Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[NH:21][N:20]=[N:19][N:18]=2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH:21]1[C:17]([CH:13]2[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]2)=[N:18][N:19]=[N:20]1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N1CCCC(c2nnn[nH]2)C1
Agent: [Pd]
Solvent: CO
Product: C1CNCC(c2nnn[nH]2)C1
Reaction time: 30 h

Procedure:
To a solution of 3-(1H-tetrazol-5-yl)-piperidine-1-carboxylic acid benzyl ester (1 g, 3.5 mmol) in MeOH (20 mL) is added Pd on carbon (10%, 150 mg) at room temperature. The mixture is charged with Ar gas a few times before attaching a hydrogen gas balloon. After 30 h at 20° C., the mixture is filtered, and concentrated to afford 3-(1H-tetrazol-5-yl)-piperidine. LCMS: RT=0.54 minutes, MS: 154 (M+H).
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:26])=[C:6]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[NH:7][C:8]([C:10]1[N:14](CC2C=CC=CC=2)[N:13]=[N:12][N:11]=1)=[O:9])(=[O:3])[CH3:2].[H][H]>C(O)(=O)C.[Pd]>[C:1]([C:4]1[C:5]([OH:26])=[C:6]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[NH:7][C:8]([C:10]1[NH:14][N:13]=[N:12][N:11]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C)cc(NC(=O)c2nnnn2Cc2ccccc2)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)c1cc(C)cc(NC(=O)c2nnn[nH]2)c1O
Yield: 59.2 %

Procedure:
A solution of 3'-acetyl-1-benzyl-2'-hydroxy-5'-methyl-1H-tetrazole-5-carboxanilide (5.0 g) in glacial acetic acid was hydrogenated at 4.1 kg/cm2 and 28° C., using a 5% w/w palladium on charcoal catalyst. The reaction was carefully monitored, and when the theoretical quantity of hydrogen had been used (after 9.5 hours) the catalyst was filtered off and extracted with acetic acid in a Soxhlet apparatus. The acetic acid solutions were then combined and evaporated, and the resulting residue was recrystallised from a mixture of dimethylformamide and water to give 3'-acetyl-2'-hydroxy-5'-methyltetrazole-5-carboxanilide (2.2 g), m.p. 257° C. (with decomposition).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)=O)(C)(C)C.[CH2:20](N1CCCC1C1C=CC(Br)=CC=1)[CH:21]=C>>[CH2:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=1)[CH:20]=[CH2:21]
Reactant: C=CCN1CCCC1c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(N)cc1
Product: C=CCN1CCCC1c1ccc(N)cc1
Yield: 87 %

Procedure:
Using the same procedure described for the preparation of 2-(4-Amino-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, the title compound is prepared from 1-Allyl-2-(4-bromo-phenyl)-pyrrolidine (470 mg, 1.77 mmol) in 87% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:32]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:34])[F:35])=[CH:30][CH:29]=2)=[O:33])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)c3)c2cc1OC
Yield: 86.7 %

Procedure:
The title compound was prepared from 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (94 mg, 0.3 mmol) and 4-(trifluoromethyl)phenyl isocyanate (42 uL, 0.3 mmol) using the procedure in Example 182 to give 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(4-(trifluoromethyl)phenyl)urea (130 mg, 0.26 mmol, 87%). 1H NMR (300 MHz, DMSO-d6) δ 9.19 (s, 1H), 9.03 (s, 1H), 8.70 (s, 1H), 7.83 (s, 1H), 7.68-7.60 (m, 4H), 7.56 (d, 1H), 7.44 (t, 1H), 7.35 (d, 2H), 7.27 (d, 1H), 3.99 (s, 6H); LC-MS (ESI) m/z 501 (M+H)+.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([P:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1)=O.[NH2:27][C:28]([NH2:30])=[O:29]>C(O)C>[OH:29][C:28]1[N:30]=[C:5]([C:7]2[CH:8]=[C:9]([P:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:10]=[CH:11][CH:12]=2)[CH:4]=[CH:3][N:27]=1
Reactant: CN(C)C=CC(=O)c1cccc(P(c2ccccc2)c2ccccc2)c1
Reactant: NC(N)=O
Solvent: CCO
Product: Oc1nccc(-c2cccc(P(c3ccccc3)c3ccccc3)c2)n1
Yield: 90 %

