Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[C:11]([O:14][CH:15](OC(=O)C)[C:16]([CH3:18])=[CH2:17])(=[O:13])[CH3:12]>[Cl-].[Zn+2].[Cl-]>[C:11]([O:14][CH:15]=[C:16]([CH3:18])[CH2:17][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:9][CH3:10])[CH:5]=1)(=[O:13])[CH3:12]
Reactant: C=C(C)C(OC(C)=O)OC(C)=O
Reactant: COc1ccccc1OC
Agent: [Cl-]
Agent: [Zn+2]
Product: COc1ccc(CC(C)=COC(C)=O)cc1OC
Temperature: 25.5 °C
Reaction time: 1.5 h
Yield: 95.1 %

Procedure:
In an argon gas atmosphere, a four necked flask having a capacity of 100 ml was charged with 69.2 g (500 m moles) of 1,2-dimethoxybenzene and 9.61 g (50 m moles) of 3,3-diacetoxy-2-methylpropene having a purity degree of 89.6% by mass. Then, the resultant mixture was mixed with 1.36 g (10 m moles) of zinc chloride at an internal temperature of 25 to 26° C. The mixture was stirred at an internal temperature of 25 to 26° C. for 1.5 hours to cause the mixed compounds to react with each other. After the reaction was completed, the resultant reaction liquid was washed three times with 50 ml of saturated aqueous sodium chloride solution. The resultant reaction liquid was subjected to a layer separation treatment, the resultant organic layer was collected and subjected to a distillation under reduced pressure (8 to 10 mmHg, 80 to 84° C.), the resultant residue was refined by a chromatography on silica gel using an elusion solvent:hexane/ethyl acetate mixture in a mixing ratio by volume of 10/1. The target 1-acetoxy-2-methyl-3-(3,4-dimethoxyphenyl)propene was obtained in a yield of 95.1% in an amount of 11.9 g in the form of a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22]CC4C=CC=CC=4)=[O:21])[CH:18]=3)[NH:13][CH:12]=2)=[C:6]([O:30][CH3:31])[CH:5]=1>CN(C)C=O.C(O)=O.[Pd]>[CH3:31][O:30][C:6]1[CH:5]=[C:4]([C:3]([O:2][CH3:1])=[O:32])[CH:9]=[CH:8][C:7]=1[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:22])=[O:21])[CH:18]=2)[NH:13][CH:12]=1
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(C(=O)OCc4ccccc4)cc23)c(OC)c1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: O=CO
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc(C(=O)O)cc23)c(OC)c1
Reaction time: 1.5 h
Yield: 72 %

Procedure:
To a solution of 4-[5-benzoxycarbonyl-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid methylester (3.46 grams, 8.06 mmol) in dimethylformamide (40 mL) and formic acid (2 mL) was added 10% palladium on carbon (1.5 grams). The resulting mixture was hydrogenated at 30 psi for 1.5 hours. The mixture was filtered through celite and the filtrate diluted with ethyl acetate. This solution was washed several times with 1 M hydrochloric acid (aq). The organics were then dried over magnesium sulfate and concentrated. Recrystallization from methylene chloride gave 3-(2-methoxy-4-methoxycarbonyl-benzyl)-1H-indole-5-carboxylic acid (1.97 grams, 73% yield).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:12][S:13](O)(=[O:15])=[O:14].C(Cl)(=O)C(Cl)=O.CN(C=O)C>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:13]([Cl:12])(=[O:15])=[O:14])=[CH:8][CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: ClCCCOc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(OCCCCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 52.75 g (0.265 mol) of (3-chloro-propoxy)-benzene in 100 ml of CH2Cl2, a solution of 19.4 ml (0.292 mol) of chlorosulfonic acid in 100 ml of CH2Cl2 is added dropwise at 0–5° C. under N2 atmosphere. The mixture is allowed to warm to ambient temperature and stirred for 2 hours. To the mixture, 29.6 ml (0.345 mol) of oxalyl chloride and 4 ml (0.052 mol) of DMF are added dropwise at r.t. and the mixture is stirred for 18 h at r.t. The reaction mixture is poured into ice-water, extracted with CH2Cl2. The combined extracts are dried over MgSO4 and concentrated under reduced pressure to give 58.5 g of 4-(3-chloropropoxy) benzenesulfonyl chloride; NMR(CDCl3): 2.26–2.36 (m, 2H), 3.76 (t, 2H, J=6.04 Hz), 4.24 (t, 2H, J=6.04 Hz), 7.06 (d, 2H, J=9.08 Hz), 7.98 (d, 2H, J=9.08 Hz).
Reaction SMILES: [OH-:1].[Na+].[OH:3][CH:4]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:9]#[N:10].OO.Cl>O.C(O)C>[OH:3][CH:4]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:9]([NH2:10])=[O:1]
Reactant: [OH-]
Reactant: CCCCCC(O)CCCN(C#N)CCCCCCC(=O)O
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCC(O)CCCN(CCCCCCC(=O)O)C(N)=O

