Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([CH2:23][O:24][CH3:25])[O:17]2)=[C:9]([NH:26][CH2:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]=1)(=O)=O.[CH3:41][C:42]1[C:47]([NH2:48])=[CH:46][CH:45]=[C:44]([CH3:49])[N:43]=1.C(N(CC)CC)C>C(OCC)(=O)C.CN(C)C=O>[CH3:41][C:42]1[C:47]([NH:48][CH2:6][C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@H:16]3[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([CH2:23][O:24][CH3:25])[O:17]3)=[C:9]([NH:26][CH2:27][CH:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:8]=2)=[CH:46][CH:45]=[C:44]([CH3:49])[N:43]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COS(C)(=O)=O)nc32)[C@H](O)[C@@H]1O
Reactant: Cc1ccc(N)c(C)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNc4ccc(C)nc4C)nc32)[C@H](O)[C@@H]1O
Temperature: 60 °C
Reaction time: 24 h
Yield: 11.6 %

Procedure:
{9-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl methanesulfonate (preparation 25) (75 mg, 0.13 mmol) was added to a solution of 2,6dimethyl-3-pyridinylamine (22 mg, 0.17 mmol) and triethylamine (0.036 ml, 0.26 mmol) in ethyl acetate (3 ml) and N,N-dimethylformamide (1 ml) in the reaction vessel of a Argonaut Quest 210 machine. The reaction mixture was agitated and heated to 60° C. for 12 hr. More 2,6-dimethyl-3-pyridinylamine (22 mg, 0.17 mmol) and triethylamine (0.036 ml, 0.26 mmol) were added and heating and agitation continued for a further 24 hr. The reaction mixture was then washed with water and the organic phase separated and dried with anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give a residue which was purified by reverse phase HPLC using firstly a Lana C8 (2) column and then a Magellan C18 column eluting with 5 mM ammonium acetate in water:2 mM ammonium acetate in acetonitrile (90:10) decreasing in polarity to 5 mM ammonium acetate in water:2 mM ammonium acetate in acetonitrile (10:90) as eluant. This gave the title compound (9 mg) as a gum. MS: 596 (MH+).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[C:11]([CH2:13]O)[CH:10]=[CH:9][N:8]=2)=[O:6])[CH2:3][CH2:2]1.S(Cl)([Cl:17])=O>>[Cl:17][CH2:13][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:6])[CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(NC1CC1)c1cc(CO)ccn1
Product: O=C(NC1CC1)c1cc(CCl)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.5 g (13.01 mmol) of N-cyclopropyl-4-(hydroxymethyl)pyridine-2-carboxamide (Example 52A) and 11.76 g (98.84 mmol) of thionyl chloride were combined and stirred at RT overnight. The reaction mixture was concentrated using a rotary evaporator. The residue was dissolved in ethyl acetate and washed once with saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated using a rotary evaporator. The residue was purified by column chromatography on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 2/1).
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1>C(OCC)(=O)C>[C:1]1([C:3]2[CH2:2][C@H:1]([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH:4]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1CC=CCC1
Solvent: CCOC(C)=O
Product: O=C(O)[C@@H]1CCC=C(c2ccccc2)C1

Procedure:
3-Phenyl-3-cyclohexenecarboxylic acid (8.1 g, Step C) is dissolved in 2-butanone (20 mL) and (S)-α-methylbenzylamine (4.85 g) in 2-butanone (10 mL) added. The salt precipitates and more 2-butanone (200 mL) is added and the mixture heated to dissolve the salt. The salt recrystallizes on cooling to 25° C. and it is collected and dried to give 10.02 g of the salt. The salt is recrystallized 5 times from 2-butanone to give 3.14 g of a white powder. The powder is slurried in ethyl acetate and washed with 2N hydrochloric acid. The ethyl acetate layer is dried over magnesium sulfate, filtered, and evaporated to give (R)-3-phenyl. 3-cyclohexenecarboxylic acid as a white powder; mp 77°-80° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][N:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH:22]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]>>[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]3)[CH:22]=2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CN1CCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)CC1
Product: CN1CCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)cc34)cn2)CC1
Yield: 61.2 %

