Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[N+:12]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[N:8]=[CH:9][O:10][CH:11]=2)=[CH:6][CH:5]=1)([O-:14])=[O:13]
Reactant: c1ccc(-c2cocn2)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(-c2cocn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
4-Phenyloxazole (1 g, 6.89 mmol) was dissolved in concentrated sulfuric acid (5 mL) at 0° C. A cold solution of nitrating mixture (prepared by adding 3 mL conc. nitric acid to 5 mL of ice-cold conc. sulfuric acid) was added over 10 minutes. The mixture was allowed to warm to r.t. and stirred for 1 h. The resulting solution was poured into ice-cold water giving a white precipitate, which was filtered and washed thoroughly with water. The solid was dissolved in DCM and washed with water then brine. The organic phase was dried over sodium sulfate and concentrated to yield 4-(4-nitro-phenyl)-oxazole (550 mg, 42%) as a white solid.
Reaction SMILES: [NH2:1][N:2]1[C:6]([CH2:7][CH3:8])=[CH:5][CH:4]=[C:3]1[C:9]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15])=O.[CH3:19][C:20](=O)[CH2:21][C:22](=[O:24])[CH3:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:22]([C:21]1[C:20]([CH3:19])=[N:1][N:2]2[C:6]([CH2:7][CH3:8])=[CH:5][CH:4]=[C:3]2[C:9]=1[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15])(=[O:24])[CH3:23]
Reactant: CCc1ccc(C(=O)c2cccc(C#N)c2)n1N
Reactant: CC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1ccc2c(-c3cccc(C#N)c3)c(C(C)=O)c(C)nn12
Yield: 24.8 %

Procedure:
To a solution of 3-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (200 mg) in toluene (6 mL) was added 2,4-pentanedione (837 mg) and p-toluenesulfonic acid monohydrate (32 mg) at ambient temperature. The reaction mixture was refluxed for 1 hour. The residue was purified by flash silica gel chromatography (silica gel, 80 mL) eluted with hexane-ethyl acetate=10-1 to give 3-(3-acetyl-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl)benzonitrile (63 mg, 24.8%) as an yellow solid.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH2:9][CH2:10][CH3:11])[NH:5][C:6]=1[CH:7]=[O:8].C1(C)C=CC=CC=1.[C:19]1(B(O)O)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:27]1([C:2]2[N:3]=[C:4]([CH2:9][CH2:10][CH3:11])[NH:5][C:6]=2[CH:7]=[O:8])[C:28]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: CCCc1nc(I)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCc1nc(-c2cccc3ccccc23)c(C=O)[nH]1
Reaction time: 0.08 h

Procedure:
A solution of 2.64 g (0.01 mol) of 4-iodo-2-n-propylimidazole-5-carboxaldehyde, toluene (40 mL), and 0.33 g (0.00029 mol) of tetrakistriphenylphosphine palladium (0) was stirred at room temperature under nitrogen, while a solution of 3.44 g (0.022 mol) of 1-naphthylboronic acid in 50 mL of ethanol was slowly added. The reaction was stirred for 5 minutes, after which 12 mL of 2M sodium carbonate was slowly added. After the addition was completed, the reaction was refluxed for 48 h and cooled. The reaction was filtered, the filtrate was evaporated under reduced pressure, and the resulting residue was dissolved in 300 mL of methylene chloride, washed twice with 100 mL of saturated sodium chloride solution, washed twice with 100 mL of distilled water, and washed twice with 300 mL of 10% HCl. The HCl layer was made basic with 50% sodium hydroxide until the pH=10. At this point, the basic water layer was extracted three times with 300 mL of methylene chloride, the methylene chloride layer was dried over sodium sulfate and evaporated under reduced pressure. Yield: 0.90 g (0.0034 mol, 34%) of product. NMR (CDCl3) δ 11.45 (m, 1H); 9.42 (s, 1H); 7.28 (m, 7H); 2.82 (t, 2H); 1.85 (m, 2H); 1.01 (t, 3H). ##STR75##
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[CH3:20][O:21][CH2:22][C:23]([CH3:27])([OH:26])[C:24]#[CH:25]>CN(C=O)C.CCN(CC)CC.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6]([C:25]#[C:24][C:23]([OH:26])([CH3:27])[CH2:22][O:21][CH3:20])[N:5]=2
Reactant: C#CC(C)(O)COC
Reactant: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(Cl)nc21
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(C#CC(C)(O)COC)nc21

