Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[C:5]([C:14]([O:16]CC)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[OH-].[Na+]>C1COCC1.CO.O>[C:1]([C:3]1[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)#[N:2]
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1-c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.1 %

Procedure:
To a solution of ethyl 4-cyano-3-(2,4-dichlorophenyl)-5-morpholin-4-ylthiophene-2-carboxylate (0.060 g, 0.15 mmol) in THF/MeOH/water (2:1:2) (5 mL) was added sodium hydroxide (0.061 g, 1.5 mmol). The reaction mixture was allowed to stir at rt for 20 h and was concentrated. The residue was acidified with 1N HCl and was extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated to give 4-cyano-3-(2,4-dichlorophenyl)-5-morpholin-4-ylthiophene-2-carboxylic acid (62) (0.034 g, 62%). LCMS: (FA) ES+ 382.9. 1H NMR (400 MHz, d6-DMSO) δ: 7.75 (d, 1H), 7.50 (dd, 1H), 7.39 (d, 1H), 3.74-79 (m, 4H) and 3.55-61 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[O:9])[S:5][C:6]=1Br.C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([SH:24])[CH:21]=[CH:22][CH:23]=1.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[O:9])[S:5][C:6]=1[S:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH3:16])[CH:19]=1
Reactant: O=Cc1cc(Br)c(Br)s1
Reactant: COc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(Sc2sc(C=O)cc2Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4,5-dibromothiophene-2-carbaldehyde (1.0 g) in N,N-dimethylformamide (10 mL) were added potassium carbonate (665 mg) and 3-methoxybenzenethiol (571 mg) at room temperature. After stirring at room temperature overnight, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→7:1) to give the title compound as a pale-yellow crude oil (yield 1.30 g).
Reaction SMILES: [CH3:1][I:2].[CH2:3]([S:11][C:12]1[C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[N:14][S:15][N:16]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>>[I-:2].[CH2:3]([S:11][C:12]1[C:13]([C:17]2[CH:18]=[N+:19]([CH3:1])[CH:20]=[CH:21][CH:22]=2)=[N:14][S:15][N:16]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CI
Reactant: CCCCCCCCSc1nsnc1-c1cccnc1
Product: CCCCCCCCSc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methyl iodide (0.5 ml, 7.5 mmol) was added to a solution of 3-(4-octylthio-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) and the reaction mixture was stirred at room temperature for 48 h and evaporated.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([S:16]([OH:19])(=[O:18])=O)[C:10]=2[CH:9]=[CH:8][N:7]=1.C[N:21]([CH3:24])C=O.[C:25](=O)([O-])[OH:26].[Na+]>O>[OH:26][CH2:25][CH2:24][NH:21][S:16]([C:11]1[C:10]2[CH:9]=[CH:8][N:7]=[C:6]([Cl:5])[C:15]=2[CH:14]=[CH:13][CH:12]=1)(=[O:18])=[O:19]
Reactant: O=S(=O)(O)c1cccc2c(Cl)nccc12
Reactant: O=C([O-])O
Reactant: CN(C)C=O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Product: O=S(=O)(NCCO)c1cccc2c(Cl)nccc12
Reaction time: 1 h
Yield: 96 %

Procedure:
To 50 ml of thionyl chloride were added 5.85 g of 1-chloro-5-isoquinolinesulfonic acid as obtained in Example 1 and 0.5 ml of N,N-dimethylformamide. Then, the resulting mixture was refluxed while heating for 2 hours, followed by removal of the thionyl chloride and N,N-dimethylformamide under reduced pressure to obtain a residue. Then, the residue was dissolved in 50 ml of water, and the pH of the aqueous solution was adjusted to 6.0 with an aqueous sodium hydrogencarbonate saturated solution, followed by extraction twice with 50 ml of dichloromethane. The dichloromethane layer was added to a 50 ml of dichloromethane solution containing 1.84 g of ethanolamine and 3.03 g of triethylamine for 5 minutes while cooling with ice. Then, the mixture was stirred for 1 hour at a temperature of 10° C. to 20° C. The thus obtained reaction mixture was washed thrice with water, dried with anhydrous sodium sulfate and then distilled under reduced pressure to obtain 5.04 g of N-(2 -hydroxy- ethyl)-1-chloro-5-isoquinolinesulfonamide in a 96% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH3:23][O:24][C:25]1[CH:48]=[CH:47][C:28]([CH2:29][O:30][C:31]([NH:33][C:34]2[N:42]=[CH:41][N:40]=[C:39]3[C:35]=2[N:36]=[CH:37][N:38]3[CH2:43][C:44](O)=[O:45])=[O:32])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:44](=[O:45])[CH2:43][N:38]1[CH:37]=[N:36][C:35]2[C:39]1=[N:40][CH:41]=[N:42][C:34]=2[NH:33][C:31]([O:30][CH2:29][C:28]1[CH:47]=[CH:48][C:25]([O:24][CH3:23])=[CH:26][CH:27]=1)=[O:32])[CH3:2]
Reactant: COc1ccc(COC(=O)Nc2ncnc3c2ncn3CC(=O)O)cc1
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cnc2c(NC(=O)OCc3ccc(OC)cc3)ncnc21
Yield: 102.5 %

