Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10](=[O:12])[CH3:11].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>C(OC)(C)(C)C>[CH3:9][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)[C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: COc1ccc(CCl)cc1
Reactant: COc1cccc(O)c1C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: COc1ccc(COc2cccc(OC)c2C(C)=O)cc1
Temperature: 35 °C
Reaction time: 12 h
Yield: 68.7 %

Procedure:
1-(2-Hydroxy-6-methoxyphenyl)ethanone (1300 g, 7.82 mol) and dimethylformamide (10.4 L) are added to a 22 L flask and stirred to obtain a solution. Potassium carbonate (2700 g, 19.54 mol) is added in portions, then stirred for at least 30 min. Using an addition funnel, 4-methoxybenzyl chloride (14700 g, 9.39 mol) is added dropwise over 2.5 h to the mixture while maintaining the temperature <30° C. The reaction mixture is warmed to 35° C. and that temperature is held for 12 h. The reaction conversion is monitored by HPLC and deemed complete after 13 h at 35° C. The slurry is filtered and the resulting solids washed with dimethylformamide (1 L). Extractive work-up of the filtrate with ethyl acetate and water, followed by concentration, provided a waxy yellow solid. To the waxy yellow solid is added methyl t-butyl ether (2.6 L). The resulting slurry is agitated. The now free flowing slurry is filtered and washed with methyl t-butyl ether (1 L). The white solid is vacuum dried yielding 1539 grams (69%) of the title compound. mp 105-107° C.
Reaction SMILES: C[O:2][C:3](=[O:28])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[C:20]([F:21])=[CH:19][CH:18]=[C:17]([O:22][CH:23]([CH3:25])[CH3:24])[C:16]=2[F:26])=[CH:11][C:10]1=[O:27])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1>[F:26][C:16]1[C:17]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:28])=[O:2])[C:10](=[O:27])[CH:11]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2c(F)ccc(OC(C)C)c2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2c(F)ccc(OC(C)C)c2F)=CC1=O
Temperature: 20 °C
Yield: 86.1 %

Procedure:
To a solution containing (S)-2-[4-(2,6-difluoro-3-isopropoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (3.10 g, 0.008 mol) in tetrahydrofuran (35 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 35 mL, 0.018 mol). The mixture was stirred at 20° C. for 2H, and the solvents evaporated. The residue was dissolved in water and washed with diethyl ether, and the diethyl ether layer discarded. The aqueous phase was acidified with dilute hydrochloric acid (pH <2), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford (S)-2-[4-(2,6-difluoro-3-isopropoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (2.64 g, 88%) as a tan solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH:17]=[O:18])[CH:14]=[CH:13][C:12]=1[N+:19]([O-])=O)[CH3:2].O>C(O)C.Cl>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH:17]=[O:18])[CH:14]=[CH:13][C:12]=1[NH2:19])[CH3:2]
Reactant: CCOC(=O)CCCCCOc1cc(C=O)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCCCCOc1cc(C=O)ccc1N
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6-(5-formyl-2-nitro-phenoxy)-hexanoic acid ethyl ester (1.0 g, 3.23 mmol) in ethanol (20 ml) and concentrated HCl (5 ml) was added stannous chloride (2.17 g, 11.63 mmol). The mixture was stirred at 70° C. for 90 minutes while being monitored by thin layer chromatography. After cooling to room temperature, the mixture was poured into water (100 ml) and neutralized with a saturated solution of sodium bicarbonate resulting in the precipitation of tin salts and a dark brown oil. The salts were washed with ethyl acetate and the washings were combined with the original filtrate, the aqueous phase was separated and the remaining ethyl acetate phase was dried with magnesium sulfate, filtered and concentrated by rotary evaporation to a brown oil which was purified by column chromatography (45% CH2Cl2, 45% hexane, 10% Et3N). The product, 6-(2-amino-5-formyl-phenoxy)-hexanoic acid ethyl ester, was obtained as a red oil (0.33 g, 35%). An additional 0.32 g of red oil was obtained from the column but found to be a mixture of unidentified byproducts. 1H NMR (400 MHz, CDCl3) δ: 9.72 (s, 1H), 7.30 (m, 2H), 613 (d, 1H, J=8.4 Hz), 4.50 (s, 2H), 4.15 (q, 2H, J=7.2 Hz), 4.08 (t, 2H, J=6.8 Hz), 2.35 (t, 2H, J=8.8 Hz), 1.88 (m, 2H), 1.74 (m, 2H), 1.55 (m, 2H) 1.30 (t, 3H, J=6.8 Hz). 13C NMR (400 MHz, CDCl3) δ: 109.59, 173.60, 146.08, 143.31, 127.78, 127.55, 112.72, 109.11, 68.18, 60.35, 34.20, 28.83, 25.69, 24.61, 14.18. IR (neat): 3481, 3362, 2936, 2868, 2722, 2360, 2341, 2229, 2156, 1964, 1727, 1671, 1612, 1587, 1572, 1517, 1444, 1394, 1368, 1313, 1243, 1164, 1140, 1095, 1029, 864, 817, 789, 748.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][C@@H:20]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:21]([O:23][CH3:24])=[O:22]>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][C@@H:20]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccn1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccn1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2) and methyl (S)-2-amino-3-(2-pyridyl)propionate hydrochloride (Synthetech), the tide compound was prepared as a solid (mp=121-124° C.). The reaction was monitored by tlc (Rf=0.39 in 10% MeOH/DCM) and the product was purified by silica gel column chromatography.
Reaction SMILES: [CH3:1][C:2]1[C:3](C=C)=[C:4]([CH2:23]/[CH:24]=[C:25](\[CH3:32])/[CH2:26][CH2:27][C:28]([O:30]C)=[O:29])[C:5]([O:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[C:6]2[C:10]=1[CH2:9][O:8][C:7]2=[O:11].[OH-].[Li+].S([O-])(O)(=O)=[O:38].[Na+]>CO.O>[OH:38][C:3]1[C:2]([CH3:1])=[C:10]2[C:6]([C:7](=[O:11])[O:8][CH2:9]2)=[C:5]([O:12][S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)(=[O:14])=[O:15])[C:4]=1[CH2:23][CH:24]=[C:25]([CH3:32])[CH2:26][CH2:27][C:28]([OH:30])=[O:29]
Reactant: C=Cc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Reactant: O=S(=O)([O-])O
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=CCc1c(O)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2)CCC(=O)O

