Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[CH:11]=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=2[C:6](=[O:14])[C:5]2[N:15]([CH3:18])[N:16]=[CH:17][C:4]1=2)[CH3:2].Cl.[CH3:20][N:21]([CH3:26])[CH2:22]CC[Cl:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[ClH:25].[CH3:20][N:21]([CH3:26])[CH2:22][CH2:2][CH2:1][N:3]1[C:12]2[CH:11]=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=2[C:6](=[O:14])[C:5]2[N:15]([CH3:18])[N:16]=[CH:17][C:4]1=2
Reactant: CCn1c2ccc(C)cc2c(=O)c2c1cnn2C
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c(=O)c1c(cnn1C)n2CCCN(C)C
Temperature: 100 °C
Reaction time: 6 h
Yield: 78.8 %

Procedure:
A mixture of 1,7-dimethyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one (UK-264650) (EXAMPLE 47, step 2, 100 mg, 0.375 mmol), 3-(dimethylamino)propyl chloride hydrochloride (178 mg, 1.13 mmol) and potassium carbonate (311 mg, 2.25 mmol) in N,N-dimethylformamide (2 ml) was stirred at 100° C. for 6 h. After cooling to room temperature, water (50 ml) was added and extracted with ethyl acetate (50 ml×3). The combined organic layer was dried over magnesium sulfate and evaporated. To this residue (106 mg) was added methanolic hydrochloric acid and the mixture was concentrated in vacuo. The solid was recrystallized from ethanol/diisopropyl ether to give 99 mg (79%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([O-:16])(O)=O.[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[NH:30]1[CH:37]=[CH:36][C:34](=[O:35])[NH:33][C:31]1=[O:32]>ClCCl.C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[O:32]=[C:31]1[NH:33][C:34](=[O:35])[CH:36]=[CH:37][N:30]1[C:13]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:16]
Reactant: O=C([O-])O
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: NCCCCCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(NCCCCCc1ccccc1)n1ccc(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
5-phenylpentan-1-amine (0.07 g, 0.43 mmol) was dissolved in dry dichloromethane (4.5 mL). The solution was cooled to 0° C. and saturated aqueous NaHCO3 solution (4.5 mL) was added. The biphasic mixture was stirred for 10 min at 0° C., the layers were allowed to separate then a solution of triphosgene (0.51 g, 0.52 mmol) in dry toluene (2.5 mL) was added to the organic layer. After 15 min the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over Na2SO4 and the solvent was removed under reduced pressure. The resulting residue was added to a solution of uracil (0.05 g, 0.43 mmol) and DMAP (0.01 g, 0.01 mmol) in dry pyridine (5 mL). The suspension was stirred at room temperature for 18 hrs. The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 75:25) to afford the title compound (0.04 g, 32%) as a white solid. 1H NMR (400 MHz, DMSO-d6): 1.25-1.42 (m, 2H), 1.46-1.64 (m, 5H), 2.54-2.60 (m, 2H), 3.21-3.28 (m, 2H), 5.79 (d, J=8.38 Hz, 1H), 7.06-7.36 (m, 5H), 8.20 (d, J=8.40 Hz, 1H), 9.11 (t, J=5.65 Hz, 1H), 11.71 (s, 1H). 13C NMR (101 MHz, DMSO-d6) δ 26.18, 28.56, 30.79, 35.12, 41.81, 40.26, 103.48, 125.78, 128.11, 129.30, 139.70, 149.23, 151.13, 161.80.
Reaction SMILES: N1C=CC=CC=1.S(Cl)([Cl:9])=O.[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21]O)([O-:13])=[O:12].C1(C)C=CC=CC=1>C(Cl)(Cl)Cl>[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][Cl:9])([O-:13])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccccc1CCO
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccccc1CCCl
Temperature: 0 °C
Yield: 83.3 %