Procedure:
To the mixture of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (172 mg, 0.5 mmol), [6-N-(4-methoxybenzyloxycarbonyl)-adenin-9-yl]-acetic acid (179 mg, 0.5 mmol), and HBTU (190 mg, 0.5 mmol) in DMF (2 ml) was added diisopropylethylamine (0.09 ml, 0.5 mmol) at ambient temperature. The resulting reaction mixture was stirred for 2 h at the same temperature and 1N HCl was added to the reaction mixture. The resulting precipitate product was filtered off, washed with water, and dried in vacuo to give the title compound as a white solid (0.35 g, 97%). 1H NMR (500 MHz; DMSO-d6) δ 8.97 (t, 0.6H), 8.76 (t, 0.4H), 8.64 (s, 0.4H), 8.60 (s, 0.6H), 8.53 (d, 1H), 8.28 (m, 1H), 8.17 (d, 1H), 7.66 (m, 2H), 7.40 (d, 2H), 6.95 (d, 2H), 5.41 (s, 1.2H), 5.20 (s, 0.8H), 5.18 (s, 2H), 4.46 (s, 0.8H), 4.18 (q, 0.8H), 4.08 (s, 1.2H), 4.03 (q, 1.2H), 3.75 (s, 3H), 3.70 (q, 1.2H), 3.48 (q, 1.2H), 3.42 (t, 0.8H), 3.22 (q, 0.8H), 1.24 (t, 1.2H), 1.13 (t, 1.8H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[F:6][C:7]1[CH:16]=[CH:15][C:10]([NH:11][CH:12]([CH3:14])[CH3:13])=[CH:9][CH:8]=1>>[F:6][C:7]1[CH:16]=[CH:15][C:10]([N:11]([CH:12]([CH3:14])[CH3:13])[C:3](=[O:4])[CH2:2][Cl:1])=[CH:9][CH:8]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)Nc1ccc(F)cc1
Product: CC(C)N(C(=O)CCl)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
357.5 parts (3.2 mol) of chloroacetyl chloride are added dropwise over the course of 2 hours at from 10° to 20° C. to 920 parts of 4-fluoro-N-isopropylaniline solution (~3 mol of 4-fluoro-N-isopropylaniline) from Example 1. Stirring is subsequently carried out at 20° C. for one hour and then the majority of the hydrogen chloride formed is removed as a gas by heating to about 90° C.
Reaction SMILES: [P:1]([CH:5]([C:10]([OH:12])=[O:11])[CH2:6][C:7]([OH:9])=[O:8])([OH:4])([OH:3])=[O:2].P([O-])(OCC)O[CH2:15]C>>[P:1]([C:5]([C:10]([OH:12])=[O:11])([CH2:6][C:7]([OH:9])=[O:8])[CH3:15])([OH:4])([OH:3])=[O:2]
Reactant: CCOP([O-])OCC
Reactant: O=C(O)CC(C(=O)O)P(=O)(O)O
Product: CC(CC(=O)O)(C(=O)O)P(=O)(O)O

Procedure:
1-Phosphono-1,2-ethane-dicarboxylic acid can be prepared by reaction of maleic ester (diethyl maleate) with diethyl phosphite in the presence of sodium alcoholate followed by acid saponification of the ester. 2-Phosphono-2,3-propane dicarboxylic acid can be obtained in the same manner with addition of the step of reacting the mixture with methyl chloride before the saponification step.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1.[C:12]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1.CCCCCC>ClCCl>[CH2:10]([O:9][C:7]([C:4]1[S:3][C:2]([NH:1][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([C:12]([CH3:14])([CH3:13])[CH3:15])=[CH:17][CH:18]=2)=[N:6][CH:5]=1)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1cnc(N)s1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CCOC(=O)c1cnc(NC(=O)c2ccc(C(C)(C)C)cc2)s1
Yield: 88.2 %

