtOAc and washed with H2O saturated NaCl. The organic layer was dried Na2SO4, filtered and concentrated. The crude oil/solid was purified column chromatography on silica gel (30% EtOAc/Hexane) to yield 3-chloro-6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (160 mg, 0.448 mmol, 38.4% yield), LCMS (m/z): 357.0 (MH+), retention time=1.02 min.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH:6]([CH2:8][CH2:9][OH:10])[NH2:7].C(N(CC)CC)C>C(Cl)Cl>[NH2:7][N:6]([CH2:8][CH2:9][OH:10])[C:2](=[O:3])[O:4][CH3:5]
Reactant: NNCCO
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N(N)CCO
Reaction time: 3 h
Yield: 98.9 %

Procedure:
At 0-5° C., 248.4 g (2.628 mol) of methyl chloroformate were added with stirring, over a period of 30 min, to a mixture of 200 g (2.628 mol) of 2-hydrazinoethanol and 266 g (2.628 mol) of triethylamine in 1600 ml of methylene chloride. After 3 h of stirring at from 3 to 22 C, the resulting hydrochloride was removed by filtration and washed with THF. The filtrates were combined. The filter cake was suspended in 800 ml of THF and filtered again. This filtrate, too, was combined with the previous filtrate. The combined filtrates were concentrated under reduced pressure. This gave 366 g of the title compound as colorless oil having an HPLC purity of 95.3%, corresponding to a yield of 98.9% of theory. According to GC, the purity was 85.2%.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:63])([CH3:62])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[N+:58]([O-:60])=[O:59])[C:47]1=[O:61])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:63])([CH3:62])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[N+:58]([O-:60])=[O:59])[C:47]1=[O:61])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2ccccc2[N+](=O)[O-])C1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2[N+](=O)[O-])C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
A solution containing the product from Example 2C (0.082 g, 0.154 mmol) in THF (1.5 mL) was treated with the product from Example 123A (0.057 g, 0.17 mmol), DEPBT (0.069 g, 0.231 mmol), and N,N-diisopropylethylamine (0.135 mL, 0.77 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% acetate/dichloromethane, followed by 0-5% methanol in ethyl acetate to give the title compound (0.080 g, 61% yield).
Reaction SMILES: [CH2:1]([N:7]1[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[C:10]([CH3:17])=[C:9]([N+:18]([O-])=O)[C:8]1=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>C(OCC)(=O)C.[Pd]>[NH2:18][C:9]1[C:8](=[O:21])[N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[C:10]=1[CH3:17]
Reactant: CCCCCCn1cc(C(=O)OC)c(C)c([N+](=O)[O-])c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCn1cc(C(=O)OC)c(C)c(N)c1=O
Yield: 101.9 %

Procedure:
A mixture of 1-hexyl-4-methyl-3-nitro-5-methoxycarbonyl-2-pyridone (0.145 g, 0.49 mmol) and a catalytic amount of 10% Pd/C in ethyl acetate (100 mL) was hydrogenated at 45 psi in a Parr apparatus for 5 hours. The catalyst was removed by filtration and the solvent was evaporated to give 3-amino-1-hexyl-4-methyl-5-methoxycarbonyl-2-pyridone (0.133 g, 100%).
Reaction SMILES: Br[C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.CCN(CC)CC.[C:18]([PH2:22])([CH3:21])([CH3:20])[CH3:19]>C1(C)C=CC=CC=1.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>[C:18]([PH:22][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)P
Reactant: BrC1=Cc2ccccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)PC1=Cc2ccccc2C1
Temperature: 25 °C

Procedure:
To 9.61 g (0.049 mol) of 2-bromo-1H-indene and 1.13 g (0.98 mmol) of Pd(PPh3)4 in 25 ml of toluene, 7.5 ml (5.45 g, 0.054 mol) of Et3N and 4.88 g (0.054 mol) of tBuPH2 were added. This mixture was refluxed for 14 hours, cooled to room temperature, and filtered through glass frit (G3) to separate out compound 15. The filtrate was evaporated to dryness. The crude product was distilled in vacuum (108–110° C./3 mm). Yield 3.07 g (31%) of crystalline solid of 14.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[N:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:30]3[CH2:29][CH2:28][CH2:27][NH:26][C:25]=3[CH:24]=[N:23]2)=[CH:18][CH:17]=1>C(Cl)(Cl)Cl>[F:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:30]3[CH2:29][CH2:28][CH2:27][N:26]([C:8](=[O:10])[CH2:7][N:6]4[C:2]([CH3:1])=[N:3][C:4]([C:11]([F:14])([F:13])[F:12])=[N:5]4)[C:25]=3[CH:24]=[N:23]2)=[CH:20][CH:21]=1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: Cc1nc(C(F)(F)F)nn1CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1nc(C(F)(F)F)nn1CC(=O)N1CCCc2c1cnn2-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2-(5-methyl-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)acetic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method B. The product mixture was diluted with 1 mL of CHCl3 and washed with H2O. The organic layer was concentrated and the residue was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to provide 37 mg of the title compound as a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.34 (s, 0.8H), 7.59 (s, 0.2H), 7.44-7.50 (m, 2H), 7.14-7.27 (m, 2H), 5.29 (s, 0.4H), 5.18 (s, 1.6H), 3.93 (m, 0.4H), 3.86 (m, 1.6H), 2.88 (m, 2H), 2.56 (s, 2.4H), 2.55 (m, 0.6H), 2.14 (m, 1.6H), 2.06 (m, 0.4H); MS: (ES) m/z calculated for C18H17F4N6O [M+H]+ 409.1, found 409.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH2:9][N+:10]([O-])=O)[CH:5]=[CH:6][CH:7]=1>[Ni].CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([O:13][Si:14]([CH2:15][CH3:16])([CH2:19][CH3:20])[CH2:17][CH3:18])[CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC[Si](CC)(CC)OC(C[N+](=O)[O-])c1cccc(Cl)c1
Agent: [Ni]
Solvent: CO
Product: CC[Si](CC)(CC)OC(CN)c1cccc(Cl)c1
Yield: 61.2 %