Procedure:
A solution of methyl (E) 6-(1,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6-vinylisobenzofuran-5-yl)-4-methyl-4-hexenoate (0.37 g) and lithium hydroxide (0.4 g) in methanol (6 ml) and water (6 ml) was heated at 62° C. for 15 hours. The reaction was acidified with aqueous sodium hydrogen sulfate and extracted with ethyl acetate. The extract was dried and evaporated and the residue chromatographed on silica gel, eluting with ethyl acetate/hexane/acetic acid to give (E) 6-(1,3-dihydro-4-hydroxy-7-methyl-3-oxo-6-vinylisobenzofuran-5-yl)-4-methyl-4-hexenoic acid, m.p. 148°-149° C. (tert-butylmethyl ether/hexane).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[N:13]=2)=[O:11])=[N:5][CH:6]=[N:7][CH:8]=1)#[N:2].S(=O)(=O)(O)[OH:30]>>[C:1]([C:3]1[C:4]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[N:13]=2)=[O:11])=[N:5][CH:6]=[N:7][CH:8]=1)(=[O:30])[NH2:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cncnc1NC(=O)c1nn(Cc2ccccc2F)c2ncccc12
Product: NC(=O)c1cncnc1NC(=O)c1nn(Cc2ccccc2F)c2ncccc12
Reaction time: 0.5 h

Procedure:
581 mg (1.56 mmol) of the compound from example 47A were introduced in portions at 0° C. into conc. sulfuric acid (2.0 ml) and the mixture was stirred for a further 30 min. Subsequently, the solution was added to ice and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was stirred with ethyl acetate, and the solids were filtered off and dried under high vacuum. This gave 246 mg (40% of theory) of the title compound in solid form.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7](/[C:15](/[CH3:22])=[CH:16]/[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1)=[C:8]2[C:12]([OH:14])=[O:13])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl.[C:30](=[NH:35])(OCC)[CH3:31]>O>[C:30]([N:18]1[CH2:19][CH2:20][CH2:21][C@H:17]1/[CH:16]=[C:15](/[C:7]1[CH2:6][C@H:5]2[N:9]([C:10](=[O:11])[C@@H:4]2[C@H:2]([OH:1])[CH3:3])[C:8]=1[C:12]([OH:14])=[O:13])\[CH3:22])(=[NH:35])[CH3:31]
Reactant: CCOC(C)=N
Reactant: C/C(=C\[C@@H]1CCCN1)C1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=N)N1CCC[C@H]1/C=C(\C)C1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1
Reaction time: 0.25 h
Yield: 48.3 %