Procedure:
A suspension of 3 g (10.69 mmol) of 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxamide in 20 ml of a DMF/Et3N mixture (V/V; 1/1) is placed in an 80 ml microwave tube. This suspension is sparged with argon for 10 minutes and then 1.83 g of (±)-1-methoxy-2-methyl-3-butyn-2-ol (16.03 mmol), 0.081 g of CuI (0.43 mmol) and 0.375 g of bis(triphenylphosphine) palladium(II)dichloride (0.53 mmol) are successively added.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:15])([CH3:14])[C@H:8]1[O:12][C:11]([NH2:13])=[N:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:16](OCC)(=[O:19])[C:17]#[CH:18]>C(O)C>[C:1]([SiH2:5][O:6][C:7]([CH3:15])([CH3:14])[C@H:8]1[O:12][C:11]2=[N:13][C:16](=[O:19])[CH:17]=[CH:18][N:10]2[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1CN=C(N)O1
Reactant: C#CC(=O)OCC
Solvent: CCO
Product: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1Cn2ccc(=O)nc2O1
Temperature: 25 °C

Procedure:
To a solution of (S)-5-(tert-butyl-dimethyl-silanyloxymethyl)-4,5-dihydro-oxazol-2-ylamine (6.65 g, 28.9 mmol) in ethanol (150 mL) was added ethyl propiolate (2.92 mL, 28.9 mmol). The reaction mixture was stirred at reflux for 2 hours. The mixture was cooled to room temperature, concentrated under vacuum and purified by column chromatography on silica gel (0-10% methanol in dichloromethane). This afforded 2.45 g (30%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[NH:14]([CH2:16]C(O)=O)[CH3:15].O>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:9])[CH2:15][N:14]([CH3:16])[C:7](=[O:8])[C:6]=2[CH:13]=1
Reactant: CNCC(=O)O
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Solvent: CS(C)=O
Solvent: O
Product: CN1CC(=O)Nc2ccc(F)cc2C1=O
Temperature: 100 °C

Procedure:
24 g (132.5 mmol) of 5-fluoroisatoic acid anhydride are dissolved in 140 ml of dimethyl sulphoxide and treated with 11.8 g (132.5 mmol) of sarcosine. The solution is stirred at 100° C. until the gas evolution ceases (duration: ca 1.5 hours) and subsequently poured into ca 1.2 liters of water. After stirring for 10 minutes, a solid crystallises out. The crystals are filtered off under suction, washed with 1 liter of water and dried. There is obtained 7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione of melting point 262°-263° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([N+:17]([O-:19])=[O:18])=[CH:9][C:8]=1[N+:20]([O-:22])=[O:21])(=O)=O.[Na+].[I-:26]>CCOC(C)=O>[I:26][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([N+:17]([O-:19])=[O:18])=[CH:9][C:8]=1[N+:20]([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c2ccccc2c1OS(=O)(=O)C(F)(F)F
Reactant: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c2ccccc2c1I
Temperature: 25 °C
Yield: 91.2 %

Procedure:
A solution of (2) (5.0 g, 13.7 mmol) and NaI (7.0 g) in EtOAc (200 mL) was heated under reflux for 2 h. The mixture was cooled to room temperature and washed with sat. aq. Na2S2O3. The organic phase was dried, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel. Elution with CH2Cl2, gave 1-iodo-2,4-dinitronaphthalene (3) (4.3 g 91%) as yellow needle: mp (EtOAc/CH2Cl2) 194–195° C.; 1H NMR [(CD3)2SO] δ 8.76 (s, 1H, H-3), 8.54 (m, 1H), 8.33 (m, 1H), 8.00(m, 2H); 13C NMR δ 151.81, 147.05, 134.97, 132.18, 131.24, 123.88, 123.26, 117.50, 102.66. Anal. (C10H5IN2O4) C, H, N.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([N+:31]([O-])=O)[CH:22]=3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)([O-])=O.[H][H]>[Pd].COCCO>[NH2:31][C:23]1[CH:22]=[C:21]([CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=1)[O:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][C:6]3[CH:34]=[C:35]([C:37]([F:38])([F:40])[F:39])[CH:36]=[C:4]([NH2:1])[CH:5]=3)=[CH:9][CH:10]=2)=[CH:15][CH:16]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Oc2ccc(-c3ccc(Oc4cc([N+](=O)[O-])cc(C(F)(F)F)c4)cc3)cc2)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: COCCO
Product: Nc1cc(Oc2ccc(-c3ccc(Oc4cc(N)cc(C(F)(F)F)c4)cc3)cc2)cc(C(F)(F)F)c1
Yield: 96 %