Procedure:
Raney nickel (1 g) was washed with distilled water five times and methanol three times. [1-(3-Chloro-phenyl)-2-nitro-ethoxy]-triethyl-silane (10 g, 0.032 mol) and Raney nickel in methanol (100 mL) was hydrogenated (35 psi) at room temperature for 14 h. The reaction mixture was filtered through a pad of celite and rinsed with methanol. Concentration of the filtrate to dryness gave the title compound (5.6 g, 62%) as a colorless oil which was used for the next step without purification. 1H NMR (300 MHz, CDCl3) δ 7.32 (1H, s), 7.18–7.26 (3H, m), 4.70 (1H, t, J=5.8 Hz), 2.86 (2H, m), 0.89 (9H, t, J=7.9 Hz), 0.56 (6H, q, J=7.8 Hz). LRMS (M+H)+ m/z 286.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:40])[C@H:7]([CH2:15][C:16]1[CH:21]=[C:20]([I:22])[C:19]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)=[C:18]([I:39])[CH:17]=1)[NH:8]C(=O)C(F)(F)F.Cl>O1CCCC1.O>[OH:38][C:35]1[CH:34]=[CH:33][C:32]([O:31][C:28]2[CH:29]=[CH:30][C:25]([CH2:24][O:23][C:19]3[C:18]([I:39])=[CH:17][C:16]([CH2:15][C@@H:7]([C:6]([OH:40])=[O:5])[NH2:8])=[CH:21][C:20]=3[I:22])=[CH:26][CH:27]=2)=[CH:37][CH:36]=1
Reactant: COC(=O)[C@H](Cc1cc(I)c(OCc2ccc(Oc3ccc(O)cc3)cc2)c(I)c1)NC(=O)C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H](Cc1cc(I)c(OCc2ccc(Oc3ccc(O)cc3)cc2)c(I)c1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
Lithium hydroxide monohydrate (47 mg, 1.12 mmol) was added to a solution of N-trifluoroacetyl-O-[4-(4-hydroxy-phenoxy)benzyl]-3,5-diiodo-L-tyrosine methyl ester (235 mg, 0.317 mmol) in tetrahydrofuran (2 ml)-water (1 ml) under ice cooling and the mixture was reacted at room temperature for 7.5 hrs., and then at 0-5° C. for 16 hrs. The reaction mixture was diluted with water, adjusted to pH 4-5 under ice cooling with 1N hydrochloric acid (0.79 ml) and stirred at room temperature for 1.5 hrs. The precipitates were collected by filtration, washed with water and ethanol in turn and dried to give O-[4-(4-hydroxyphenoxy)benzyl]-3,5-diiodo-L-tyrosine (188 mg, 90%) as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([O:18][CH2:19][CH2:20][O:21][CH3:22])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:23][C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([NH2:33])=[CH:28][CH:27]=2>>[CH3:22][O:21][CH2:20][CH2:19][O:18][C@@H:15]1[CH2:16][CH2:17][N:13]([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:33][C:29]3[CH:30]=[C:31]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24]([CH3:23])=[CH:32]4)[CH:8]=2)=[O:12])[CH2:14]1
Reactant: COCCO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: COCCO[C@@H]1CCN(C(=O)c2cc3nccc(Nc4ccc5[nH]c(C)cc5c4)c3s2)C1

Procedure:
The title compound was prepared from (3R)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-[3-(2-methoxy-ethoxy)-pyrrolidin-1-yl]-methanone and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 451.3 (MH+); HPLC Rf: 4.385 min.; HPLC purity: 97%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[CH2:5][OH:6].[H][H]>CO.[Pd]>[NH2:10][C:9]1[CH:8]=[CH:7][C:4]([CH2:5][OH:6])=[CH:3][C:2]=1[CH3:1]
Reactant: [H][H]
Reactant: Cc1cc(CO)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(CO)ccc1N
Yield: 91.1 %

Procedure:
A solution of 3-methyl-4-nitrobenzyl alcohol (Aldrich; 2.000 g; 12.0 mmol) in MeOH (90 ml) is passed through the H-Cube flow hydrogenator fitted with a 10 mol % Pd/C catalyst cartridge (30×4 mm) heated to 25° C. with the full hydrogen option enabled. The flow rate is set at 1 mL/min. Solvent was removed to give the title compound (1.50 g, 91.4%) without further purification.