Procedure:
2.1 ml abs. pyridine and 21.62 g thionyl chloride (13.3 ml,. 0.18 mol) is added to 10.13 9 2-(2-nitrophenyl)ethanol (60 mmol) in 36 ml abs. toluene. After 2 h reflux, this is cooled and poured onto ice. The ice water is mixed with 50 ml chloroform and extracted 2× each with 50 ml chloroform. The combined organic phases are neutralized 2× each with 100 ml saturated bicarbonate solution. After drying with Na2SO4, this is filtered and rotary evaporated. After distillation under high-vacuum, 9.7 9 (50 mmol,. 87%) 2-(2-nitrophenyl)ethyl chloride is obtained as a yellow oil with a boiling point of 66 to 67° C. (0.001 mbar).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl-].[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([CH2:36][NH:37][CH:38]=[S:39])=[CH:35][C:30]=2[O:29][CH2:28]1.CO>ClCCl>[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([CH2:36][NH:37][C:38]([N:4]3[CH2:5][CH2:6][N:1]([C:7]4[C:8]5[O:15][C:14]6[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=6[C:9]=5[N:10]=[CH:11][N:12]=4)[CH2:2][CH2:3]3)=[S:39])=[CH:35][C:30]=2[O:29][CH2:28]1
Reactant: S=CNCc1ccc2c(c1)OCO2
Reactant: c1ccc2c(c1)oc1c(N3CCNCC3)ncnc12
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: S=C(NCc1ccc2c(c1)OCO2)N1CCN(c2ncnc3c2oc2ccccc23)CC1
Reaction time: 8 h

Procedure:
To a solution of 4-piperazinobenzofurano[3,2-d]pyrimidine (200 mg, 0.79 mmol) and pyridine (0.5 mL, 7.9 mmol) in dichloromethane (20 mL) was added a solution of product 1c in dichloromethane (20 mL) and this was stirred overnight. Methanol was added to quench excess thiophosgene, and the residue after removal of solvent was purified by silica gel column chromatography eluting with 5% methanol/dichloromethane and further recrystallized from dichloromethane/hexane to give 150 mg (37%).
Reaction SMILES: ClCCl.C[O:5][C:6]([C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[CH3:32])=[N:22][C:21]=1[CH3:33])(OC)[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>O>[CH3:32][C:26]1[CH:27]=[C:28]([CH3:31])[CH:29]=[CH:30][C:25]=1[C:23]1[S:24][C:20]([C:6](=[O:5])[CH2:7][O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[C:21]([CH3:33])[N:22]=1
Reactant: COc1ccc(COCC(OC)(OC)c2sc(-c3ccc(C)cc3C)nc2C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(COCC(=O)c2sc(-c3ccc(C)cc3C)nc2C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.6 %

Procedure:
To dichloromethane (2 ml), 5-[1,1-dimethoxy-2-(4-methoxybenzyloxy)ethyl]-2-(2,4-dimethylphenyl)-4-methylthiazole (35 mg) prepared in the Step 31-1-3 was added, and trifluoroacetic acid (0.3 ml) and water (0.1 ml) were added thereto. Thereafter, the mixture was stirred at a room temperature for 5 hours. To the reaction solution, a saturated sodium bicarbonate solution was added, and then the resulting mixture was subjected to extraction with chloroform. The extract was washed with a saturated saline solution, and then dried over sodium sulfate and concentrated under a reduced pressure. The residue was purified by thin-layer chromatography (hexane:ethyl acetate=3:1, toluene:ethyl acetate=3:1) to give the title compound (18 mg, 57%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)[CH3:2].C(=O)([O-])[O-:14].[K+].[K+].C1OC1>CO>[OH:14][CH2:2][CH2:1][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: [K+]
Solvent: CO
Solvent: C1CO1
Product: C=Cc1ccc(OCCO)cc1