Procedure:
To a reducing apparatus equipped with a thermometer, reflux condenser and stirrer, 33 g (0.0585 mol) of 4,4'-bis(3-nitro-5-trifluoromethylphenoxy) biphenyl, 100 ml of methyl cellosolve and 1.7 g of 5%-Pd/c having a moisture content of 50% were charged and reacted in a hydrogen atmosphere at 70°~80° C. for 4 hours. After finishing the reaction, the catalyst was filtered off. The filtrate was concentrated under reduced pressure to obtain 4,4'-bis(3-amino-5-trifluoromethylphenoxy) biphenyl as light yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([N:17]2[CH:21]=[C:20]([C:22](O)=[O:23])[C:19]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:18]2)([CH2:14][C:15]#[N:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[CH2:33][N:34](C(C)C)C(C)C.CN.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[C:15]([CH2:14][C:11]1([N:17]2[CH:21]=[C:20]([C:22](=[O:23])[NH:34][CH3:33])[C:19]([NH:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:18]2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]1)#[N:16]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(C(=O)O)c(Nc3ccccc3)n2)CC1
Agent: CN
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CNC(=O)c1cn(C2(CC#N)CCN(C(=O)OC(C)(C)C)CC2)nc1Nc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 1-[1-(tert-butoxycarbonyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxylic acid (25 mg, 0.059 mmol) in DCM (0.6 mL) was added DIPEA (0.030 mL, 0.18 mmol), methylamine (0.040 mL, 0.082 mmol, 2.0 M in THF), HOBT (13 mg, 0.082 mmol), and EDC (16 mg, 0.082 mmol). The resulting mixture was maintained at ambient temperature for 18 hours, then purified directly by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](I)=[C:9]([CH3:11])[N:10]=[C:4]2[CH:3]=1.[F:13][C:14]1[CH:15]=[CH:16][C:17]2=[C:18]([CH:34]=1)[O:19][CH2:20][C:21]1[CH:31]=[C:30]([CH:32]=[O:33])[CH:29]=[CH:28][C:22]=1/[C:23]/2=[C:24](/[CH3:27])\[C:25]#[N:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH:32]([OH:33])[C:30]3[CH:29]=[CH:28][C:22]4/[C:23](=[C:24](/[CH3:27])\[C:25]#[N:26])/[C:17]5[CH:16]=[CH:15][C:14]([F:13])=[CH:34][C:18]=5[O:19][CH2:20][C:21]=4[CH:31]=3)=[C:9]([CH3:11])[N:10]=[C:4]2[CH:3]=1
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Reactant: Cc1nc2cc(Cl)ccn2c1I
Product: C/C(C#N)=C1/c2ccc(C(O)c3c(C)nc4cc(Cl)ccn34)cc2COc2cc(F)ccc21
Yield: 85.3 %

Procedure:
[step 3] Using 7-chloro-3-iodo-2-methylimidazo[1,2-a]pyridine (700 mg, 2.39 mmol) obtained in step 2 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (351 mg, 1.20 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8F, step 4, (E)-2-(8-{[7-chloro-2-methylimidazo[1,2-a]pyridin-3-yl](hydroxy)methyl}-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (471 mg, 86%) was obtained.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[N:24][C:23]([NH:26][CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)=[CH:22][N:21]=2)=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.O[CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl>[NH2:8][C@@H:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[N:24][C:23]([NH:26][CH2:27][C:28]3[CH:37]=[CH:36][C:31]4[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:29]=3)=[CH:22][N:21]=2)=[CH:18][CH:19]=1)[C:10]([O:12][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[O:11]
Reactant: OCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cnc(NCc3ccc4ccccc4c3)cn2)cc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N[C@@H](Cc1ccc(-c2cnc(NCc3ccc4ccccc4c3)cn2)cc1)C(=O)OCCN1CCOCC1
Reaction time: 8 h
Yield: 4.3 %

