Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]([F:20])=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O.[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(OCC)C.O>[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=[C:6]([F:5])[F:20]
Reactant: Nc1ccccc1Cl
Reactant: O=C(O)CCCCCCCCCC=C(F)F
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(CCCCCCCCCC=C(F)F)Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.4 %

Procedure:
With stirring 3.7 ml (0.05 mole) of thionyl chloride was added dropwise to 5.2 grams (0.022 mole) of 12,12-difluoro-11-dodecenoic acid. Upon completion of addition the reaction mixture stirred at ambient temperature for 16 hours, and then it was heated to 70° C. to remove the excess thionyl chloride under reduced pressure. The residual 12,12-difluoro-11-dodecenoic acid chloride was dissolved in 50 ml of toluene, and, in turn, 0.1 gram (catalyst) of 4-dimethylaminopyridine (DMAP), 3.2 grams (0.025 mole) of 2-chloroaniline, and 2.2 grams (0.022 mole) of triethylamine were added. Upon completion of addition the reaction mixture was stirred at ambient temperature for 60 hours. After this time the reaction mixture was shaken with 50 ml of water and 100 ml of diethyl ether. The water layer was removed, and the ether layer was in turn washed with 25 ml of aqueous 0.1N hydrochloric acid, 25 ml of water, 25 ml of an aqueous solution saturated with sodium bicarbonate, 25 ml of water, and 25 ml of an aqueous solution saturated with sodium chloride. The ether layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was recrystallized from ethanolwater yielding, in two crops, 5.7 grams of N-(2-chlorophenyl)-12,12-difluoro-11-dodecenamide; m.p. 54°-55° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C:2]1=[O:7].[H-].[Na+].Br[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1/[CH:21]=[CH:22]/[CH:23]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([O:45][CH3:46])=[O:44])=[CH:39][CH:38]=1)[CH2:24][CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1.[Cl-].[NH4+]>CN(C=O)C>[CH3:46][O:45][C:43]([C:40]1[CH:39]=[CH:38][C:37]([CH2:36][CH:23](/[CH:22]=[CH:21]/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH2:13][CH2:12][CH2:11][N:1]2[CH2:6][CH2:5][O:4][CH2:3][C:2]2=[O:7])[CH2:24][CH2:25][C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)=[CH:42][CH:41]=1)=[O:44]
Reactant: O=C1COCCN1
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCBr)Cc2ccc(C(=O)OC)cc2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCN2CCOCC2=O)Cc2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 0.175 g (1.73 mmol) of morpholin-3-one [CAS Reg. No. 109-11-5] is initially charged in 6 ml of dry DMF, and 71 mg (1.78 mmol) of sodium hydride (60% in paraffin oil) are added. The mixture is stirred at room temperature for 45 min. The reaction solution is then cooled to 0° C., and a solution of 0.28 g (0.495 mmol) of methyl 4-{(4E)-5-[2-(3-bromopropoxy)phenyl]-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate (Example 22A) in 3 ml of dry DMF is added. The mixture is stirred at room temperature for 1 h. The reaction solution is then carefully poured into 50 ml of ice-cold 10% strength ammonium chloride solution. The mixture is extracted twice with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered and concentrated. This gives 0.29 g (0.495 mmol, 100% of theory) of a colorless oil which is reacted without further purification.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:30]=[CH:29][CH:28]=[CH:27][C:9]=3[N:10]([CH2:19][C:20]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[C:11](=[O:18])[N:12]([CH2:14][C:15](Cl)=[O:16])[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:31][C:32]1[CH:33]=[C:34]([C:38]2[NH:39][O:40][C:41](=[O:43])[N:42]=2)[CH:35]=[CH:36][CH:37]=1.Cl.CCN(C(C)C)C(C)C>C(#N)C.CC(OC)(C)C.C1COCC1.C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH:1]1([C:7]2[C:8]3[CH:30]=[CH:29][CH:28]=[CH:27][C:9]=3[N:10]([CH2:19][C:20]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[C:11](=[O:18])[N:12]([CH2:14][C:15]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]4[NH:39][O:40][C:41](=[O:43])[N:42]=4)[CH:33]=3)=[O:16])[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cccc(-c2nc(=O)o[nH]2)c1
Reactant: O=C(Cl)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O)Nc1cccc(-c2nc(=O)o[nH]2)c1