Procedure:
To a solution of sodium hydroxide (0.4 g., excess) in water (50 ml.) and ethanol (50 ml.) is added 7-[N-(4-hydroxynonyl)cyanamido]heptanoic acid (1.5 g., 0.005 mole). The clear solution that is obtained is treated with 30% hydrogen peroxide (1.25 ml., excess). At the end of two hours the reaction mixture is poured into water (150 ml.), acidified with hydrochloric acid (dil.) and extracted with methylene chloride (3 × 75 ml.). The organic layer is washed with brine then dried over sodium sulfate. Evaporation of the solvent affords an oil which becomes solid on standing. The solid is crystallized from butyl chloride to give 7-[1-(4-hydroxynonyl)ureido]heptanoic acid. The yield is 1.4 g. (85%) of natural melting at 75°-76° C.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[Al](C)C.[C:17]([C:19]1[CH:20]=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1)#[N:18]>C1(C)C=CC=CC=1>[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:17](=[NH:18])[C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[N:21][CH:20]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: Cc1cncc(C#N)c1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1cncc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a suspension of 4-(methylsulfonyl)aniline hydrochloride (10.5 g, 0.051 mol) in toluene (500 mL) was added trimethylaluminum (2M solution in toluene, 75.0 mL, 0.150 mol) over 15 minutes at 0° C. The reaction mixture was warmed up to room temperature and stirred for 2 hours. A solution of 3-cyano-5-methylpyridine from step 3 in 90 mL of toluene was added over 10 minutes and the mixture was stirred at 85–90° C. for 16 hours. The reaction mixture was cooled to room temperature and filtered through a slurry of silica gel. After filtration, the residue was washed with methanol (800 mL). The combined filtrate was concentrated under reduced pressure and the residue was treated with a mixture of ether and hexane (2/1, 1000 mL). The brownish solid was filtered and washed with more ether and hexane to give 11.8 g of N-[4-(methylsulfonyl)phenyl]-5-methylnicotinamidine (80%). To a mixture of the above crude amidine (11.3 g, 0.039 mol) and sodium bicarbonate (9.83 g, 0.12 mol) in isopropanol (400 mL) was added 3-bromo-1,1,1-trifluoroacetone (11.2 g, 0.059 mol) quickly at room temperature. After heating the reaction mixture at 75–80° C. for 16 hours, the solvent was removed and the residue was partitioned between water and methylene chloride. The organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (ethyl acetate/acetone, 98:2) to give pure 3-methyl-5-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine as a yellow solid (3.85 g, 25%): mp (DSC) 237–239° C.; Anal. Calc'd. for C17H16F3N3O3S: C, 51.12, H, 4.04, N, 10.52,. S, 8.03. Found: C, 51.02, H, 3.94, N, 10.19, S, 8.11.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[CH2:16][CH2:15][N:14](CC3C=CC=CC=3)[CH2:13][CH2:12]2)[N:4]=1.[H][H]>C(O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[N:4]=1
Reactant: [H][H]
Reactant: COc1cc(OC)nc(N2CCN(Cc3ccccc3)CC2)n1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(OC)nc(N2CCNCC2)n1
Temperature: 25 °C
Yield: 49.2 %

Procedure:
In 110 ml of ethanol was dissolved 3.9 g (0.0125 mole) of 4-(4,6-dimethoxy-2-pyrimidinyl)-1-benzylpiperazine obtained as described above, and 2.5 g of 5% palladium carbon was added thereto. While refluxing the mixture under heating, hydrogen gas was passed for 6 hours. The reaction mixture was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was applied to silica gel column chromatography (the eluent used was a mixture of chloroform:methanol=9:1) to obtain 1.38 g of 1-(4,6-dimethoxy-2-pyrimidinyl)piperazine as pale red crystals.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[OH:7][N:8]=[C:9]([C:15]1[N:16]=[C:17]([CH3:20])[S:18][CH:19]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:1][O:7][N:8]=[C:9]([C:15]1[N:16]=[C:17]([CH3:20])[S:18][CH:19]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(=NO)c1csc(C)n1
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)C(=NOC)c1csc(C)n1
Yield: 93.9 %