Procedure:
10 mmol of 4 are dissolved in 100 ml of aqueous ethanol and mixed with 25 mmol of urea. It is refluxed for 7 h, the solvent is removed and the colorless solid is washed with water. Recrystallization from chloroform gives 20 in a yield above 90%. ESI MS, m/z (%): 366.3703 (100) [M+H]+. 31P{1H} NMR (101.2 MHz, 25° C., DMSO-d6): 5-7.45.
Reaction SMILES: [Mg].I[CH3:3].[C:4]1(=[O:19])[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=[CH:5]1.[Cl-].[NH4+]>CCOCC>[CH3:3][CH:17]1[CH2:18][C:4](=[O:19])[CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CI
Reactant: O=C1C=CCCCCCCCCCCC=C1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1CCCCCCCCCCC=CC(=O)C1
Reaction time: 0.5 h

Procedure:
To the Grignard reagent prepared from 72 mg (3 mg-atoms) of magnesium and 0.25 ml (4 mMole) of iodomethane in 5 ml of ether was added 50 mg of cuprous iodide, and the mixture was heated at reflux for 5 min. Cyclopentadeca-2,14-dien-1-one (0.44 g; 2 mMole) in 5 ml of ether was then added over a period of 10 min without cooling, and stirring was continued for 30 min at room temperature. The reaction mixture was poured into cold ammonium chloride solution and extracted with ether. The organic layer was washed with water, dried over sodium sulphate, evaporated and distilled to give 0.33 g (69%) of dehydromuscone having b.p. 110°/0.1 Torr;
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[CH3:40][C:41]1[O:45][N:44]=[C:43]([C:46](Cl)=[O:47])[CH:42]=1>>[CH3:40][C:41]1[O:45][N:44]=[C:43]([C:46]([O:1][CH:2]2[CH2:20][CH:19]3[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]4[C:16]([C:22]([NH:24][S:25]([CH:28]5[CH2:30][CH2:29]5)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]3=[O:21])[CH2:15]4)[CH2:3]2)=[O:47])[CH:42]=1
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: Cc1cc(C(=O)OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCCC(NC(=O)OC(C)(C)C)C(=O)N3C2)no1
Yield: 26.1 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 5-methylisoxazole-3-carbonyl chloride (188 mg, 1.06 mmol). The final trituration (diethyl ether/hexane) and filtration gave 31 mg (26%) of 18-(5-methylisoxazole-3-carbonyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 99.9% pure (HPLC), MS m/z 676 (M−H)−, HRMS: calcd. 678.2809 and found 678.2795 (M+H)+, mp 157-159° C.
Reaction SMILES: [C:1]([NH2:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11].N1CCCC1.I[C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]#[C:28][C:29]#[C:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>[Cu]I>[C:1]([NH2:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]#[C:28][C:29]#[C:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: C#CCCCCCCCCC(N)=O
Reactant: CCCCCCCCC#CC#CCCCCCC#CI
Agent: [Cu]I
Solvent: C1CCNC1
Product: CCCCCCCCC#CC#CCCCCCC#CC#CCCCCCCCCC(N)=O
Reaction time: 48 h