Procedure:
A solution of (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(E)-2-{(2S)-pyrrolidin-2-yl}-1-methylethenyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.44 g) in water (30 ml) was adjusted to pH 8.5 with aqueous potassium carbonate at 0° C. and ethyl acetimidate hydrochloride (5.4 g) was added in portions while adjusting around pH 8.5 with addition of aqueous potassium carbonate. After stirring for 15 minutes at pH 8.5, the reaction mixture was washed with a mixture of ethyl acetate and tetrahydrofuran (9:1 V/V, 150 ml), and concentrated in vacuo. The residue was chromatographed on nonionic adsorption resin "Diaion HP-20" (Trademark, made by Mitsubishi Chemical Industries) (80 ml) eluting successively with water (200 ml) and 5% aqueous isopropyl alcohol (200 ml). The fractions containing the desired compound were collected and lyophilized to give (5R,6S)-3-[(E)-2-{(2 S)-1-acetimidoylpyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (241 mg).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]2[CH2:20][C@H:19]2[CH2:21][OH:22])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C@@H:18]2[CH2:20][C@H:19]2[CH:21]=[O:22])=[CH:16][CH:17]=1
Reactant: OC[C@@H]1C[C@H]1c1ccc(Br)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C[C@@H]1C[C@H]1c1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
DMSO (0.8 mL, 3 equivalents) was added dropwise to a solution of oxalyl chloride (0.48 mL) in anhydrous dichloromethane (50 mL) under N2 at −78° C. A solution of (1R,2R)-[2-(4-bromophenyl)cyclopropyl]methanol (the product of Example 3A, 823 mg) in dichloromethane (20 mL) was then added dropwise at −78° C. Stirring at this temperature was continued for 30 minutes, then triethylamine (2 mL, 4 equivalents) was added and the dry ice bath was removed. After stirring for 1 hour, the mixture was treated with saturated aqueous NH4Cl. The mixture was extracted with diethyl ether. The combined organic extracts were dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by elution through a pad of silica gel with hexane to provide the title compound. 1H NMR (300 MHz, CDCl3): δ 1.48 (m, 1H), 1.65 (dt, J=9 Hz, J=6 Hz, 1H), 2.15 (m, 1H), 2.57 (m, 1H), 6.98 (d, J=9 Hz, 2H), 7.45 (d, J=9 Hz, 2H), 9.46 (d, J=4.5 Hz, 1H). MS (DCl—NH3) m/z 226 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]([NH:6][C@@H:7]1[C@@H:14]2[C@@H:10]([CH2:11][NH:12][CH2:13]2)[CH2:9][CH2:8]1)=[O:5].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:29]([N:12]1[CH2:13][C@@H:14]2[C@@H:7]([NH:6][C:4](=[O:5])[CH:3]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:2]([CH3:21])[CH3:1])[CH2:8][CH2:9][C@@H:10]2[CH2:11]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CN(C(=O)c3ccccc3)C[C@@H]21)c1ccccc1
Reaction time: 0.08 h

Procedure:
3-Methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A (25 mg, 0.087 mmol), triethylamine (0.018 mL, 0.131 mmol), and benzoyl chloride (10.12 μL, 0.087 mmol) were combined in dichloromethane (5 mL). After 5 minutes, TLC shows no more starting material. The crude reaction mixture was concentrated and applied to a silica gel cartridge (Analogix®, Burlington, Wis., RS-4) eluting with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 7.49-7.42 (m, 2H), 7.41-7.35 (m, 3H), 7.33-7.27 (m, 3H), 5.43 (d, J=6.7, 1H), 3.97 (m, 1H), 3.74 (m, 2H), 3.56 (m, 2H), 3.39 (m, 1H), 2.74 (m, 2H), 2.48 (m, 1H), 2.38 (m, 2H), 2.07 (dd, J=4.6, 10.8, 1H), 1.94 (m, 1H), 1.52-1.31 (m, 2H), 1.01 (d, J=6.3, 3H), 0.68 (d, J=6.6, 3H); MS (ESI+) m/z 391 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:19][CH2:20][CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)=[CH:11][C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ClC1C(=O)C(C#N)=C(C#N)C(=[O:40])C=1Cl>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:29][CH:30]=2)=[CH:11][C:12]2[C:13](=[O:40])[CH2:14][CH2:15][CH2:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(CCCc2cc3c(cc2OCc2ccccc2)CCCC3)cc1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(CCCc2cc3c(cc2OCc2ccccc2)CCCC3=O)cc1
Reaction time: 2 h
Yield: 18.1 %