Procedure:
Pulverized potassium carbonate (0.33 g.) was suspended in a solution of ethyl 2-hydroxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (syn isomer) (0.5 g.) in acetone (20 ml.). A solution of dimethyl sulfate (0.3 g.) in acetone (5 ml.) was dropwise added thereto with stirring at 40° to 45° C. After stirring for 2 hours at the same temperature, an insoluble material was filtered off. The filtrate was concentrated and water was added to the residue. The resulting mixture was extracted with ethyl acetate. The extract was in turn washed with water, a sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give pale yellow oil of ethyl 2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (syn isomer) (0.5 g.).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1.[NH2:16][C:17]1[C:22]2[O:23][CH2:24][O:25][C:21]=2[C:20]([C:26]#[C:27][CH2:28][O:29][CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[CH:19][C:18]=1[Cl:36].Cl[C:38]1[C:47]2[C:42](=[CH:43][C:44]([O:50][CH3:51])=[C:45]([O:48][CH3:49])[CH:46]=2)[N:41]=[CH:40][N:39]=1>CN(C=O)C.[Cl-].[NH4+]>[Cl:36][C:18]1[CH:19]=[C:20]([C:26]#[C:27][CH2:28][O:29][CH2:30][C:31]([N:33]([CH3:34])[CH3:35])=[O:32])[C:21]2[O:25][CH2:24][O:23][C:22]=2[C:17]=1[NH:16][C:38]1[C:47]2[C:42](=[CH:43][C:44]([O:50][CH3:51])=[C:45]([O:48][CH3:49])[CH:46]=2)[N:41]=[CH:40][N:39]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: CN(C)C(=O)COCC#Cc1cc(Cl)c(N)c2c1OCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2ncnc(Nc3c(Cl)cc(C#CCOCC(=O)N(C)C)c4c3OCO4)c2cc1OC
Temperature: 0 °C
Yield: 34.8 %

Procedure:
A solution of sodium bis(trimethylsilyl)amide (1.3 ml) in tetrahydrofuran (1.0M, 1.3 mmol) was added over 5 minutes to a stirred mixture of 2-{[3-(7-amino-6-chloro-1,3-benzodioxol-4-yl)prop-2-yn-1-yl]oxy}-N,N-dimethylacetamide (0.200 g) and 4-chloro-6,7-dimethoxyquinazoline (0.132 g) in DMF (5.7 ml) cooled to 0° C. under a nitrogen atmosphere; the resultant mixture was stirred for 1.5 hr at ambient temperature. The reaction mixture was diluted with saturated aqueous ammonium chloride (60 ml) and extracted with ethyl acetate (3×30 ml). The organic extracts were washed with brine (20 ml), dried over sodium sulphate and then evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methanol and dichloromethane as eluent. There was thus obtained the title compound as a solid (0.102 g). NMR Spectrum: (DMSOd6) 2.82 (s, 3H), 2.92 (s, 3H), 3.92 (s, 6H), 4.26 (s, 2H), 4.51 (s, 2H), 6.15 (s, 2H), 7.16 (s, 1H), 7.18 (s, 1H), 7.82 (s, 1H), 8.32 (s, 1H), 9.52 (s, 1H); Mass Spectrum: M+H+ 499 and 501.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Br:17])=[O:5])C.[OH-].[Na+].OS([O-])(=O)=O.[K+]>CO.O>[Br:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[N:9]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH:8]=[N:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1ncn(CC(C)C)c1-c1ccccc1Br
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)Cn1cnc(C(=O)O)c1-c1ccccc1Br
Reaction time: 15 h
Yield: 87.2 %

Procedure:
A 0.2 M solution of 5-(2-bromophenyl)-1-isobutyl-1H-imidazole-4-carboxylic acid ethyl ester (1.77 g; 5.04 mM) in 1/1 v/v methanol/water is added with NaOH (605 mg; 15.12 mM). The mixture is kept at room temperature for about 15 hours, then acidified with KHSO4, extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated under reduced pressure, thereby obtaining 1.42 g of 5-(2-bromophenyl)-1-isobutyl-1H-imidazole-4-carboxylic acid, as a white-pale yellow solid which is used in the subsequent reaction without further purification. (Yield: 87%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8](=[NH:34])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C@H:19]2[N:23]3[C:24](=[O:33])[C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:26][N:27]=[C:22]3[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC(C1C=CC(CNC([C@H]2N3C(=O)C(N(CC)CC)=CN=C3CC2)=O)=CC=1)=N)(C)(C)C.[F:71][C:72]1[CH:77]=[CH:76]C(S(Cl)(=O)=O)=[CH:74][CH:73]=1>>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C@H:19]2[N:23]3[C:24](=[O:33])[C:25]([NH:28][S:29]([C:32]4[CH:76]=[CH:77][C:72]([F:71])=[CH:73][CH:74]=4)(=[O:31])=[O:30])=[CH:26][N:27]=[C:22]3[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)=[NH:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NS(C)(=O)=O)c(=O)n32)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: CCN(CC)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OC(C)(C)C)cc1)CC2
Product: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NS(=O)(=O)c4ccc(F)cc4)c(=O)n32)cc1
Yield: 41 %