Procedure:
CuI (0.126 g, 0.66 mmol) and 10-undecynoic acid amide (0.29 g, 1.59 mmol) were added to a flask and inerted with nitrogen. Pyrollidine (5 mL) was then added. In a separate flask 1-Iodo-nonadeca-1,8,10-triyne (0.5 g, 1.3 mmol) was mixed with pyrollidine (5 mL) and subsequently added slowly to the amide solution. The reaction mix was left in darkness under nitrogen for 48 hours, then quenched with aqueous 1M NH4Cl (10 mL), and worked up with CH2Cl2 and 1 M HCl. The organic was dried over anhydrous MgSO4. Organic products were concentrated by rotary evaporation, although polymer formed, decreasing yield. Hexanes trituration removed unreacted 1-Iodo-nonadeca-1,8,10-triyne. Desired product was obtained by several crystallizations from hexanes/ethyl acetate, again under dark conditions. All handling of the solid was done under red light. Final product triaconta-10,12,19,21-tetraynoic acid amide was made up of white crystals (0.377 g, 0.86 mmol) and was stored frozen (liquid nitrogen) in methylene chloride. 65% yield; 1H NMR (CDCl3) δ: 5.31 (s, 2H, NH2), 2.22-2.26 (m, 10H, CH2—C≡C & CH2—CO), 1.58-1.66 (quin, 2H, J=7, CH2—C—CO), 1.45-1.56 (m, 8H, CH2—C—C≡C), 1.28-1.4 (m, 20H, C—CH2—C), 0.86-0.91 (t, 3H, CH3); 13C NMR (CDCl3) δ 175.69, 77.98, 77.84, 77.34, 65.69, 69.45, 65.37, 57.68, 53.63, 38.37, 38.35, 33.80, 32.97, 32.92, 32.03, 29.34, 29.27, 29.07, 28.94, 28.55, 28.47, 28.26, 28.26, 28.06, 27.17, 25.67, 22.86, 19.39, 19.32 14.30. MS (ESI) [M+H]+ calc. 436.3574 found 436.3560.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[C:6]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1)#[N:7]>C(#N)C>[CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([C:6]#[N:7])=[CH:9][CH:10]=1
Reactant: COCCN
Reactant: N#Cc1ccc(CBr)cc1
Solvent: CC#N
Product: COCCNCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
2-Methoxyethylamine (2.2 mL, 25.5 mmol) was added into a solution of 4-cyanobenzyl bromide (1.0 g, 5.1 mmol) in ACN (10 mL) and the resulting mixture was stirred at RT for 1 hour. The reaction mixture was concentrated under vacuum. The crude product was dissolved in EtOAc, and then washed with a saturated aqueous solution of NaHCO3 and brine, dried (MgSO4) and concentrated under vacuum to give the title compound (958 mg, 99%). LC/MS (Method B): 191.0 (M+H)+. HPLC (Method A) Rt 1.44 min (Purity: 93.4%).
Reaction SMILES: C(O[CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([B:17]3[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=O)C.BrC1C=C[C:30]([N:33]2CCC(N(C)C)C[CH2:34]2)=CC=1>>[CH3:30][N:33]([CH3:34])[CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([B:17]3[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: CC(=O)OC1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CN(C)C1CCN(c2ccc(Br)cc2)CC1
Product: CN(C)C1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 120 °C
Yield: 23 %

Procedure:
The title compound was synthesized according to the method described for the synthesis of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-yl acetate, except substituting 1-(4-bromophenyl)-N,N-dimethylpiperidin-4-amine (139 mg, 0.49 mmol) δ 0 and the reaction was heated to 120° C. for 4 h. Crude product was purified by flash chromatography using EtOAc/Et3N as eluent (1:0 to 98:2) to give the title compound as a yellow solid (37 mg, 23%). 1H NMR (400 MHz, MeOD) δ 7.61 (d, J=8.6 Hz, 2H), 6.92 (d, J=8.5 Hz, 2H), 3.89-3.86 (m, 2H), 2.75-2.69 (m, 2H), 2.36-2.30 (m, 1H), 2.30 (s, 6H), 1.96-1.64 (m, 2H), 1.65-1.48 (m, 2H), 1.32 (s, 12H); MS ESI 331.1 [M+H]+, calcd for [C19H31BN2O2+H]+ 331.25.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:15])[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[C:5]([CH3:16])[CH:4]=[C:3]1[CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[Na+]>>[CH3:1][N:2]1[C:6]([C:7](=[O:15])[C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)=[C:5]([CH3:16])[CH:4]=[C:3]1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(F)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(CC(=O)O)n(C)c1C(=O)c1ccc(F)cc1
Yield: 91 %

Procedure:
A suspension of 3.03 g. (0.01 mole) of ethyl 1,4-dimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetate in 11 ml. of 1N sodium hyroxide solution is heated under reflux for 30 minutes. The solution is filtered while hot and acidified with dilute hydrochloric acid. The precipitate is collected, air dried and recrystallized from 2-propanol to give about 2.5 g. (91% yield) of 1,4-dimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetic acid as a white solid, m.p. 176-178° C.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[C:4]1([C:10](=O)[CH:11]([CH2:20][CH3:21])[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)(C)C>[C:4]1([C:10]2[C:11]([CH2:20][CH3:21])=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:2]([CH3:1])[N:3]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNN
Reactant: CCC(C(=O)c1ccccc1)C(=O)c1ccccc1
Solvent: CC(C)O
Product: CCc1c(-c2ccccc2)nn(C)c1-c1ccccc1
Temperature: 80 °C
Yield: 56 %