Procedure:
The [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl]-acetyl chloride is reacted with 3-(3-amino-phenyl)-2H-[1,2,4]oxadiazol-5-one, a known compound or compound prepared by known methods, wherein the 3-(3-amino-phenyl)-2H-[1,2,4]oxadiazol-5-one may be present as a free base or, for example, as its corresponding HCl salt; in the presence of an organic base such as TEA, DIPEA, pyridine, and the like, preferably DIPEA; wherein the base is preferably present in an amount from about 1 to about 2 equivalents; in an aprotic organic solvent such as acetonitrile, toluene, THF, MTBE, and the like, preferably acetonitrile; to yield the 2-[5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl]-N-[3-(5-oxo-2,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-acetamide, the compound of formula (Is).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:18])C=1.[OH-].[Na+]>ClCCl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[O:18])=[N:7][CH:8]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1ccc(C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCc1ccc(C=O)nc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 20 %

Procedure:
In dichloromethane (25.0 ml), 5-ethyl-2-methyl-pyridine (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (2.31 g) was dissolved. After having been cooled to 0° C., the reaction solution was added with m-chloroperbenzoic acid (4.43 g) and the whole was stirred at room temperature for 2.5 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. Subsequently, the organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. The drying agent was filtrated out and the solvent was then distilled off. The resultant was dissolved in dichloromethane (40.0 ml). The reaction solution was added with trifluoroacetic anhydride (5.6 ml) and the whole was refluxed under heating for 3.5 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off. The resultant was dissolved in methanol (80.0 ml). After having been cooled to 0° C., the reaction solution was added with a 12.5% sodium methoxide/methanol solution to adjust the reaction solution to pH 10, followed by stirring at room temperature for 16.5 hours. After the solvent was distilled off, the residue was added with distilled water and subjected to extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. The drying agent was filtrated out and the solvent was then distilled off. The resultant was dissolved in chloroform (50.0 ml). The reaction solution was added with manganese dioxide (chemically processed product) (7.44 g) and then stirred at room temperature for 18 hours. The reaction solution was filtrated through Celite. The solvent in the filtrate was distilled off and the resultant residue was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (515.6 mg) as a yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19])[CH2:7][CH2:6]2.[OH-].[Na+].Cl.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C:27](Cl)=O>ClCCl>[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[CH2:27][NH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:9]1
Reactant: COc1ccc2c(c1)CCC(c1ccccc1N)C2
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc2c(c1)CCC(c1ccccc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a solution of 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride (2.0 g) in thionyl chloride (20 ml) was added toluene (20 ml), the solution was stirred for 30 minutes at 100° C., then the reaction solution was concentrated in vacuo to provide 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoyl chloride hydrochloride (2.0 g). To a solution of 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (253 mg) in dichloromethane (8 ml) were sequentially added an aqueous solution of 1N sodium hydroxide (4 ml) and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoyl chloride hydrochloride (400 mg), and the solution was stirred overnight at room temperature. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo. Synthesized from the resulting 3-fluoro-N-[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]-4-(2-piperidin-1-ylethoxy)benzamide (423 mg) according to an analogous synthetic method to Example 337 described below, the title compound (418 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[O:9]CC)=[CH:4][CH:3]=1.Br[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]=1[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[CH2:41]Br>CC1C=CC=CC=1C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]([CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][C:32]=2[CH2:41][P:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[O:9])([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: BrCc1ccc2ccccc2c1-c1c(CBr)ccc2ccccc12
Reactant: CCOP(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: Cc1ccccc1C
Product: O=P(Cc1ccc2ccccc2c1-c1c(CP(=O)(c2ccc(F)cc2)c2ccc(F)cc2)ccc2ccccc12)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 135 °C

Procedure:
While stirring under nitrogen, 10.70 g (0.04 mol) of ethyl bis(4-fluorophenyl)phosphinite are added dropwise to a solution of 8.80 g (0.02 mol) of 2,2'-bis(bromo-methyl)-1,1'-binaphthyl in 40 ml of o-xylene, which solution has been heated to 135° C. After the end of the addition, the mixture is heated under reflux for a further 1.5 hours. After cooling to room temperature, the precipitated crystals are filtered off with suction and washed with xylene. This gives 14.1 g (94 %) of colorless crystals having a melting point of 211°-214° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:15]=[C:16]1[N:20]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[NH:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:24]2[CH2:23][CH2:22][CH:21]([N:20]3[C:19]4[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=4[NH:17][C:16]3=[O:15])[CH2:26][CH2:25]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 103.8 %

Procedure:
A mixture of 20.6 g N-t-butyloxycarbonyl-4-piperidone, 15 g of 4-(2-oxo-1-benzimidazolinyl)piperidine, 300 mL of 1,2-dichloroethane, 4.2 mL of glacial acetic acid and 24 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was poured into 500 mL chloroform and 500 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×250 mL of chloroform and the combined organic layers dried over MgSO4 and concentrated under reduced pressure. Recrystallization of the crude product from 200 mL of ethyl acetate gave in two crops 28.7 g of pure 1,3-dihydro-1-{1-[1-(t-butyloxycarbonyl)piperidin-4-yl]piperidin-4-yl}-2H-benzimidazol-2-one as a white solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][N:4]=1.F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[OH-].[Na+]>CN(C=O)C>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([O:9][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:8]=2)=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: Oc1ccnc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc(C(F)(F)F)c2)cc1
Temperature: 100 °C