Procedure:
Following a procedure similar to that for the preparation of 16a, intermediate 3a (50 mg, 0.117 mmol) and 4-fluorobenzene sulfonyl chloride (29.6 mg, 0.158 mmol) yielded 28.2 mg (41.0%) of 32a. MS (ESI) 585.0 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.CCN(CC)CC>CC#N>[F:18][C:14]1[CH:13]=[C:12]([CH2:11][NH:10][C:8]([C:7]2[C:2]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:3][C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:5][C:6]=2[CH3:19])=[O:9])[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc(N2CCOCC2)nc(Cl)c1C(=O)NCc1cccc(F)c1
Reactant: C1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCOCC2)nc(N2CCCC2)c1C(=O)NCc1cccc(F)c1
Temperature: 140 °C
Yield: 58.6 %

Procedure:
To a solution of 254 mg (0.7 mmol) 2-chloro-N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (synthesis is described in section a) of example 9) in MeCN (0.5 ml) were added 115 μl (1.4 mmol) pyrrolidine and 290 μl (2.1 mmol) NEt3. The RM was heated in the microwave to 120° C. for 30 min and subsequently to 140° C. for 45 min. Then the mixture was filtered through celite and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 2:1), followed by crystallization (hexane/EtOAc) provided 164 mg (0.41 mmol, 59%) N-[(3-Fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-2-pyrrolidin-1-yl-pyridine-3-carboxylic acid amide (example 24). [M+H]+ 399.2.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7](/[CH:9]=[CH:10]/[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:18](OC)(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[SH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:26]=[C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:1]([C:3]2[N:8]=[C:7](/[CH:9]=[CH:10]/[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=2)=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)/C=C/c1cccc(C#N)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 21.1 %

Procedure:
tert-Butyl (E)-3-(6-cyano-2-pyridyl)-2-propenoate (2.32 g, 10.1 mmol) and methyl thiosalicylate (1.86 g, 11.0 mmol) were dissolved in toluene (12 ml), and triethylamine (1.63 g, 25.7 mmol) was added thereto. The reaction mixture was refluxed for 38 hrs, concentrated, subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (5:2, v/v) to give the titled compound (0.78 g, 27%) as white crystals.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CCOC(C)=O.[Pd]>[CH:1]1([C:8]2[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(-c2cccc(OC)c2)c(C2=CCCCCC2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cccc(OC)c2)c(C2CCCCCC2)c1
Reaction time: 4 h
Yield: 99.6 %

Procedure:
To a stirred solution of 78.8A (0.291 g, 0.86 mmol) in EtOAc (2.00 mL) at 23° C. was added palladium on carbon (0.092 g, 0.86 mmol). The reaction was placed under an atmosphere of hydrogen and stirred for four hours. The reaction was then concentrated in vacuo to yield 78.8B (0.290 g, 99% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:33][C:13]3[N:14]([CH2:24][C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:15]=[C:16]([S:19]([CH:21]([CH3:23])[CH3:22])=[O:20])[C:17](=[O:18])[C:12]=3[C:11]=2[CH3:34])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:35]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:33][C:13]3[N:14]([CH2:24][C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:15]=[C:16]([S:19]([CH:21]([CH3:23])[CH3:22])=[O:20])[C:17](=[O:18])[C:12]=3[C:11]=2[CH2:34][Br:35])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1c(-c2ccc([N+](=O)[O-])cc2)sc2c1c(=O)c(S(=O)C(C)C)cn2Cc1c(F)cccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)S(=O)c1cn(Cc2c(F)cccc2F)c2sc(-c3ccc([N+](=O)[O-])cc3)c(CBr)c2c1=O
Yield: 93.7 %