Procedure:
(S)-2-(Tert-butoxycarbonylamino)-3-(4-(5-(naphthalen-2-ylmethylamino)pyrazin-2-yl)phenyl)propanoic acid (48 mg, 0.090 mmol), 4-(2-hydroxyethyl)morpholine (12 mg, 0.090 mmol), triethylamine (18 mg, 0.180 mmol), and benzotriazole-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (BOP, 18 mg, 0.090 mmol), in dichloromethane (3.0 ml) were stirred at room temperature for 5 hours. Additional triethylamine (18 mg, 0.180 mmol) and BOP (18 mg, 0.090 mmol) were added, and the mixture was stirred overnight. The mixture was concentrated and purified via prep HPLC to give 2 mg of the captioned compound.
Reaction SMILES: C([O:8][C:9]1[CH:56]=[CH:55][CH:54]=[CH:53][C:10]=1[CH2:11][S:12]([NH:15][CH2:16][CH2:17][C:18]1[N:19]([CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:20]2[C:25]([C:26]=1[CH2:27][CH2:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=1)=[CH:24][C:23]([Cl:39])=[CH:22][CH:21]=2)(=[O:14])=[O:13])C1C=CC=CC=1.[CH2:57]1COCC1>[Pd].CO>[CH3:57][O:36][C:34](=[O:35])[C:33]1[CH:37]=[CH:38][C:30]([O:29][CH2:28][CH2:27][C:26]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Cl:39])[CH:24]=3)[N:19]([CH:40]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:18]=2[CH2:17][CH2:16][NH:15][S:12]([CH2:11][C:10]2[CH:53]=[CH:54][CH:55]=[CH:56][C:9]=2[OH:8])(=[O:13])=[O:14])=[CH:31][CH:32]=1
Reactant: C1CCOC1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3OCc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To 4-{2-[2-[2-({[2-(benzyloxy)benzyl]sulfonyl}amino)ethyl]-5-chloro-1-(diphenylmethyl)-1H-indol-3-yl]ethoxy}benzoic acid (Step 9, Example 1, 109 mg, 0.14 mmol) was added THF and MeOH. 10% of Pd/C (11 mg) was added. The mixture was stirred at room temperature under H2 (1 atm) overnight and filtered through celite, concentrated, and column chromatographed (35% EtOAc/hex) to give 4-(2-{1-benzhydryl-5-chloro-2-[2-(2-hydroxy-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid methyl ester (74 mg, 76%), an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH3:8].[C@H:10]12[CH2:16][C@H:13]([NH:14][CH2:15]1)[CH2:12][N:11]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:14]2[CH2:15][C@@H:10]3[CH2:16][C@H:13]2[CH2:12][N:11]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(Cl)nnc1Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Product: Cc1cc(N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)nnc1Cl
Yield: 56 %

Procedure:
3,6-Dichloro-4-methylpyridazine (Aldrich Chemical Company) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), were processed as described in Example 2A to provide the title compound (56% yield). 1H NMR (CDCl3, 300 MHz) δ 1.41 (s, 4.5H), 1.43 (s, 4.5H), 1.90-2.09 (m, 2H), 2.31(s, 3H), 3.35-3.45 (m, 3H), 3.53-3.60(m, 1H), 4.56(s, 0.5H), 4.69(s, 0.5H), 4.90(s, 0.5H), 5.08(s, 0.5H), 6.48(s, 1H); MS (DCI/NH3) m/z 325 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:17]=3)[NH:12][N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34]>C1COCC1>[C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][N:35]([CH2:36][CH3:37])[CH2:33][CH3:34])[CH:17]=3)[NH:12][N:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4ccccc4)c3c2)cc1
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc2[nH]nc(S(=O)(=O)c3ccccc3)c2c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 46.7 %

