Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[C:4]([CH3:18])[C:3]=1[CH3:19].O>C1(C)C(C)=CC=CC=1>[CH3:19][C:3]1[C:2]([OH:1])=[CH:17][C:16]2[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:7][O:6][C:5]=2[C:4]=1[CH3:18]
Reactant: Cc1c(O)ccc(OCC(=O)c2ccccc2)c1C
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1c(O)cc2c(-c3ccccc3)coc2c1C
Temperature: 150 °C
Reaction time: 5 h
Yield: 50 %

Procedure:
A mixture of 2-(4-hydroxy-2,3-dimethyl-phenoxy)-1-phenyl-ethanone (1.2 g, 4.70 mmol) and polyphosphoric acid (ca. 100 mg) in xylene (10 mL) was stirred at 150° C. for 5 h. The mixture was poured into water, extracted with ethylacetate, washed and dried to give 6,7-dimethyl-3-phenyl-benzofuran-5-ol (560 mg) as a light brown solid. 1H NMR (CDCl3, 300 MHz) δ: 7.71 (s, 1H), 7.60-7.20 (m, 5H), 7.06 (s, 1H), 4.76 (s, 1H, OH), 2.47, 2.29 (2s, 6H) ppm. 13C NMR (CDCl3, 75 MHz), δ: 150.43, 150.30, 141.15, 132.58, 129.00, 127.32, 123.48, 122.13, 121.31, 120.59, 102.25, 12.31, 11.95 ppm. MS (m/z): 239 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:8]([CH:12]=1)[C:9]([OH:11])=O)([O-:3])=[O:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:53]([NH2:64])[C:54]1[CH:63]=[CH:62][C:59]([O:60][CH3:61])=[C:56]([O:57][CH3:58])[CH:55]=1>>[CH3:58][O:57][C:56]1[CH:55]=[C:54]([CH:63]=[CH:62][C:59]=1[O:60][CH3:61])[CH2:53][NH:64][C:9](=[O:11])[C:8]1[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[NH:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1NC1CCOCC1
Reactant: COc1ccc(CN)cc1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2NC2CCOCC2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
A mixture of 5.8 g of the compound obtained in Step 6.1, 7.02 g of DIEA and 12.38 g of HBTU is stirred for 30 minutes at room temperature. 4.37 g of veratrylamine are then added and the resulting mixture is stirred overnight at room temperature. The resulting mixture is evaporated under reduced pressure and the residue is taken up in EtOAc. This solution is washed with water and then sequentially with 1N HCl solution, with water, with saturated NaHCO3 solution, with water and with saturated NaCl solution. The resulting solution is dried over Na2SO4 and filtered, and the solvent is evaporated off under reduced pressure. The residue is chromatographed on silica gel, eluting with an EtOAc/heptane mixture from (50/50, v/v) to (70/30, v/v) to give 7.7 g of the expected product.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([F:13])[C:7]=1[F:14])[CH2:2][CH2:3][CH3:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[CH2:24][CH:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH3:39])=[C:33]([F:40])[C:32]=2[F:41])[CH2:27][CH2:26]1>CN(C=O)C>[F:41][C:32]1[C:33]([F:40])=[C:34]([O:37][CH2:38][CH3:39])[CH:35]=[CH:36][C:31]=1[C@H:28]1[CH2:29][CH2:30][C@H:25]([CH2:24][O:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[C:7]([F:14])[C:8]=2[F:13])[CH2:26][CH2:27]1
Reactant: CCCCOc1ccc(O)c(F)c1F
Reactant: CCOc1ccc(C2CCC(CCl)CC2)c(F)c1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1ccc(OC[C@H]2CC[C@H](c3ccc(OCC)c(F)c3F)CC2)c(F)c1F
Temperature: 30 °C
Reaction time: 7 h