Procedure:
Methylhydrazine (2.86 g, 0.06 mole) is added to an isopropanol (100 ml) solution of 1,3-diphenyl-2-ethyl-1,3-propanedione (11.0 g, 0.044 mole) with constant stirring at 80° C. The reaction mixture is heated at reflux for 31/2 hours, then stirred at room temperature overnight. The reaction mixture is poured into ice-water, stirred for 1/2 hour, and the resulting mixture extracted with chloroform (3×50 ml). Evaporation of the organic layer gives an oil, which is crystallized from hexane with cooling to give 6.47 g (56%) of product, m.p. 80° C to 81° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10][CH3:11])[CH:5]=[O:6].[BH4-].[Na+].O>CO>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[S:10][CH3:11]
Reactant: CSc1ccc(C=O)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CSc1ccc(CO)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
The mixture of 3-fluoro-4-(methylsulfanyl)benzaldehyde (19.44 g, 114.2 mmol) and sodium borohydride (2.1 g, 55.46 mmol) in methanol (200 mL) was stirred at room temperature for 2 hour. Water was added to the mixture, and the mixture was evaporated, diluted with ethyl acetate (300 mL), washed with water (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1/4) to provide the subtitle compound (19.91 g, 100% yield) as an oil.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:6][C:7]=1[C:8]([O:10]C)=O.[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[SH:32]>>[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32][CH2:2][C:3]1[O:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:6][C:7]=1[CH2:8][OH:10]
Reactant: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1CBr
Reactant: Sc1ccc2ccccc2n1
Product: OCc1cc(-c2ccc(C(F)(F)F)cc2)oc1CSc1ccc2ccccc2n1

Procedure:
The title compound was prepared using methyl 2-(bromomethyl)-5-[4-(trifluoromethyl)phenyl]-3-furoate (intermediate 44) and 2-quinolinethiol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH:7]=[C:8]([P:12]1(=[O:18])[O:17][CH2:16][CH2:15][CH2:14][O:13]1)[C:9]([CH3:11])=O)([O-:3])=[O:2].[NH2:22]/[C:23](/[CH3:29])=[CH:24]\[C:25]([O:27][CH3:28])=[O:26]>C(O)(C)C>[CH3:29][C:23]1[NH:22][C:9]([CH3:11])=[C:8]([P:12]2(=[O:18])[O:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:7]([C:6]2[CH:19]=[CH:20][CH:21]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)P1(=O)OCCCO1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(P2(=O)OCCCO2)C1c1cccc([N+](=O)[O-])c1
Yield: 49.9 %

Procedure:
Into 80 ml of isopropanol were dissolved 5.5 grams of 2-(1-(3-nitrobenzylidene)-acetonyl)-2-oxo-1,3,2-dioxaphosphorinane and 2.1 grams of methyl 3-aminocrotonate and the mixture was heated to reflux for 10 hours. After the reaction, the reaction solution was concentrated in vacuo, the residue was made crystallized by addition of ethyl acetate, and crystals separated out were collected by filtration. The crude crystals were recrystallized from ethyl acetate to give 3.6 grams of methyl 2,6-dimethyl-4-(3-nitrophenyl)-5-(2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydropyridine-3-carboxylate, m. p. 221°-3° C.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([O:8][C:9]2[C:14]([I:15])=[CH:13][C:12]([CH2:16][CH:17]([NH2:21])[C:18]([OH:20])=[O:19])=[CH:11][C:10]=2[I:22])[CH:2]=1.[ClH:23].[CH3:24]O>>[ClH:23].[CH3:24][O:19][C:18](=[O:20])[C@H:17]([CH2:16][C:12]1[CH:11]=[C:10]([I:22])[C:9]([O:8][C:3]2[CH:4]=[CH:5][C:6]([OH:7])=[CH:1][CH:2]=2)=[C:14]([I:15])[CH:13]=1)[NH2:21]
Reactant: NC(Cc1cc(I)c(Oc2ccc(O)cc2)c(I)c1)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)[C@@H](N)Cc1cc(I)c(Oc2ccc(O)cc2)c(I)c1
Reaction time: 16 h
Yield: 95 %