Procedure:
Para-(hydroxyethoxy)styrene was prepared using the method described in Example 1, except that the following amounts of reagents were used: 86 g (0.53 mol, 1 eq) of p-acetoxystyrene, 3.7 g (26.77 mmol, 0.05 eq) of anhydrous potassium carbonate, and 35 g (0.795 mol, 1.5 eq) of ethylene oxide in 530 mL of methanol. The isolated product yield was 61.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])(=[O:10])=[O:9])=[CH:4][N+:3]=1[O-].O.P(Cl)(Cl)([Cl:22])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])(=[O:10])=[O:9])=[C:4]([Cl:22])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=S(=O)(c1ccc(Cl)[n+]([O-])c1)c1ccccc1F
Solvent: O
Product: O=S(=O)(c1ccccc1F)c1ccc(Cl)nc1Cl
Temperature: 120 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
2-Chloro-5-[(2-fluorophenyl)sulfonyl]pyridine 1-oxide from Step 1 (0.27 g, 0.938 mmol) was suspended in phosphorus oxychloride (10 mL) and stirred at 120° C. overnight. The cooled solution was poured into water and extracted with ethyl acetate (×2). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo while loading onto silica. Dry flash column chromatography using 10-20% ethyl acetate/isohexane gave the product 2,6-dichloro-5-[(2-fluorophenyl)sulfonyl]pyridine (115 mg) and impure product (100 mg). The latter material was recrystallised from ethanol to give further clean product (42 mg, total yield 55%). δH (400 MHz, d6 DMSO): 8.68 (1H, dd, J=1.1, 8.3 Hz), 8.15 (1H, td, J=7.6, 1.7 Hz), 7.93 (1H, d, J=8.2 Hz), 7.89-7.85 (1H, m), 7.55 (1H, td, J=7.6, 0.9 Hz), 7.48-7.44 (1H, m); m/z (ES+) 306, 308 [MH+].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[Li+].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)[O:23][C:24]=1[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:25][C:24]1[O:23][C:22]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)=[N:21][C:20]=1[CH2:19][S:14]([C:11]1[CH:10]=[CH:9][C:8]([CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:13][CH:12]=1)(=[O:16])=[O:15]
Reactant: O=S([O-])c1ccc(CN2CCOCC2)cc1
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(CN4CCOCC4)cc3)c(C)o2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
A mixture of lithium 4-(morpholinomethyl)benzenesulfinate (2.0 g, 8.10 mmol, 1.43 equiv), methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (1.5 g, 5.66 mmol, 1.00 equiv) and potassium carbonate (780 mg, 5.65 mmol, 1.00 equiv) in N,N-dimethylformamide (60 mL) was stirred overnight at 70° C. The reaction mixture was cooled to room temperature and the product was precipitated by the addition of 150 mL of ice and water. The solid was collected by filtration, washed with 2×20 mL of water and dried in a vacuum oven to afford 1.5 g (57%) of methyl 4-(5-methyl-4-((4-(morpholinomethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoate as a white solid. LC-MS: (ES, m/z): 512 [M+CH3CN+H]+, 471 [M+H]+. 1HNMR (400 MHz, DMSO-d6, ppm) δ 8.04 (d, J=8.0 Hz, 2H), 7.90 (d, J=8.0 Hz, 2H), 7.72 (d, J=7.6 Hz, 2H), 7.52 (d, J=7.6 Hz, 2H), 4.67 (s, 2H), 3.88 (s, 3H), 3.55 (s, 6H), 3.31-3.29 (d, 4H), 2.32 (s, 4H), 2.15 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:17](Cl)=[O:18].[C:25]([O:29][C:30]([N:32]1[CH2:36][C@@H:35]([CH2:37][NH:38][CH:39]([CH3:41])[CH3:40])[C@H:34]([CH2:42][N:43]([S:48]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)(=[O:50])=[O:49])[CH2:44][CH:45]([CH3:47])[CH3:46])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:25]([O:29][C:30]([N:32]1[CH2:33][C@H:34]([CH2:42][N:43]([CH2:44][CH:45]([CH3:46])[CH3:47])[S:48]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)(=[O:50])=[O:49])[C@H:35]([CH2:37][N:38]([CH:39]([CH3:41])[CH3:40])[C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:14]([O:13][CH2:12][CH2:11][CH2:10][O:9][CH3:8])[CH:15]=2)[CH2:36]1)=[O:31])([CH3:26])([CH3:27])[CH3:28]
Reactant: CC(C)CN(C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CNC(C)C)S(=O)(=O)c1ccccc1
Reactant: COCCCOc1cc(C(=O)Cl)ccc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2CN(CC(C)C)S(=O)(=O)c2ccccc2)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Triethylamine (0.48 mL, 3.43 mmol) followed by 3-(3-methoxy-propoxy)-4-methoxy-benzoic acid chloride (621 mg, 2.4 mmol) (prepared from 3-(3-methoxy-propoxy)-4-methoxy-benzoic acid and SOCl2 in CH2Cl2) is added to a solution of (3S*,4R*)-3-[(benzenesulfonyl-isobutyl-amino)-methyl]-4-(isopropylamino-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.07 g, 2.3 mmol) in CH2Cl2 (30 mL) and stirred at RT for 16 h. For workup a sat. solution of NaHCO3 is added and the mixture is extracted with ethyl acetate. The combined organic extracts are dried (Na2SO4), filtered and the solvent is evaporated. Purification of the crude product by flash chromatography on silica gel (eluent gradient: c-hexane/AcOEt 1:1 to 3:7) yields the title compound. TLC, Rf (c-hexane/AcOEt 3:7)=0.40; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 6.10 min.
Reaction SMILES: [CH2:1]1[O:5][CH:4]([CH:6]([OH:9])[CH2:7][OH:8])[C@@H:3]([OH:10])[CH:2]1[OH:11].[C:12](OC)(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].CO.C[O-].[Na+].[PH2]([O-])=O.[Na+]>>[CH3:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]([O:8][CH2:7][CH:6]([OH:9])[C@H:4]1[O:5][CH2:1][C@H:2]([OH:11])[C@H:3]1[OH:10])=[O:30]
Reactant: OCC(O)C1OCC(O)[C@@H]1O
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC
Agent: C[O-]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O
Temperature: 65 °C
Reaction time: 1 h