Procedure:
A mixture of 2-trifluoromethyl-pyridin-4-ol (0.675 g, 4.14 mmol), 1-fluoro-4-nitro-benzene (0.54 mL, 4.97 mmol, 1.2 equiv), and NaOH (0.203 g,4.97 mmol, 1.2 equiv) in DMF abs. is heated to 100° C. (oil bath temperature) for 21.5 h, under an argon atmosphere. The reaction mixture is allowed to cool to rt, filtered through a glass sintered funnel and concentrated in vacuo. The residual yellow solid is purified by silica gel (100 g) column chromatography (CH2Cl2/hexane, 70/30) to afford the title compound as a white solid: ES-MS: 285.0 [M+H]+; single peak at tR=8.71 min (System 2); Rf=0.25 (CH2Cl2/hexane, 70/30).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([CH2:27][S:28][CH2:29][C:30](=[O:32])[NH2:31])[CH2:10]1)(C(C)(C)C)(C)C.Cl>CO.C(OCC)(=O)C>[C:30]([CH2:29][S:28][CH2:27][C@@H:11]1[CH2:10][C@@H:9]([OH:8])[CH2:13][N:12]1[C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)=[O:15])(=[O:32])[NH2:31]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CSCC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: NC(=O)CSC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 67.3 %

Procedure:
To a solution of (2S,4R)-4-t-butyldimethylsilyloxy-2-(carbamoylmethyl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.10 g) in methanol (40 ml) was added conc. hydrochloric acid (0.72 ml) at ambient temperature After stirring at the same temperature for 1 hour, this reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate (60 ml). The solution was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride successively, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give a residue. The residue was washed with a mixture of ethyl acetate (30 ml) and diisopropyl ether (15 ml). The resulting precipitates were collected by filtration and air-dried to give (2S,4R)-2-(carbamoylmethyl)thiomethyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.08 g).
Reaction SMILES: [NH3:1].F[C:3]1[N:8]=[C:7]([F:9])[C:6]([O:10][CH:11]([F:13])[F:12])=[C:5]([Cl:14])[N:4]=1>O1CCCC1>[NH2:1][C:3]1[N:4]=[C:5]([Cl:14])[C:6]([O:10][CH:11]([F:13])[F:12])=[C:7]([F:9])[N:8]=1
Reactant: Fc1nc(F)c(OC(F)F)c(Cl)n1
Reactant: N
Solvent: C1CCOC1
Product: Nc1nc(F)c(OC(F)F)c(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.8 g (0.578 mol) of gaseous ammonia were passed into a mixture of 62.5 g (0.289 mol) of 2,4-difluoro-6-chlorodifluoromethoxypyrimidine in 300 ml of tetrahydrofuran at from -75° to -70° C. in the course of one hour while stirring. Stirring was continued for one hour at -70° C., after which the mixture was warmed up to room temperature. The precipitate which had separated out was filtered off under suction and partitioned between ethyl acetate and water and the organic phase was dried over mangesium sulfate. The reaction filtrate was evaporated down, the residue was dissolved in the above ethyl acetate phase, the solution was chromatographed over silica gel using 5:1 petroleum ether/ether and the eluate was evaporated down. 46.5 g (75.3% of theory) of the title compound were obtained as colorless crystals of melting point 77°-80° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:6]2[N:5]=[CH:4][N:3]=1.[CH2:31]([N:38]1[CH:46]=[C:45]2[C:40]([CH:41]=[C:42](B3OC(C)(C)C(C)(C)O3)[CH:43]=[CH:44]2)=[N:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[NH2:1][C:2]1[C:7]2=[C:8]([C:42]3[CH:43]=[CH:44][C:45]4[C:40]([CH:41]=3)=[N:39][N:38]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:46]=4)[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cc(Br)c4c(N)ncnn34)cc2)CC1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cc2)CC1
Temperature: 80 °C
Yield: 50.3 %