Procedure:
4-Butoxy-2,3-difluorophenol (24) (4.6 g) and tripotassium phosphate (K3PO4) (14.0 g) were added to DMF (100 ml) under a nitrogen atmosphere, and the stirring was continued at 70° C. The compound (20) (3.0 g) was added thereto, and the stirring was continued at 70° C. for 7 hours. After the reaction mixture obtained had been cooled to 30° C. and separated from solid materials by filtration, toluene (100 ml) and water (100 ml) were added thereto, and mixed. The mixture was then allowed to separate into organic and aqueous phases, and the extraction into an organic phase was carried out. The organic phase obtained was washed with brine and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off, and the residue obtained was purified by means of column chromatography (silica gel; heptane/toluene=1/2 by volume). The product was further purified by means of recrystallization (Solmix A-11: heptane=1:2 by volume), giving 4.02 g of 2,3-difluoro-4-ethoxy-[trans-4-(2,3-difluoro-4-butoxyphenoxymethyl)cyclohexyl]benzene (No. 831). The yield based on the compound (20) was 85.1%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([OH:39])=[O:38])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)=[O:23].[CH2:40](O)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:20][O:21][C:22]([O:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:38])=[CH:33][CH:32]=2)=[CH:29][CH:30]=1)=[O:23]
Reactant: CCCCCCCCO
Reactant: COC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOC(=O)c1ccc(-c2ccc(OC(=O)OC)cc2)cc1

Procedure:
A solution of triphenylphosphine (3.78 g, 0.014 mol) in dry tetrahydrofuran (50 ml) was added to a stirred solution of compound 4 (3.92 g, 0.014 mol), octan-1-ol (1.88 g, 0.014 mol) and diethyl azodicarboxylate (DEAD) (2.51 g, 0.014 mol) in dry tetrahydrofuran (100 ml) under an atmosphere of dry nitrogen. The addition was such that the triphenylphosphine was added over 30 seconds in which time the solution became hot and the white solid (4) and orange colour (DEAD) disappeared. The resultant solution was stirred overnight, the solvent was removed in vacuo and the viscous, oily residue was purified by column chromatography (10% petrol/dichloromethane) to give a colourless solid which was recrystallised from ethanol to leave colourless plates.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[F:26][C:27]1[CH:28]=[C:29]([NH:33][CH3:34])[CH:30]=[CH:31][CH:32]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[F:26][C:27]1[CH:28]=[C:29]([N:33]([CH3:34])[C:8]([C:5]2[C:4]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:24])([F:25])[F:23])[CH:16]=3)(=[O:14])=[O:13])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:9])[CH:30]=[CH:31][CH:32]=1
Reactant: CNc1cccc(F)c1
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1cccc(F)c1

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (50 mg, 0.12 mmol), (3-fluoro-phenyl)-methyl-amine (45 mg, 0.36 mmol), BOP (69 mg, 0.36 mmol), DIEA (130 μL, 0.72 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (3-fluoro-phenyl)-methyl-amide: MS m/z: (M+H) 521.9.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[O:15][CH2:16][CH3:17])=[O:4].[C:18]([O-:21])(=[O:20])[CH3:19].[Na+]>CN(C)C=O>[CH2:16]([O:15][C:6]1[CH:7]=[CH:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[C:3](=[O:4])[CH2:2][O:21][C:18](=[O:20])[CH3:19])[CH3:17]
Reactant: CC(=O)[O-]
Reactant: CCOc1ccc2ccccc2c1C(=O)CBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc2ccccc2c1C(=O)COC(C)=O
Temperature: 80 °C
Yield: 93.8 %

Procedure:
A mixture of 2-bromo-1-(2-ethoxy-naphthalen-1-yl)-ethanone (7.0 g), sodium acetate (2.0 g) and N,N-dimethylformamide (80 mL) was heated at 80° C. for 1.5 hours. After cooling to room temperature the N,N-dimethylformamide was removed under reduced pressure and the resulting residue was partitioned between dichloromethane (60 mL) and water (60 mL). The organic phase was washed with water (60 mL), brine (60 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to afford acetic acid 2-(2-ethoxy-naphthalen-1-yl)-2-oxo-ethyl ester (6.1 g, 94%) as dark red oil. 1H NMR (CDCl3): 1.45 (3H, t, J=7.0 Hz), 2.2 (3H, s), 4.2 (2H, q, J=7.0 Hz), 5.15 (2H, s), 7.2 (1H, d, J=9.4 Hz), 7.35 (1H, m), 7.45 (1H, m), 7.75 (1H, d, J=8.1 Hz), 7.85 (2H, m).
Reaction SMILES: C([NH:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>C(O)C>[NH2:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(C=CC(=O)O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(C=CC(=O)O)cn1
Reaction time: 16 h
Yield: 49.7 %