Procedure:
To a solution of 4-[3-(3-benzyloxy-5,6,7,8-tetrahydro-2-naphthyl) propyl]benzoic acid (1.6 g) in ethyl acetate (50 ml) was added water (1 ml) and 2,3-dichloro-5,6-dicyanobenzoquinone (1.9 g). The mixture was stirred for 2 hours, the solvent evaporated and the residue subjected to chromatography on silica gel, eluting with 0.1% formic acid in EtOAc. The residue was purified by trituration with diethyl ether to give the title compound (0.3 g) mpt. 155°-160° C.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:13]2[C:9]([CH3:21])([C:10]([CH:14]([CH3:20])[CH2:15][CH:16]([Cl:19])[CH2:17]O)=[CH:11][CH2:12]2)[CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O.[Br-:34].[Li+]>ClCCl.N1C=CC=CC=1>[C:1]([O:4][CH:5]1[CH:13]2[C:9]([CH3:21])([C:10]([CH:14]([CH3:20])[CH2:15][CH:16]([Cl:19])[CH2:17][Br:34])=[CH:11][CH2:12]2)[CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCCC2(C)C(C(C)CC(Cl)CO)=CCC12
Reactant: [Br-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li+]
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)OC1CCCC2(C)C(C(C)CC(Cl)CBr)=CCC12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 1.50 g (4.76 mmol) of [3aS-[3(βS*,δR*),3aα,7β,7aβ]]-7-(acetyloxy)-β-chloro-3a,4,5,6,7,7a-hexahydro-δ,3a-dimethyl-1H-indene-3-butanol in 20 mL of dichloromethane and 20 mL of pyridine was treated at 0° C. and under argon with 4.50 g (23.60 mmol) of p-toluenesulfonyl chloride and then stirred overnight at 0° C. Water (8 mL) was then added and, after stirring the resulting mixture for 1 hour at room temperature, the solvents were removed in vacuo and the residue diluted with water and extracted with ethyl acetate. The combined organic extracts were subsequently washed with 1N hydrochloric acid, water, 2N aqueous potassium bicarbonate solution and brine and dried. The residue obtained after evaporation of the ethyl acetate (weighing 2.10 g) was dissolved in 40 mL of N,N-dimethylformamide and heated under argon at 50° C. with 4.00 g (46.06 mmol) of anhydrous lithium bromide for 17 hours. After cooling, the reaction mixture was diluted with ice water and extracted with ethyl acetate. The combined organic extracts were washed several times with water, dried and evaporated to dryness to give 1.62 g (90% overall yield) of the title compound. 1H NMR (60 MHz, CDCl3) δ0.88 (s, 3H), 1.07 (d, J=6.4 Hz, 3H), 2.03 (s, 3H), 3.60 (br AB q, J=10.2 Hz, Δγ=14.0 Hz, 2H), 5.00 br m, 1H), 5.33 (br s, 1H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13].C(N(CC)CC)C.Cl>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:13]=[CH:12]/[C:11]([OH:15])=[O:14])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: C=CC(=O)O
Reactant: COc1cc(I)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(/C=C/C(=O)O)ccc1Br
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-bromo-4-iodo-2-methoxybenzene (L. A. Hasvold et al, US 2004/0254159, EXAMPLE 57B) (33.45 g, 107 mmol) in MeCN (100 mL) was added acrylic acid (9.61 g, 133 mmol), triethylamine (37.2 mL, 267 mmol) and palladium acetate (719 mg, 3.2 mmol). The reaction mixture was heated to 90° C. for 40 min, cooled to RT and poured into 2.4 L 1M HCl. After stirring for 30 min, the solid was filtered, heated to reflux in EtOH (230 mL), allowed to cool to RT and stirred overnight. The solid was filtered and washed with 1:1 EtOH hexane (50 mL) to give desired product. LRMS ESI+ (M+H)+ 257.0.
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=[O:2].[C:5]([OH:9])(=[O:8])[CH:6]=[CH2:7].C(O)(=O)/C=C/CC(O)=O.[C:19]([OH:26])(=[O:25])/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23]>CO>[CH:1]([CH:3]=[CH2:4])=[O:2].[C:5]([OH:9])(=[O:8])[CH:6]=[CH2:7].[C:19]([OH:26])(=[O:25])/[CH:20]=[CH:21]\[C:22]([OH:24])=[O:23]
Reactant: O=C(O)/C=C/C(=O)O
Agent: C=CC(=O)O
Agent: C=CC=O
Agent: O=C(O)/C=C/CC(=O)O
Solvent: CO
Product: O=C(O)/C=C\C(=O)O