Procedure:
After 469 g of a 70% by weight sorbitan aqueous solution (aldehyde value of sorbitan: 7.4 ppm) and 872 g of methyl stearate were charged into a 2000 mL four-neck flask fitted with a stirring apparatus, a thermometer, and a nitrogen gas inlet, dehydration was performed at 110° C. under a nitrogen stream at normal pressure for 1 hour and further at 110° C. under a nitrogen stream at 4 kPa for 1 hour. The whole was cooled to 65° C. and, after 30.0 g of a 20% by weight sodium methoxide methanol solution and 0.06 g of sodium hypophosphite were added thereto, was heated under a nitrogen stream at normal pressure to 190° C. as a reaction temperature. After the temperature reached 190° C., pressure was reduced to 6.5 kPa and the reaction was carried out under a nitrogen stream. At the time point when the spot of methyl stearate as a raw material disappeared on thin-layer chromatography, it was judged that the reaction was completed. The reaction time was 5 hours and, after the completion of the reaction was confirmed, the mixture was filtrated at 80° C. to obtain sorbitan monostearate.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[Cl:10][C:4]1[CH:3]=[C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(N)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 4-amino-2-chlorobenzonitrile (5.02 g, 32.9 mmol) in dichloromethane (80 mL) was added N,N-diisopropylethylamine (17.0 mL, 97.8 mmol) and methanesulfonyl chloride (3.0 mL, 38.8 mmol) at −78° C. The reaction was then allowed to warm to room temperature slowly. After stirring at room temperature for 12 h, the reaction was quenched with 1 N hydrochloric acid. The organic phase was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 50:50 hexanes/ethyl acetate) to give the desired product.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:31]([OH:33])=[O:32])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][CH:18]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.FC(F)(F)C([O-])=O.[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([S:58](Cl)(=[O:60])=[O:59])=[CH:54][CH:53]=1>>[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([S:58]([NH:8][C@H:9]([C:31]([OH:33])=[O:32])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][CH:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]3[C:30]2=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:15])(=[O:60])=[O:59])=[CH:54][CH:53]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCCC[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 33 %