Procedure:
A solution of toluene-4-sulfonic acid 2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl ester (0.420 g, 0.889 mmol) and diethylamine (1.0 mL, 9.7 mmol) in THF (8 mL) was stirred at 70° C. for 6 hours in a sealed tube. Additional diethylamine (1.0 mL, 9.7 mmol) was added, and the reaction mixture was stirred at 80° C. in a sealed tube for an 6 hours. After cooling somewhat, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 7.5% methanol in chloroform. After drying in vacuo at 80° C. for 20 minutes, [2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl]-diethyl-amine as a pale yellow solid (0.155 g, 46.6%) was obtained. This was dissolved in methanol and chloroform and ethereal hydrochloride was added. The mixture was concentrated and dried in vacuo at 74° C. for 13.5 hours to yield the hydrochloride as a light orange foam (0.163 g); Mass Spectrum (+EI, [M+H]+) m/z 374. 1HNMR (500 MHz, DMSO-d6): δ14.24 (s, 1H), 9.94 (br, 1H), 7.96-7.99 (m, 2H), 7.56-7.68 (m, 4H), 7.41 (d, 1H, J=2.20 Hz), 7.16-7.19 (m, 1H), 4.40-4.43 (m, 2H), 3.52 (br, 2H), 3.19-3.23 (m, 4H), 1.23 ppm (t, 6H, J=7.20 Hz). Elemental Analysis for C19H23N3O3S.1.00 mol HCl.0.20 mol H2O: Calcd: C, 55.18; H, 5.95; N, 10.16; Found: C, 54.85; H, 5.85; N, 10.02.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:8][C:9]([CH2:11][O:12][NH2:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=O)[C:27]([OH:29])=[O:28])[N:25]=1.CO>CN(C)C=O>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:13]/[O:12][CH2:11][C:9]([O:8][CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:10])/[C:27]([OH:29])=[O:28])[N:25]=1
Reactant: NOCC(=O)OC(c1ccccc1)c1ccccc1
Reactant: Nc1nc(C(=O)C(=O)O)cs1
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1nc(/C(=N/OCC(=O)OC(c2ccccc2)c2ccccc2)C(=O)O)cs1
Yield: 76.1 %

Procedure:
16.5 g of O-diphenylmethoxycarbonylmethylhydroxylamine and 9.9 g of (2-amino-4-thiazolyl)glyoxylic acid are stirred for 3 hours at room temperature in 30 ml of dimethylformamide. The reaction mixture is introduced into 500 ml of methanol, and the resultant deposit is filtered off. 18 g of the title compound are obtained as colourless crystals. M.p.: 125°.
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])[CH2:2][CH:3]=[CH2:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C@:52]1([C:61]2[CH:66]=[CH:65][C:64]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[C:63]([CH:73]=[CH2:74])[CH:62]=2)[CH2:56][NH:55][C@H:54]([C:57]([O:59][CH3:60])=[O:58])[CH2:53]1>C(Cl)Cl>[CH2:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([N:55]1[CH2:56][C@:52]([O:51][CH3:50])([C:61]2[CH:66]=[CH:65][C:64]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[C:63]([CH:73]=[CH2:74])[CH:62]=2)[CH2:53][C@H:54]1[C:57]([O:59][CH3:60])=[O:58])=[O:12])=[O:7])[CH2:2][CH:3]=[CH2:4]
Reactant: C=Cc1cc([C@@]2(OC)CN[C@H](C(=O)OC)C2)ccc1-c1ccccc1
Reactant: C=CCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCOC(=O)N[C@H](C(=O)N1C[C@](OC)(c2ccc(-c3ccccc3)c(C=C)c2)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
(S)-2-((but-3-enyloxy)carbonylamino)-3,3-dimethylbutanoic acid (117 mg, 0.511 mmol), DIEA (0.179 mL, 1.022 mmol) and HATU (143 mg, 0.375 mmol) were added to a solution of (2S,4R)-methyl 4-methoxy-4-(2-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (115 mg, 0.341 mmol) in DCM (4 mL). The reaction was stirred at r.t. overnight. The reaction was evaporated and purified by flash chromatography on the Biotage (0-40% EtOAc:Hex) to give (2S,4R)-methyl 1-((S)-2-((but-3-enyloxy)carbonylamino)-3,3-dimethylbutanoyl)-4-methoxy-4-(2-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (150 mg, 0.273 mmol, 80% yield) as a white foam. LCMS: rt=1.89 min. [M+Na]+=571; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.
Reaction SMILES: [NH2:1][C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][C:4]1[CH:11]=[C:9]([I:10])[C:8]([O:12][C:13]2[CH:20]=[C:18]([I:19])[C:17]([OH:21])=[C:15]([I:16])[CH:14]=2)=[C:6]([I:7])[CH:5]=1.[CH3:25][C:26](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:27].O>C1COCC1.CN(C)C1C=CN=CC=1>[C:26]([O:23][C:22](=[O:24])[C@H:2]([CH2:3][C:4]1[CH:5]=[C:6]([I:7])[C:8]([O:12][C:13]2[CH:14]=[C:15]([I:16])[C:17]([OH:21])=[C:18]([I:19])[CH:20]=2)=[C:9]([I:10])[CH:11]=1)[NH2:1])(=[O:27])[CH3:25]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OC(=O)[C@@H](N)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Reaction time: 0.75 h
Yield: 115.5 %