Procedure:
Five g (9.52 mmoles) of L-3,5-diiodothyronine (Sigma Chemical Company, St. Louis, Mo. 63178, Catalog No. D0629) was suspended in 50 ml of methanol (MCB, Norwood, Ohio 45212, Catalog No. MX0488-1). Dry hydrogen chloride was bubbled through the resulting suspension until the methanol was saturated with hydrogen chloride. The mixture warmed as the 3,5-diiodothyronine dissolved, resulting in a yellowish-green solution. The reaction mixture was allowed to stand for 16 hours at ambient temperature in a closed vessel. Dry hydrogen chloride was again passed through the reaction mixture. The reaction mixture was allowed to stand for an additional six hours in a closed vessel. The methanol was allowed to evaporate from the reaction mixture in a fume hood at ambient temperature, leaving 5.2 g (95% yield) of white, crystalline powder, 3,5-diiodothyronine methyl ester hydrochloride.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][C:10]2[C:9]([NH:12][C:13](=[O:21])OC3C=CC=CC=3)=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[I:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26].O>CS(C)=O>[OH:1][CH:2]1[CH2:11][C:10]2[C:9]([NH:12][C:13]([NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[C:23]([I:22])[CH:24]=3)=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: Nc1cccc(I)c1
Reactant: O=C(Nc1cccc2c1CC(O)CC2)Oc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1cccc(I)c1)Nc1cccc2c1CC(O)CC2
Temperature: 100 °C
Yield: 45.2 %

Procedure:
Next, a mixture of phenyl (7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)carbamate (30.0 mg, 0.11 mmol) and 3-iodoaniline (25.5 mg, 0.12 mmol) in 0.2 mL of DMSO was heated at 100° C. for 16 hours. After cooled to room temperature, water was added and the product was extracted with ethylacetate. The organic layer was washed with water then brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(3-iodophenyl)urea (20.3 mg, 47% yield).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[C:13]2=[N:14][S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][N:12]2[CH:11]=[CH:10][CH:9]=1.[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.O>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>[C:20]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:25]=[CH:24][C:23]([C:8]2[C:13]3=[N:14][S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][N:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: O=S1(=O)CCN2C=CC=C(Br)C2=N1
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: O
Solvent: COCCOC
Product: O=S1(=O)CCN2C=CC=C(c3ccc(-c4ccccc4)cc3)C2=N1
Temperature: 100 °C
Reaction time: 8 h
Yield: 23.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (32.9 mg) was added to a mixture of 2M aqueous sodium carbonate solution (0.428 mL), 9-bromo-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (150 mg) and biphenyl-4-ylboronic acid (135 mg) in 1,2-dimethoxyethane (5.701 ml). The reaction mixture was stirred under a nitrogen atmosphere at 100° C. overnight, added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane, then ethyl acetate/methanol) to give the title compound (44.5 mg) as a pale-brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=1)([O-])=O>C1C=CC=CC=1.[Pd]>[CH3:15][Si:14]([CH3:17])([CH3:16])[C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=1)[NH2:1]
Reactant: C[Si](C)(C)c1cc([N+](=O)[O-])cc([Si](C)(C)C)c1
Agent: [Pd]
Solvent: c1ccccc1
Product: C[Si](C)(C)c1cc(N)cc([Si](C)(C)C)c1
Yield: 96 %

Procedure:
1-Nitro-3,5-bis(trimethylsilyl)benzene (264 mg, 0.99 mmol) was catalytically hydrogenated over 10% Pd-C in 15 ml of benzene at atmospheric pressure for 135 minutes. The catalyst was filtered off and washed with benzene. The filtrate and washings were mixed and evaporated. The residue was purified by column chromatography on silica gel [eluent: methylene chloride-n-hexane (2:1)] to give 224 mg of light tan-colored low melting solid (yield 96%).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][O:28][C:29](=[O:65])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:45]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[O:25])C=CC=CC=1>C(O)(=O)C>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][O:28][C:29](=[O:65])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][OH:45])=[O:25]
Reactant: O=C(CCCCCCCCCCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1)OCOC(=O)CCCCCCCCCCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Product: O=C(CCCCCCCCCCCCCCCO)OCOC(=O)CCCCCCCCCCCCCCCO
Temperature: 55 °C

Procedure:
Methylene bis(16-triphenylmethoxyhexadecanoate) (0.07 g, 0.07 mmol) from Example 1b(iii) above was dissolved in glacial acetic acid (8 ml) and heated at 55° C. The reaction was monitored by TLC. After 10 hours the reaction mixture was poured onto ice, and the crude product was filtered, washed with aqueous sodium bicarbonate and water, and dried under reduced pressure. The product was purified by flash chromatography on a silica column with chloroform/methanol (20:1) as eluent to yield the title compound as a white solid.