Procedure:
To 3-(6-acetylamino-pyridin-3-yl)-acrylic acid (0.80 g, 3.88 mmol) in ethanol (10 mL) is added 1N NaOH (20 mL). The solution is heated to reflux. After 16 h, the solution is concentrated to ⅓ its volume. The aqueous solution is diluted with water and acidified to pH=2 with 6N HCl. The solution is concentrated to dryness. The residue is dissolved in methanol. The solution is filtered. The organic solution is concentrated. The crude product is purified by RP-HPLC eluting with a gradient of 5%CH3CN/H2O (0.1% TFA) to 30% CH3CN/H2O (0.1%TFA) to give the product as a white solid (0.54 g, 1.93 mmol). 1H NMR (300 MHz, CD3OD) δ8.34 (d, 1H), 8.07 (s, 1H), 7.54 (d, 2H), 7.06 (d, 1H), 6.47 (d, 1H). MS (ion spray) 165, (M+H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[NH2:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=1[C:16]#[N:17]>>[NH2:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8](=[O:12])[CH:9]([CH3:10])[CH3:11])[CH2:4][CH2:3]2)[C:15]=1[C:16]#[N:17]
Reactant: CC(C)C(=O)N1CCC(O)CC1
Reactant: N#Cc1c(N)cccc1F
Product: CC(C)C(=O)N1CCC(Oc2cccc(N)c2C#N)CC1

Procedure:
Prepared as in Example Ca from 1-(4-hydroxypiperidin-1-yl)-2-methylpropan-1-one (Example 10c) and 2-amino-6-fluorobenzonitrile as an off-white solid (87%). MS 288 (MH+).
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].C([O-])([O-])=O.[K+].[K+]>CO.CCCCC>[CH2:13]([O:12][C:5]([O:6][CH2:7][CH3:8])([O:9][CH2:10][CH3:11])[C:4]#[CH:3])[CH3:14]
Reactant: CCOC(C#C[Si](C)(C)C)(OCC)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCCCC
Product: C#CC(OCC)(OCC)OCC
Temperature: 23 °C
Reaction time: 15 h
Yield: 75.4 %

Procedure:
A solution of trimethyl(3,3,3-triethoxyprop-1-ynyl)silane (25 g, 102 mmol) in MeOH (400 mL), was treated with K2CO3 (14 g, 102 mmol). The reaction was stirred at 23° C. After 15 hours, the reaction was diluted with pentane (500 mL). The pentane layer was separated, and the MeOH layer was extracted with pentane (2×250 mL). The combined pentane layers were washed with water (200 mL), dried over MgSO4, and concentrated (at 220 torr on rotary evaporator). The crude product was filtered through a silica gel plug using 10% diethyl ether/pentane as the eluant and concentrated (at 220 torr on rotary evaporator) affording 13.25 g of 3,3,3-triethoxyprop-1-yne.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1([CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH2:35]O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(Br)(Br)(Br)[Br:38]>ClCCl>[Br:38][CH2:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCCCOCCOCCCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCOCCOCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
Triphenylphosphine (12.59 g), in dry dichloromethane was added dropwise over 20 min to a stirred solution of 3-[2-(3-phenylpropoxy)ethoxy]-1-propanol (8.8 g) and carbon tetrabromide (15.92 g) in dry dichloromethane (170 ml) at 0° C. under nitrogen. The solution was allowed to warm to room temperature and stirred under nitrogen for 30 min. The solution was concentrated to ca 30 ml and then purified by FCC eluting with System B (0:10→2:3) to give the title compound (9.94 g) as an oil. T.l.c. (System B 1:1) Rf 0.50
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1>CC1C=CC=CC=1C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: Cc1ccccc1C
Product: O=Cc1ccc(OCc2ccc(Cl)cc2)cc1
Temperature: 80 °C
Yield: 122.7 %