Procedure:
The N-FMOC protected L-Thyroxine (26.3 g, 23.2 mmol) was dissolved in 150 mL THF, 3.28 mL (34.8 mmol) of acetic arthydride added, 283 mg (2.32 mmol) of 4-dimethylaminopyridine added, and reaction stirred under N2 for 45 minutes, then poured into 400 mL H2O and extracted with CHCl3 (3×400 mL). The CHCl3 extracts were combined, dried over Na2SO4, and solvent removed in vacuo. The residue was then purified by silica gel column chromatography, eluting with CH2 Cl2/MeOH/HOAc (90/10/0.4, v/v), to yield 21.95 g (91%) of the desired O-acetyl thyroxine as a beige solid; 1H NMR (300 MHz, DMSO-D6) d 7.12-7.91 (m, 12H), 4.07-4.31 (m, 4H), 3.07-3.19 (m, 1H), 2.82 (t, 1H), 2.29-2.40 (m, 3H); mass spec (FAB) (M+H)+1042.
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13](=[O:45])[CH2:14][NH:15][C@H:16]([CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)[C:17]([N:19]1[CH2:22][CH2:21][C@H:20]1[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[N:34]1[CH:38]=[N:37][CH:36]=[N:35]1)=[O:24])=[O:18])(C)(C)C>C(Cl)Cl>[Cl:33][C:31]1[CH:30]=[CH:29][C:28]([N:34]2[CH:38]=[N:37][CH:36]=[N:35]2)=[C:27]([CH:32]=1)[CH2:26][NH:25][C:23]([C@@H:20]1[CH2:21][CH2:22][N:19]1[C:17](=[O:18])[C@H:16]([NH:15][CH2:14][C:13]([OH:45])=[O:12])[CH:39]1[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1)=[O:24]
Reactant: CC(C)(C)OC(=O)CN[C@@H](C(=O)N1CC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cncn1)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN[C@@H](C(=O)N1CC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cncn1)C1CCCCC1
Reaction time: 16 h

Procedure:
TFA (5 mL) was added to a solution of tert-butyl({(1R)-2-[(2S)-2-({[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]amino}carbonyl)azetidin-1-yl]-1-cyclohexyl-2-oxoethyl}amino)acetate (22 mg, 0.04 mmol) in CH2Cl2 (5 mL) at 0° C. After stirring for 16 h the reaction mixture was concentrated. The title compound was isolated by reverse phase HPLC. LCMS (M+H): 489.3. 1H NMR (400 MHz, CD3OD): δ 8.80 (s, 1H), 8.22 (s, 1H), 7.67 s, 1H), 7.50 (m, 2H), 4.79 (m, 1H), 4.45–4.20 (m, 5H), 3.91 (m, 3H), 2.61 (m, 1H), 2.21 (m, 1H), 1.87–1.72 (m, 5H), 1.37–1.17 (m, 5H).