Procedure:
To a stirred solution of tert-butyl 4-[4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)phenyl]piperazine-1-carboxylate (4 mg, 1.25 mmol), 2-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-Indazole (1.04 g, 1.87 mmol), and tetrakis(triphenylphosphine)palladium(0) (144 mg, 0.13 mmol) in degassed DME (5.5 mL) was added aqueous Na2CO3 solution (2 M, 1.87 mL). The reaction was heated (80° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (25 mL) and H2O (25 mL). The layers were separated and the aqueous phase was back extracted with ethyl acetate. The combined organics were washed with brine, dried (Na2SO4), and concentrated to dryness. The crude material was purified by ISCO® chromatography using a gradient of 25 to 75% ethyl acetate in hexanes to afford 378 mg (58%) of the desired product, which contained trace impurities. 1H NMR (300 MHz, DMSO-d6) δ 8.52 (s, 1 H), 7.88 (s, 1 H), 7.78 (d, 1 H), 7.57 (s, 1 H), 7.36-7.31 (m, 5 H), 7.13 (d, 1 H), 6.61 (s, 1 H), 5.64 (s, 2 H), 4.13-3.98 (m, 2 H), 3.35-3.25 (m, 1 H), 2.05-1.96 (m, 2 H), 1.63-1.50 (m, 2 H), 1.41 (s, 9 H); ES-MS m/z 524.2 [M+H]+, HPLC RT (min) 3.08.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:8]1([CH2:13][CH:14]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[C:15](O)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C.O.C(Cl)(Cl)(Cl)Cl>[CH:8]1([CH2:13][CH:14]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[C:15]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: Nc1ccccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 2-aminopyridine (95 mg, 1.01 mmol) in acetonitrile (2 mL) was treated with 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid (prepared as in Example 3A, 250 mg, 0.84 mmol), triphenylphosphine (243 mg, 0.93 mmol), triethylamine (350 μL, 2.53 mmol), and carbon tetrachloride (1 mL). The resulting reaction mixture was stirred at 25° C. for 15 h. The cloudy reaction mixture was diluted with water and then extracted with methylene chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/3 hexanes/ethyl acetate) afforded impure 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-pyridin-2-yl-propionamide. Recrystallization from hexanes/methylene chloride provided pure 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-pyridin-2-yl-propionamide (170 mg, 54%) as a white solid: mp 172-173° C.; EI-HRMS m/e calcd for C20H24N2O3S (M+) 372.1508, found 372.1498.
Reaction SMILES: [Na+].[NH2:2][C@H:3]([C:23]([O-:25])=[O:24])[CH2:4][C:5]1[CH:12]=[C:10]([I:11])[C:9]([O:13][C:14]2[CH:21]=[C:19]([I:20])[C:18]([OH:22])=[C:16]([I:17])[CH:15]=2)=[C:7]([I:8])[CH:6]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].Cl>[NH4+].[OH-].CN(C=O)C.O.[OH-].[Na+]>[C:26]([NH:2][C@H:3]([C:23]([OH:25])=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([I:8])[C:9]([O:13][C:14]2[CH:15]=[C:16]([I:17])[C:18]([OH:22])=[C:19]([I:20])[CH:21]=2)=[C:10]([I:11])[CH:12]=1)(=[O:28])[CH3:27]
Reactant: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Reaction time: 1.5 h
Yield: 90 %

Procedure:
L-Thyroxine sodium salt, pentahydrate (1) (10 g, 11 mmol) was nearly completely dissolved in 400 mL of ETCH/2N NH4OH (1/1, v/v), filtered, and filtrate poured into 425 mL of 5% HCl. The resulting precipitate was isolated by vacuum filtration and dried under high vacuum to afford a white solid. This material was dissolved in 160 mL DMF, 100 mL (1.06 mol) of acetic anhydride added, and reaction stirred for 1.5 hours, then diluted with 850 mL H2O and allowed to stand at 4° C. for 16 hours. The resulting precipitate was isolated by filtration, then dissolved in 350 mL EtCH and 41 mL of 1N NaOH, stirred for 2.5 hours, 680 mL of 5% HCl added, and mixture allowed to stand at 4° C. for 16 hours. The resulting precipitate was isolated by vacuum filtration and dried under high vacuum to yield 8.1 g (90%) of the desired N-acetyl L-thyroxine (5) as a white solid; 1H NMR (200 MHz, CD3OD) d 7.8 (s, 2H), 7.1 (s, 2H), 4.6-4.7 (m, 1H), 2.8-3.0 (m, 2H), 2.0 (s, 3H); mass spec (FAB) (M+H)+820.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1.O.Cl>[C:18]([NH:10][C:8]([C:3]1[C:2]([OH:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:9])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=O)c1nccnc1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC(=O)c1nccnc1O)c1ccccc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
In 50 mL of tetrahydrofuran is suspended 1.00 g of 3-hydroxy-2-pyrazinecarboxamide. Then, 3.5 mL of triethylamine and 1.67 mL of benzoyl chloride are successively added thereto. The resulting solution is stirred at 60° C. for 5 hours and cooled. The deposited crystals are collected by filtration. The crystals thus obtained are suspended in a mixture of 8 mL of water and 1 mL of 1 mol/mL hydrochloric acid, stirred at ambient temperature for 30 minutes, and collected by filtration to obtain 0.41 g of N2-benzoyl-3-hydroxy-2-pyrazinecarboxamide.