Procedure:
In a 200-ml eggplant-type flask, 5.3 g (37.0 mmol) of 4-chlorobenzyl alcohol were weighed. After 80 ml of o-xylene, a nonpolar solvent, were added to form a solution, 28.0 g (37.0 mmol) of tetrakis[tris(dimethylamino)phosphoranilideneamino]phosphonium hydroxide was added to form a homogeneous solution. The solution was heated to 80° C., at which it was then maintained at 5 mmHg for 1 hour. Its pressure was allowed to rise back to normal pressure by nitrogen, followed by cooling to room temperature. Further, 50 ml of o-xylene and 5.20 g (37.0 mmol) of 4-chlorobenzaldehyde were added, followed by heating at 130° C. for 96 hours. The reaction mixture was washed four times with 100-ml portions of 1 N, hydrochloric acid. The organic layer was separated and then concentrated to dryness. The residue was recrystallized from ethanol, whereby 5.6 g of 4-(4-chlorobenzyloxy)benzaldehyde were obtained as colorless crystals. Its isolation yield was 61%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)=[O:10])[CH2:3][CH2:2]1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])=[O:10])[CH2:5][CH2:6]1
Reactant: O=C(CCN1CCOCC1)c1ccccc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1ccccc1C(=O)CCN1CCOCC1
Yield: 98 %