Procedure:
Following general procedure D, (6-bromo-4-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-ylamino)quinolin-3-yl)(cyclopropyl)methanone (50 mg, 0.11 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (47 mg, 0.17 mmol) to afford the desired product (35 mg, 59%) as a yellow-green solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.94 (s, 1H), 8.24 (m, 1H), 8.02 (m, 2H), 7.68 (s, 1H), 7.22 (s, 2H), 4.62 (t, J=5.3 Hz, 1H), 3.69 (d, J=12.7 Hz, 2H), 3.50 (s, 1H), 3.25 (m, 2H), 2.95 (s, 3H), 2.39 (m, 4H), 1.24 (m, 4H); ESI MS m/z 520 [C28H27ClFN5O2+H]+; HPLC 99.5% (AUC), tR=10.37 min.
Reaction SMILES: [C:1]1([N:7]=[N:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH2:19])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([O:27][C:28]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32](O)=[O:33])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]1([N:7]=[N:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH:19][C:32](=[O:33])[C@@H:31]3[CH2:35][CH2:36][CH2:37][N:30]3[C:28]([O:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:29])=[CH:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: Nc1ccc(N=Nc2ccccc2)c2ccccc12
Product: O=C(Nc1ccc(N=Nc2ccccc2)c2ccccc12)[C@@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
4-Phenylazo-1-naphthylamine (4.9 g, 0.02 mole) and N-benzyloxylcarbonyl-L-proline (5.0 g, 0.02 mole) were coupled and the reaction mixture was worked up as in Example 6. The final product was obtained as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[NH2:21])[CH2:7][CH2:6]1)=[O:4].O.C1C[O:26][CH2:25]C1>>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][CH2:7][C@H:8]([CH2:11][N:12]2[C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=3[NH:21][C:25]2=[O:26])[CH2:9][CH2:10]1)=[O:4]
Reactant: C1CCOC1
Reactant: COc1ccc(N)c(NC[C@H]2CC[C@H](C(=O)OC)CC2)c1
Solvent: O
Product: COc1ccc2[nH]c(=O)n(C[C@H]3CC[C@H](C(=O)OC)CC3)c2c1
Reaction time: 22 h

Procedure:
trans-4-[(2-Amino-5-methoxy-phenylamino)-methyl]-cyclohexane carboxylic acid methyl ester (5.4 g, 18.5 mmol) was dissolved in 40 ml of anhydrous THF. 1,1-carbonyldiimidazole (8.9 g, 55.5 mmol) was added and the mixture was stirred for 22 hours. Few drops of water were added and the solvent was removed under reduced pressure and the crude was dissolved in DCM (100 ml) and washed with H2O, a citric acid solution (2×70 ml) and H2O. The organic phase was separated, dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The crude material was filtered through a silica pad using EtAc/cyclohexane and then EtAc as eluent. The solvent was evaporated and the crude was purified by silica column using EtAc/hexane as eluent. In total 3.2 g of the titled compound were obtained (yield=54%)
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[NH:6]1)=[O:4].Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:10]=[C:7]1[N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:9][CH2:8]1
Reactant: COC(=O)C1CCC(=O)N1
Reactant: Brc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CCC(=O)N1c1ccccc1
Temperature: 120 °C
Reaction time: 20 h
Yield: 48.9 %