Procedure:
Invented drug (acrolein:acrylic acid:trans glutaconic acid (mol)=80:15:5): 29.20 g freshly distilled acrolein, 200.22 g freshly distilled acrylic acid and 20.16 g fumaric acid were added into a three-port flask with 800 ml absolute methanol, purged with nitrogen, 10.55 g benzoyl peroxide was added, and the solution was stirred and heated to reflux under nitrogen for 75 h. The reaction solution became a yellowish viscous liquid, which was dried under vacuum at 50-100° C. for 24 hours to form to Poly (acrolein, acrylic acid, maleic acid) with an average molecular weight no less than 1000.
Reaction SMILES: [F:1][C:2](=[CH:6][CH2:7][C:8]([F:21])=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:3]([O-])=[O:4].CC(C[AlH]CC(C)C)C>CCOCC.CCCCCC>[F:1][C:2](=[CH:6][CH2:7][C:8]([F:21])=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][OH:4]
Reactant: CCCCCC=CCCCCC=C(F)CC=C(F)C(=O)[O-]
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCCC=CCCCCC=C(F)CC=C(F)CO
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
The ester prepared in 1F (0.39 g, 1.18 mmoles) in anhydrous ether 5 ml was added at -78° C. to a mixture of DIBAL, 1M solution in hexane, (2.5 mL) and ether (20 ml). The mixture was stirred 30 min. at -78° C., the overnight at room temperature. The excess of DIBAL was destroyed with methanol (2 ml) and the aluminum salts were precipitated with an aqueous saturated solution of ammonium chloride. The mixture was filtrated and the precipitate washed with ethyl acetate. The solvents were evaporated under reduced pressure. Flash chromatography over silica gel and elution with a 8:2 mixture of hexane and ethyl acetate afforded the expected alcohol as an oil (0.33 g, 92%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[Br:17][C:18]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[CH:25][C:19]=1[CH:20]=[CH:21][C:22](O)=O>>[Br:17][C:18]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[CH:25][C:19]=1/[CH:20]=[CH:21]/[C:22]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: COc1cc(Br)c(C=CC(=O)O)cc1OC
Product: CCCn1c(=O)c2[nH]c(/C=C/c3cc(OC)c(OC)cc3Br)nc2n(CCC)c1=O
Yield: 56.3 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 2.0 g (8.85 mmol) of 5,6-diamino-1,3-dipropyluracil and 2.80 g (9.75 mmol) of 2-bromo-4,5-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 2.38 g (yield 56%) of Compound 57 as pale yellow needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[NH2:18])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>CN(C)C=O>[C:26]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:19])=[C:12]([NH2:18])[CH:13]=1)(=[O:28])[CH3:27]
Reactant: COc1ccc(NC(=O)c2ccc(N)cc2N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2ccc(NC(C)=O)cc2N)cc1
Reaction time: 8 h
Yield: 25.3 %

Procedure:
To a stirred solution of N-(4-methoxyphenyl)-2,4-diaminobenzamide (19 g, 73.8 mmol) in N,N-dimethylformamide (250 mL) was added pyridine (6.6 mL, 81 mmol), followed by acetic anhydride (6.6 mL, 70 mmol). After stirring overnight, the solvents were removed in vacuo and the residue was chromatographed over a silica gel (10% tetrahydrofuran/90% chloroform). The appropriate fractions were combined and concentrated in vacuo to give 5.3 g (24%) of the title compound as an off-white solid.
Reaction SMILES: O([BH-](OC(C)=O)OC(C)=O)C(C)=O.[Na+].[Br:15][C:16]1[CH:17]=[C:18]([NH2:22])[CH:19]=[N:20][CH:21]=1.[CH:23]1([O:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[CH:32]=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.CC(O)=O>ClCCCl>[Br:15][C:16]1[CH:17]=[C:18]([NH:22][CH2:32][C:31]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:29]([O:28][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:30]=2)[CH:19]=[N:20][CH:21]=1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Nc1cncc(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(CNc2cncc(Br)c2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Sodium triacetoxyl-borohydride (245 mg, 1.16 mmol) was added to the solution of 5-bromo-pyridine-3-amine (100 mg, 0.57 mmol) and 3-cyclopentyloxy-4-methoxy-benzaldehyde (127 mg, 0.57 mmol) in 10 ml of 1,2-dichloroethtane (DCE), of HOAc (66 μL, 2 eq. 1.16 mmol) was added, the mixture was stirred overnight at room temperature, followed by addition of 15 ml of DCE. The organic phase was washed with water, and dried over sodium sulfate. The solvent was removed by under reduced pressure to give 200 mg of crude 5-bromo-N-(3-(cyclopentyloxy)-4-methoxybenzyl)pyridin-3-amine, which was used for the next step without further purification.