Procedure:
To a solution of 3-morpholino-l-(2′-nitrophenyl) propane-1-one (200 mg, 0.758 mmol) dissolved in 10 ml of 95% ethanol was added sodium dithionite (660 mg, 3.79 mmol) and the reaction mixture was stirred under reflux for 3 hrs. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with ethanol-dichloromethane-triethylamine to yield the desired product (174 mg, 89%) as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:128])[N:6]([CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][O:75][CH2:76][CH2:77][O:78][CH2:79][CH2:80][O:81][CH2:82][CH2:83][O:84][CH2:85][CH2:86][O:87][CH2:88][CH2:89][O:90][CH2:91][CH2:92][O:93][CH2:94][CH2:95][O:96][CH2:97][CH2:98][O:99][CH2:100][CH2:101][O:102][CH2:103][CH2:104][O:105][CH2:106][CH2:107][O:108][CH2:109][CH2:110][O:111][CH2:112][CH2:113][O:114][CH2:115][CH2:116][O:117][CH2:118][CH2:119][O:120][CH2:121][CH2:122][O:123][CH3:124])[C:5](=[O:125])[C:4]([CH3:127])([CH3:126])[NH:3]1.C(O[Cl:134])(C)(C)C>CO>[Cl:134][N:3]1[C:4]([CH3:127])([CH3:126])[C:5](=[O:125])[N:6]([CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][O:75][CH2:76][CH2:77][O:78][CH2:79][CH2:80][O:81][CH2:82][CH2:83][O:84][CH2:85][CH2:86][O:87][CH2:88][CH2:89][O:90][CH2:91][CH2:92][O:93][CH2:94][CH2:95][O:96][CH2:97][CH2:98][O:99][CH2:100][CH2:101][O:102][CH2:103][CH2:104][O:105][CH2:106][CH2:107][O:108][CH2:109][CH2:110][O:111][CH2:112][CH2:113][O:114][CH2:115][CH2:116][O:117][CH2:118][CH2:119][O:120][CH2:121][CH2:122][O:123][CH3:124])[C:2]1([CH3:128])[CH3:1]
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN1C(=O)C(C)(C)NC1(C)C
Reactant: CC(C)(C)OCl
Solvent: CO
Product: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN1C(=O)C(C)(C)N(Cl)C1(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a 0° C. solution of 2,2,5,5-tetramethyl-3-(2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71,74,77,80,83,86,89,92,95,98,101,104,107,110,113,116-nonatriacontaoxaoctadecahectan-118-yl)imidazolidin-4-one (1.42 g, 0.7 mmol) in methanol (150 ml) was added tert-butylhypochlorite (209 mg, 1.9 mmol). The mixture was stirred for 1 hour at 0° C. The reaction mixture was concentrated in vacuo, and crude material is purified by silica gel flash chromatography (0 to 10% methanol in dichloromethane) to give 775 mg (54%) of the title compound. 1H NMR (400 MHz, D2O) δ 3.72 (s, 152H), 3.65 (m, 2H), 3.58 (t, J=7.5 Hz, 2H), 3.40 (s, 3H), 1.55 (s, 6H), 1.38 (s, 6H). 13C NMR (100 MHz, D2O) δ 174.9, 83.6, 71.0, 69.5 (large peak) 67.7, 66.0, 58.1, 40.2, 24.2, 22.7.
Reaction SMILES: Br[CH:2]([C:5]1[N:6]=[C:7]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:8]2[C:9](=[O:12])[C:10]=1[I:11])[CH2:3][CH3:4].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:18]([CH:2]([C:5]1[N:6]=[C:7]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:8]2[C:9](=[O:12])[C:10]=1[I:11])[CH2:3][CH3:4])=[N+:19]=[N-:20]
Reactant: CCC(Br)c1nc2cccc(C)n2c(=O)c1I
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(N=[N+]=[N-])c1nc2cccc(C)n2c(=O)c1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(1-bromopropyl)-3-iodo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (4.50 g, 11.0 mmol) and sodium azide (3.59 g, 55.3 mmol) in DMF was stirred at room temperature for 2 h. After diluting with ethyl acetate, the mixture was washed with water, brine, dried over sodium sulfate, and evaporated under reduced pressure to provide the crude product, which was used directly in next step (3.35 g, 82.1%). LCMS calculated for C12H13IN5O (M+H)+: m/z=370.0. Found: 370.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[C:5](=[O:13])[CH2:4][CH2:3]1.[N:15]([C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1)=O>C(O)(=O)C>[CH3:1][C:2]1([CH3:14])[CH2:3][CH2:4][C:5](=[O:13])[C:6]2[CH:7]=[C:8]([N:12]=[N:15][C:17]3[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=3)[CH:9]=[CH:10][C:11]1=2
Reactant: CC1(C)CCC(=O)c2cc(N)ccc21
Reactant: CCOC(=O)c1ccc(N=O)cc1
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 198.7 mg (1.05 mmol) 3,4-dihydro-4,4-dimethyl-7-amino-1-(2H)-naphthalenone (Compound Z) in 5.0 ml glacial acetic acid was added 180.0 mg (1.00 mmol) of ethyl 4-nitrosobenzoate. The resulting solution was stirred overnight at room temperature, and then concentrated under reduced pressure. The product was isolated from the residual oil as a red solid, by column chromatography (15% EtOAc--hexanes). 1H NMR (CDCl3): δ 8.57 (1H, d, J=2.0 Hz), 8.19 (2H, d, J=8.4 Hz), 8.07 (1H, d, J=8.0 Hz), 7.94 (2H, d, J=8.4 Hz), 7.58 (1H, d, J=8.6 Hz), 4.41 (2H, q, J=7.1 Hz), 2.79 (2H, t, J=6.6 Hz), 2.07 (2H, t, J=7.02 Hz), 1.44 (6H, s), 1.42 (3H, t, J=7.1 Hz).
Reaction SMILES: C([O:4][C:5]1[C:42]([CH2:43][N:44]([CH2:53][C:54]([O:56]C(C)(C)C)=[O:55])[CH2:45][C:46]([O:48]C(C)(C)C)=[O:47])=[CH:41][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH:18]([C:37]([O:39][CH3:40])=[O:38])[C:19]3[CH:24]=[C:23]([I:25])[C:22]([O:26][C:27]4[CH:32]=[C:31]([I:33])[C:30]([OH:34])=[C:29]([I:35])[CH:28]=4)=[C:21]([I:36])[CH:20]=3)[CH:12]=2)=[O:10])=[CH:7][C:6]=1[CH2:61][N:62]([CH2:71][C:72]([O:74]C(C)(C)C)=[O:73])[CH2:63][C:64]([O:66]C(C)(C)C)=[O:65])(=O)C>FC(F)(F)C(O)=O.O>[C:64]([CH2:63][N:62]([CH2:61][C:6]1[CH:7]=[C:8]([CH:41]=[C:42]([CH2:43][N:44]([CH2:53][C:54]([OH:56])=[O:55])[CH2:45][C:46]([OH:48])=[O:47])[C:5]=1[OH:4])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH:18]([C:37]([O:39][CH3:40])=[O:38])[C:19]2[CH:24]=[C:23]([I:25])[C:22]([O:26][C:27]3[CH:32]=[C:31]([I:33])[C:30]([OH:34])=[C:29]([I:35])[CH:28]=3)=[C:21]([I:36])[CH:20]=2)[CH:12]=1)=[O:10])[CH2:71][C:72]([OH:74])=[O:73])([OH:66])=[O:65]
Reactant: COC(=O)C(Cc1cccc(C(=O)c2cc(CN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)c(OC(C)=O)c(CN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)c2)c1)c1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)C(Cc1cccc(C(=O)c2cc(CN(CC(=O)O)CC(=O)O)c(O)c(CN(CC(=O)O)CC(=O)O)c2)c1)c1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1