Procedure:
A mixture of 5-oxo-pyrrolidine-2-carboxylic acid methyl ester (5.00 g, 34.9 mmol), bromobenzene (5.48 g, 34.9 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.96 g, 1.05 mmol), Xantphos™ (1.21 g, 2.09 mmol), and cecium carbonate (15.9 g, 48.9 mmol) in toluene (100 mL) was stirred at 120° C. for 20 h under argon atmosphere. The reaction mixture was cooled to room temperature, and partitioned between ethyl acetate and 2 M HCl solution. The organic layer was washed with saturated NaHCO3 solution, and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 70:30 to 0:100) to give a yellow solid. The solid was triturated with hexane-diisopropyl ether to give the title compound (3.74 g, 49%) as a yellow solid.
Reaction SMILES: [NH3:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]1[CH:15]=[CH:14][C:13](OC)=[CH:12][CH:11]=1>CO>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:15]=[CH:14][C:13](=[NH:1])[CH:12]=[CH:11]1
Reactant: COc1cc[n+](-c2ccccc2OC)cc1
Reactant: N
Solvent: CO
Product: COc1ccccc1-n1ccc(=N)cc1
Temperature: 0 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
Ammonia gas was passed into an ice-cooled solution of 3.27 g (10 millimoles) of 1-(2-methoxyphenyl)-4-methoxypyridinium methosulfate in 15 ml of methanol units 2 g of ammonia had been adsorbed. After standing at 25° for 72 hours, the reaction mixture was concentrated, the residue was triturated with cold ethanol and the product was filtered off: 3.01 g (96% yield) of 1-(2-methoxyphenyl)-4(1H)-pyridineimine methosulfate (M.P.=121°-124°) were obtained.
Reaction SMILES: [F:1][C:2]1[N:3]([C:7]([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)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1.C([Li])(C)(C)C.CN([CH:34]=[O:35])C>C1COCC1.CCCCC.CCOCC>[CH:34]([C:5]1[N:6]=[C:2]([F:1])[N:3]([C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:4]=1)=[O:35]
Reactant: CN(C)C=O
Reactant: Fc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: CCOCC
Product: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2-fluoro-1-triphenylmethylimidazole (3.28 g.) in dry THF (33 ml.) was treated, under argon, at -75° with two equivalents of t-butyl lithium (10 ml. of a 1.93M solution in pentane). After stirring 3 hours at -75°, DMF (1.5 ml.) was added. The reaction mixture was kept a further hour at -75° then allowed to warm up slowly to room temperature. The reaction was worked up by diluting with ether, washing with 2N HCl followed by brine. The ether layer was concentrated under a steam of argon to give 4-formyl-2-fluoro-1-triphenylmethylimidazole, (2.2 g.) m.p. 177°-179°.
Reaction SMILES: [C:1]([OH:15])(=[O:14])[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C@@H:6]([C:8]([CH2:11][OH:12])([CH3:10])[CH3:9])[OH:7].[OH-].[Ca+2:17].[OH-]>>[C:1]([O-:15])(=[O:14])[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C@H:6]([C:8]([CH2:11][OH:12])([CH3:10])[CH3:9])[OH:7].[Ca+2:17].[C:1]([O-:15])(=[O:14])[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C@H:6]([C:8]([CH2:11][OH:12])([CH3:10])[CH3:9])[OH:7]
Reactant: CC(C)(CO)[C@@H](O)C(=O)NCCC(=O)O
Agent: [Ca+2]
Agent: [OH-]
Product: CC(C)(CO)[C@H](O)C(=O)NCCC(=O)[O-]

Procedure:
The free pantothenic acid was neutralized with solid calcium hydroxide with stirring, that is to say a pH of approximately 7 was set. Approximately 2000 g of an aqueous calcium D-pantothenate suspension were obtained, which suspension was sterilized for 60 min. Successful destruction was demonstrated by plating out.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O-:11])=[O:10].[Na+].Cl.[NH:14]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@H:15]([C:23](ON1C(=O)CCC1=O)=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S(=O)(=O)(O)O>O1CCOCC1>[C:36]([O:35][C:33]([NH:14][C@H:15]([C:23]([CH:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH2:1])[C:9]([OH:11])=[O:10])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:34])([CH3:38])([CH3:39])[CH3:37]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: NCCCCCCCC(=O)[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)C(CCCCCCN)C(=O)O
Temperature: 0 °C
Yield: 43 %