Procedure:
Nα-tert-butoxycarbonyl-Nδ-(9-fluorenylmethoxycarbonyl)-L-ornithine was deprotected at the α position by treatment with TFA/CH2Cl2 as described in the procedure outlined in example 24 and the resulting trifluoroacetate salt was alkylated with 4-chlorobenzenesulfonyl chloride as described in example 2, affording the title compound in 33% yield.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH:8]1[C:18]2[CH:17]=[CH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[C:13](=[O:23])[C:12]=2[CH:11]=[CH:10][CH:9]=1>O1CCCC1.CS(C)=O>[O:23]1[CH2:4][C:13]21[C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[CH:16]=[CH:17][C:18]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]2=1
Reactant: O=c1c2ccccc2ccc2ccccc12
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: C1=Cc2ccccc2C2(CO2)c2ccccc21
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A mixture of 4.6 g. of sodium hydride (57%) and 100 ml. of dimethylsulfoxide is heated under nitrogen at 75° C. for 50 minutes and the resulting mixture treated by addition of 40 ml. tetrahydrofuran and then cooled to 0° C. Over a period of 3 minutes there is then added 10.2 g. of trimethylsulfonium iodide in 100 ml. of dimethylsulfoxide, the resulting mixture stirred for one minute and there is then added over a period of 10 minutes a solution of 16.4 g. of dibenzo[a,d]cyclo-hepten-5-one in 40 ml. of tetrahydrofuran. The resulting mixture is kept overnight at temperature of 5° C. and then stirred for 3 hours at room temperature (20° C.). The mixture is then poured onto 3 times its volume of ice water, extracted twice each with 600 ml. of pentane, the organic phases combined, washed four times with water, dried over anhydrous sodium sulfate and evaporated in vacuo to crystallize spiro[dibenzo[ a,d] cycloheptene-5,2'-oxirane], m.p. 90°-91° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH:21]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[CH:21][C:13]3[NH:12][C:20]4[C:15]([CH:14]=3)=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2cc(Cl)ccc2C1=Cc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
A mixture of 6-chloro-2-oxindole (41 mg) (commercially available), indole-2-carbaldehyde (42 mg) (prepared according to Synthetic Communications, 1993, 23, 3109) and piperidine (1 drop) in ethanol (3 mL) was held in a sealed tube at 95° C. for 3 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in vacuum oven to give 62 mg (87% yield) of 6-chloro-3-(1H-indol-2-ylmethylene)-1,3-dihydroindol-2-one as a shiny orange solid.
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>CCO.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: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
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 EtOH/2 N NH4OH (1/1, v/v), filtered, and flitrate 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 EtOH and 41 mL of 1 N 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: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[O:8][CH:7]([CH2:9][OH:10])[CH2:6][O:5]1.Br[CH2:13]/[CH:14]=[CH:15]/[Sn:16]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20]>CN(C=O)C>[CH2:25]([Sn:16]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])/[CH:15]=[CH:14]/[CH2:13][O:10][CH2:9][CH:7]1[CH2:6][O:5][C:4]([CH3:11])([CH3:3])[O:8]1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCC[Sn](/C=C/CBr)(CCCC)CCCC
Reactant: CC1(C)OCC(CO)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC[Sn](/C=C/COCC1COC(C)(C)O1)(CCCC)CCCC
Temperature: 20 °C
Reaction time: 20 h

Procedure:
Sodium hydride (215 mg) was added to a solution of (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (644 mg) in dry DMF (25 mL) at 0° C. [(1E)-3-bromoprop-1-enyl](tributyl)stannane (1.00 g) was added to the reaction mixture after 10 min. The reaction mixture was stirred for 20 h at 20° C. and then quenched with saturated NH4Cl (aq.). Extraction with EtOAc and drying (Na2SO4) of the organic phase gave, after concentration in vacuo, the crude product. Purification was done by chromatography eluting with petroleum ether/EtOAc 10:1 to afford the title compound as a liquid.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10](I)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[CH2:17]([Sn](CCCC)(CCCC)C=C)[CH2:18]CC>C1(C)C=CC=CC=1.CN(C)C=O.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:17]=[CH2:18])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCCCc1nc(=O)c2cc(I)ccc2[nH]1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C=Cc1ccc2[nH]c(CCCC)nc(=O)c2c1
Yield: 53.3 %

Procedure:
A mixture of 12.28 g of 2-butyl-6-iodo-4(1H)-quinazolinone 0.866 g of tetrakis (triphenylphosphine)palladium, 0.015 g of 2,6-di-t- butyl-4-methylphenol in 75 ml of toluene and 20 ml of N,N-dimethylformamide is treated with 13.06 g of tri-n-butyl vinyltin followed by heating at reflux for 4 hours. The reaction mixture is cooled and concentrated in vacuo. The residue is diluted with hexanes and filtered. The filter cake is washed with hexanes and the remaining tacky solid dissolved in 100 ml of chloroform-reethanol (8:2) and purified by chromatography on silica gel with 1:3 ethyl acetate-hexanes to afford 4.55 g of the desired product as a yellow solid. CI MASS SPEC 229MH+).