Procedure:
A solution of 630 mg of 21 in 5 mL of trifluoroacetic acid was stirred overnight, diluted with water and the solid which separated was collected and dried; yield 550 mg. The field desorption mass spectrum showed 22 (m/e1305) is present, as well as some material in which the methyl ester of the thyroxine has been hydrolyzed to the acid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17]#[C:18][CH2:19][O:20]C2CCCCO2)=[C:4]([CH2:8][O:9][C:10](=[O:16])[C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13])[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[OH:20][CH2:19][C:18]#[C:17][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:8][O:9][C:10](=[O:16])[C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13]
Reactant: CCC(C)(C)C(=O)OCc1cccc(C)c1C#CCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CCC(C)(C)C(=O)OCc1cccc(C)c1C#CCO
Temperature: 55 °C
Yield: 90.2 %

Procedure:
A solution of rac-2,2-dimethylbutanoic acid [3-methyl-2-[3-(2-tetrahydropyranyloxy)-1-propynyl]phenyl]methyl ester (2 g) and pyridinium p-toluenesulfonate in ethanol (30 mL) was stirred and heated in an oil bath maintained at 55° C. for 3.5 hours then the solvent was evaporated and the residue triturated with diethyl ether. After a small amount of pyridinium p-toluenesulfonate was Filtered off, the filtrate was evaporated and the residual oil was purified by HPLC (diethyl ether-hexane; 1:3) to furnish 1.38 g of 2,2-dimethylbutanoic acid [2-(3-hydroxy-1-propynyl)-3-methylphenyl]methyl ester as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH2:16][CH:14]([CH2:15]2)[C:13](=[O:17])[N:12]([CH2:18][CH2:19][CH3:20])[C:11]3=[O:21])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]23[CH2:15][CH:14]([CH2:16]2)[C:13](=[O:17])[N:12]([CH2:18][CH2:19][CH3:20])[C:11]3=[O:21])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CCCN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCN1C(=O)C2CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
0.35 g of 5% palladium-on-carbon catalyst is added to a solution of 3.5 g of 1-(4-nitrophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione in 70 ml of ethyl acetate and the whole is hydrogenated under normal pressure and at 30°-35° in a hydrogen atmosphere. When the absorption of hydrogen is complete, the reaction mixture is diluted with 30 ml of methylene chloride and freed of catalyst by filtration over HYFLO Super-Cel®. The solvent is evaporated off in vacuo, and the residue is recrystallised from a mixture of ethyl acetate/n-hexane, yielding the title compound in the form of white crystals having a melting point of 166°-167°.