Procedure:
To a 250 mL round bottom flask equipped with an addition funnel was added a solution of sodium 8-aminocaprylate (14.61 mmol, 32.5 mL, 1.2 equiv). The pH of the solution was adjusted to 8.2 by addition of concentrated HCl. The solution was cooled in an ice-bath. Boc-Phe-OSu (12.42 mmol, 4.50 g, 1.0 equiv) was dissolved in 1,4-dioxane (20 mL) and added dropwise. The mixture was stirred in the ice-bath for 30 min and at ambient temperature for 12 h. The solution was acidified with 1 M sulfuric acid (80 mL) and extracted with ether (100+50 mL). The combined organic layers were washed with water (40 mL), dried and evaporated to give a pale yellow oil. The oil was triturated with hexanes (3×50 mL) to afford (N-tert-butoxycarbonylphenylalanyl)-8-aminocaprylic acid (5) (2.17 g, 43%) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:9]=2/[CH:10]=[C:11]2/[C:12](=[O:17])[NH:13][C:14](=[O:16])[S:15]/2)[CH2:4]1>CO.Cl.O.[Fe]>[NH2:22][C:19]1[CH:20]=[CH:21][C:8]([N:5]2[CH2:6][CH2:7][CH:3]([N:2]([CH3:1])[CH3:25])[CH2:4]2)=[C:9]([CH:18]=1)/[CH:10]=[C:11]1/[C:12](=[O:17])[NH:13][C:14](=[O:16])[S:15]/1
Reactant: CN(C)C1CCN(c2ccc([N+](=O)[O-])cc2/C=C2\SC(=O)NC2=O)C1
Agent: [Fe]
Agent: Cl
Solvent: CO
Solvent: O
Product: CN(C)C1CCN(c2ccc(N)cc2/C=C2\SC(=O)NC2=O)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
To a mixture of (Z)-5-(2-(3-(dimethylamino)pyrrolidin-1-yl)-5-nitrobenzylidene)thiazolidine-2,4-dione (100 mg, 0.28 mmol) (Method 149) and iron (154 mg, 2.76 mmol) chip in MeOH (10 mL) was added 5 drops of conc. HCl and 5 drops of water. The mixture was stirred at 80° C. for 1 hr. The mixture was loaded into silica gel, purified with ISCO (100% ethyl acetate to methanol/ethyl acetate=50%) to yield a red solid which was repurified with Gilson (acetonitrile:water:0.1% TFA=0% to 50% fro 7 min) to yield a yellow solid as (Z)-5-(5-amino-2-(3-(dimethylamino)pyrrolidin-1-yl)benzylidene)thiazolidine-2,4-dione (51.0 mg, 38.6%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.55 (brs, 1 H), 11.32 (brs, 1 H), 10.30 (brs, 2 H), 7.80 (s, 1 H), 7.42 (m, 2 H), 7.19 (m, 1 H), 3.95 (m, 1 H), 3.39-3.27 (m, 4 H), 2.78 (s, 6 H), 2.30-2.10 (m, 2 H); m/z 333.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH:11]=O.[Cl:24][C:25](Cl)(Cl)[C:26]([O:28][CH2:29][CH3:30])=[O:27].Cl>[Zn].CN(C)C=O>[Cl:23][C:13]1[CH:14]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:21])[Cl:22])[CH:16]=[C:2]([Cl:1])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH:11]=[C:25]([Cl:24])[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: O=CCOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: CCOC(=O)C(Cl)(Cl)Cl
Agent: Cl
Agent: [Zn]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cl)=CCOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Yield: 5 %

Procedure:
To a mixture of 0.60 g of 4-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyloxyacetaldehyde, 0.29 g of zinc dust and 10 ml of N,N-dimethylformamide was added ethyl trichloroacetate with stirring at room temperature. After stirring at room temperature for 2 hours, the reaction mixture was poured into 10 ml of diluted hydrochloric acid and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over magnesium sulfate and then evaporated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.04 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(3-chloro-3-ethoxycarbonyl-2-propenyloxy)butyloxy)benzene (yield, 5%), nD23.0 1.5348.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[NH:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][C:26]1[CH:30]=[C:29]([CH3:31])[N:28]([CH:32]([CH3:49])[C:33]([CH:35]2[C:40](=O)[CH2:39][CH2:38][N:37]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:36]2)=O)[N:27]=1>CCO>[CH3:25][C:26]1[CH:30]=[C:29]([CH3:31])[N:28]([CH:32]([C:33]2[C:35]3[CH2:36][N:37]([C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])[CH2:38][CH2:39][C:40]=3[N:17]=[C:16]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[N:18]=2)[CH3:49])[N:27]=1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: Cc1cc(C)n(C(C)C(=O)C2CN(C(=O)OC(C)(C)C)CCC2=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cc(Nc2nc3c(c(C(C)n4nc(C)cc4C)n2)CN(C(=O)OC(C)(C)C)CC3)ccc1-n1cnc(C)c1
Reaction time: 8 h