Procedure:
The compound (980 mg, 2 mmol) obtained in Example 17, N-bromosuccinimide (NBS) (0.36 g, 2.04 mmol) and α,α-azobisisobutyronitrile (AIBN) (60 mg, 0.37 mmol) were suspended in carbon tetrachloride (250 ml).The mixture was refluxed under heating for 3 hours. After cooling, the reaction mixture was partitioned between chloroform (300 ml) and an aqueous sodium bicarbonate solution. The aqueous layer was extracted with chloroform (100 ml), the extracts were combined, washed with an aqueous sodium chloride solution, dried with Na2SO4, and the solvent was distilled off. Thus obtained residue was recrystallized from dichloromethane-n-hexane to give yellow crystals (1.09 g, 96%).
Reaction SMILES: N1C=CN=C1.[C:6]([Si](C)(C)Cl)([CH3:9])([CH3:8])[CH3:7].[C:14]([NH:21][C@@H:22]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@@H:23]([OH:36])[CH2:24][C@@H:25]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:26](O)=[O:27])([O:16]C(C)(C)C)=[O:15]>CN(C=O)C>[C:14]([NH:21][C@H:22]([C@H:23]1[O:36][C:26](=[O:27])[C@H:25]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:24]1)[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([O:16][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccccc1)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccccc2)C(=O)O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
8 g of imidazole and 10 g of tert-butyldimethylchlorosilane are added, with stirring, to a solution of 6.35 g of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-phenylmethylhexanoic acid in 90 ml of DMF. After being stirred for 18 hours at room temperature, the clear yellow solution is poured onto ice-water and extracted three times using 250 ml of ethyl acetate each time. The combined extracts are washed in succession three times with 10% citric acid, once with water, three times with aqueous saturated sodium hydrogen carbonate solution, once with water and finally with brine. After drying over sodium sulfate, the solvent is evaporated and the resulting tert-butyldimethylsilyl ether (13.5 g) is dissolved in 53 ml of THF and treated with 53 ml of acetic acid and 20 ml of water. After being stirred for 3 hours at room temperature, the mixture is poured onto water and extracted three times with ether. The combined ether extracts are washed twice with water and once with brine and dried over sodium sulfate. After concentration, the crude product is purified by column chromatography (SiO2, hexane/ethyl acetate: 3.5/1.5) and the title compound obtained. TLC Rf (D)=0.37; FAB-MS (M+H)+ =528.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.C([O-])(=O)C.[NH4+].[N+:17]([CH3:20])([O-:19])=[O:18]>C(O)(=O)C>[N+:17]([CH:20]=[CH:7][C:6]1[CH:1]=[CH:2][C:3]2[O:11][CH2:10][O:9][C:4]=2[CH:5]=1)([O-:19])=[O:18]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1ccc2c(c1)OCO2
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
To piperonal (15.55 kg, 103.5 mol) under mechanical stirring and under nitrogen was added ammonium acetate (13.4 kg, 173.8 mol), acetic acid (45.2 kg), and nitromethane (18.4 kg, 301.4 mol) sequentially. The mixture was warmed to 70° C. After about 30 minutes, the yellow product began to crystallize. The reaction temperature was raised to 80° C. and stirred for about 10 hours until minimal piperonal remains. The somewhat thick reaction mixture was cooled to 10° C. and filtered. The precipitate was washed with acetic acid (2×8 kg) and then water (2×90 kg). The product was dried under a nitrogen purge and then in a vacuum oven at 50° C. for 2 days to afford 15.94 kg (80%) of the title compound as a bright yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:17][CH2:18][CH2:19][OH:20])[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:4].C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([CH2:17][CH2:18][CH:19]=[O:20])[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[O:4]
Reactant: COC(=O)C1(CCCO)CCCN1C(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClC(Cl)Cl
Product: COC(=O)C1(CCC=O)CCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 32.9 %

Procedure:
To a suspension of 2-(3-hydroxypropyl)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (17.4 g) and sodium bicarbonate (12.7 g) in chloroform (175 ml) cooled to 0° C. was added Dess-Martin periodinane (28.3 g). The reaction mixture was warmed to room temperature and stirred for 1.5 hours. To the reaction mixture was added additional Dess-Martin periodinane (1.0 g), and the mixture was stirred for 50 minutes. To the reaction mixture cooled to 0° C. was added additional Dess-Martin periodinane (15 g), and the mixture was stirred for 2 hours. To the mixture were added 20% sodium thiosulfate (250 ml) and saturated aqueous sodium bicarbonate solution (250 ml), and the mixture was stirred at room temperature for 20 minutes. The mixture was extracted with chloroform (200 ml×2) twice, and the combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1 to 3/2) to give the titled compound (5.68 g).