Procedure:
1-(3-Methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)guanidine (175 mg, 0.57 mmol) and potassium carbonate (196 mg, 1.42 mmol) in EtOH (7 mL) were heated to 50° C. and tert-butyl 3-(2-(3,5-dimethyl-1H-pyrazol-1-yl)propanoyl)-4-oxopiperidine-1-carboxylate (248 mg, 0.71 mmol) added. The reaction mixture was stirred overnight. The solvent was evaporated and DCM added. The organic phase was washed with water and concentrated. The crude product was used as such in next step (450 mg, 113%).
Reaction SMILES: [OH-:1].[K+].[OH:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:7]1[CH2:16][C:15](=O)[C:14]2[C:9](=[CH:10][C:11]([O:19][CH2:20][CH2:21][Br:22])=[CH:12][C:13]=2[OH:18])[O:8]1.O.Cl>C(Cl)Cl.CO>[OH:18][C:13]1[CH:12]=[C:11]([O:19][CH2:20][CH2:21][Br:22])[CH:10]=[C:9]([OH:8])[C:14]=1[CH:15]=[CH:16][C:7]([C:6]1[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:4]([OH:3])[CH:5]=1)=[O:1]
Reactant: [OH-]
Reactant: COc1ccc(C2CC(=O)c3c(O)cc(OCCBr)cc3O2)cc1O
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)C=Cc2c(O)cc(OCCBr)cc2O)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
Ten ml of 5% KOH is added to 400 mg (1.00 mmole) of 3',5-dihydroxy-4'-methoxy-7-bromoethoxy-flavanone giving a bright yellow solution which is stirred under argon at ambient temperature for 2 hours. The reaction mixture is then poured into 100 ml of water, acidified with 10% HCl, and extracted immediately with ethyl acetate (2 × 25 ml). The combined extracts are washed with dilute NaHCO3 (1 × 25ml), dried over MgSO4 and concentrated yielding 0.51 g of a partially crystalline orange oil. Tlc (silica gel F-254, CH2Cl2 --CH3OH 95:5), indicates the reaction to have proceeded nearly quantitatively showing only the product (Rf =0.28) and a barely observable spot for starting material (Rf =0.73). Preparative tlc on silica gel PF-254, eluting with CH2Cl2 --CH3OH 95:5, yielded 302 mg (75%) of the chalcone as a yellow solid. Recrystallization from hexaneethyl acetate gives orange clusters having mp 158°-162°C and spectra consistent with material 7b.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.[CH3:25][O:26][C:27](=[O:39])[C@@H:28]([NH2:38])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([I:37])[CH:31]=1>>[CH3:25][O:26][C:27](=[O:39])[C@@H:28]([NH:38][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:21]([I:23])=[CH:22][C:14]=1[NH:13][S:10]([C:6]1[C:3]2=[N:4][S:5][N:1]=[C:2]2[CH:9]=[CH:8][CH:7]=1)(=[O:12])=[O:11])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([I:37])[CH:31]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)c(I)c1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(Cl)c(I)c1)NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoic acid was coupled to (S)-2-amino-3-(4-chloro-3-iodo-phenyl)-propionic acid methyl ester hydrochloride as in EXAMPLE 1, Part C, to afford title compound. HPLC: RT=10.87 min. MS (ESI+): mass calcd. for C23H17ClI2N4O5S2, 782.80; m/z found, 783/785 [M+H]+. 1H NMR (400 MHz, CDCl3): 11.31 (s,1H), 8.37 (dd, J=7.0, 0.9, 1H), 8.23 (dd, J=8.8, 0.9, 1H), 8.09 (d, J=1.5, 1H), 7.73 (dd, J=8.8, 7.1, 1H), 7.55 (d, J=2.0, 1H), 7.35-7.33 (m, 2H), 7.00-6.94 (m, 2H), 6.46 (d, J=7.1, 1H), 4.97-4.91 (m, 1H), 3.82 (s, 3H), 3.21-3.10 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:22]([CH3:30])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:29])[CH:27]=[CH2:28])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([O:20]C)=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[Li+].[OH-]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:22]([CH3:30])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:29])[CH:27]=[CH2:28])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([OH:20])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(C)CCC[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=CC(C)CCC[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
To a solution of (2S,4R)-methyl 1-((2S,3R)-2-(tert-butoxycarbonylamino)-3,7-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (4.3 g, 10 mmol) in THF/water (30 mL, 1:1) was added methanol (10 mL) followed by LiOH (1.3 g, 0.030 moles) at room temperature. The reaction mass was stirred at room temperature overnight. Solvent was evaporated under reduced pressure and the residue was diluted with water (100 mL). The aqueous solution was acidified with aqueous 1.5 N HCl solutions to pH˜3 and extracted with ethyl acetate (100 mL×3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduce pressure to get the desired product (2S,4R)-((2S,3R)-2-(tert-butoxycarbonylamino)-3,7-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (3.2 g, 78% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ ppm 5.70-5.61 (m, 1H), 5.14-5.12 (d, J=8.8 Hz, 1H), 4.96-4.88 (m, 2H), 4.82-4.78 (t, J=8.4 Hz, 1H), 4.52 (bs, 1H), 4.27-4.23 (m, 1H), 3.57-3.53 (m, 3H), 2.48-2.42 (m, 1H), 2.33-2.28 (m, 1H), 1.88-1.82 (m, 2H), 1.45-1.42 (s, 9H), 1.29-1.21 (m, 3H), 0.98-0.93 (m, 7H) MS: MS m/z 411.2 (M++1).