Procedure:
A solution of ethyl 2-aminothiazole-5-carboxylate (0.52 g, 3.0 mmol), 4-t-butylbenzoyl chloride (1.3 mL, 6.7 mmol) and pyridine (1.2 mL) in dichloromethane (10 mL) was stirred at 0° C. for 1.25 h. It was then diluted with dichloromethane and washed with aqueous HCl (1 N) twice, saturated aqueous sodium bicarbonate, and brine. After drying over sodium sulfate, filtration and concentration in vacuo gave a burgundy oil. Trituration with hexane afforded the desired amide as a light tan solid (0.88 g, 88% yield): LC/MS RT=3.85 min; mass spectrum (M+H)+=333.16. B. 4-(1,1-Dimethylethyl)-N-[(5-hydroxymethyl)thiazol-2-yl]benzamide
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6](O)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38]1(=[O:48])[NH:42][C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([N:42]2[C:38](=[O:48])[C:39]3[C:40](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:41]2=[O:43])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:3]1
Reactant: CC1(C)CC(c2ccncc2[N+](=O)[O-])=CC(O)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)CC(c2ccncc2[N+](=O)[O-])=CC(N2C(=O)c3ccccc3C2=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a homogeneous solution of 5,5-dimethyl-3-(3-nitropyridin-4-yl)cyclohex-2-enol (1.0 eq), triphenyl phosphine (1.5 eq), and phthalimide (1.5 eq) in THF (0.2 M) cooled to 0° C., ditertbutyl azodicarboxylate (1.5 eq) in THF was added to the solution. The mixture was stirred at 0° C. for 2 hours. The reaction was concentrated in vacco. The residue was purified by column (5% methanol in 1:1 ethyl acetate and hexanes) to give 2-(5,5-dimethyl-3-(3-nitropyridin-4-yl)cyclohex-2-enyl)isoindoline-1,3-dione (99%). LC/MS (m/z): MH+=378.2, Rt=1.10 min.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18](/[CH:21]=[CH:22]/[C:23]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:24])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[NH:15]1[CH2:20][CH2:19][CH:18](/[CH:21]=[CH:22]/[C:23]([C:25]2[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=2)=[O:24])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C/C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(/C=C/C1CCNCC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.5 %

Procedure:
3 ml of trifluoroacetic acid was added to 2.52 g of (E)-4-[3-(1-t-butoxycarbonylpiperidin-4-yl)propenoyl]nitrobenzene dissolved in 20 ml of methylene chloride, and the mixture was stirred at room temperature for 3 hours. Subsequently, 7 ml of trifluoroacetic acid was further added to the mixture, and the mixture was stirred for 3 hours. Then, the solvent was removed by distillation, and a saturated sodium hydrogen carbonate solution was added to the residue. After the mixture was extracted with ethyl acetate, the extract was dried over anhydrous sodium sulfate and condensed. The obtained solid was washed with methylene chloride to obtain 0.7 g of the title compound as pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[CH:17]=1.Cl>ClCCl>[Cl:15][C:16]1[CH:17]=[C:18]([O:24][CH3:25])[CH:19]=[C:20]([O:22][CH3:23])[C:21]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[F:1])=[O:5]
Reactant: COc1cc(Cl)cc(OC)c1
Reactant: O=C(Cl)c1ccccc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(Cl)c(C(=O)c2ccccc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of o-fluorobenzoyl chloride (47.6 g) in 100 ml dichloromethane is added AlCl3 (40.0 g) portionwise, in about thirty minutes. To this resultant dark solution is added dropwise a solution of 1-chloro-3,5-dimethoxybenzene (52.0 g) in 120 ml dichloromethane, in fifteen minutes. After stirring at ambient temperature for four hours, the mixture is poured into one liter iced-dilute HCl solution and then stirred for 30 minutes. The organic layer is collected, evaporated to an oil, which is dissolved into ether, washed with water, dilute NaOH solution, water, then dried (saturated NaCl, anhydrous MgSO4). After filtering, the solvent is evaporated to a solid, which is purified by silica gel, eluted with dichloromethane to yield 2-chloro-4,6-dimethoxy-2'-fluorobenzophenone, mp 88°-92° C.
Reaction SMILES: [C:1]([NH:24][C@@H:25]([CH3:30])[C:26]([O:28]C)=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].[OH-].[Na+]>C1COCC1.O>[C:1]([NH:24][C@@H:25]([CH3:30])[C:26]([OH:28])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)N[C@@H](C)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)N[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-methyl 2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)propanoate (2.0 g, 4.8 mmol) was taken up in THF (8 mL) along with 5M aqueous NaOH (5 mL) and stirred vigorously at room temperature for 3 h. The reaction mixture was diluted with water and concentrated under reduced pressure. Enough 6N HCl was then added to adjust the pH to 2. The resulting mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford (S)-2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)propanoic acid. This was taken up in CH3CN (15 mL) along with N-Boc-L-threonine methyl ester (1.11 g, 4.78 mmol), HATU (2.0 g, 5.3 mmol) and DIEA (1.2 mL). The resulting reaction mixture was stirred at room temperature for 6 h and diluted with EtOAc. The organic layer was washed with NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (CH2Cl2) afforded (2S,3R)-methyl 2-(tert-butoxycarbonyl)-3-(S)-2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)propanoyloxy)butanoate (1.0 g).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C:6]1[CH:7]=[C:8]([O:12][CH3:13])[CH:9]=[CH:10][CH:11]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.O.Cl>[Br:5][C:6]1[CH:7]=[C:8]([O:12][CH3:13])[CH:9]=[CH:10][C:11]=1[C:1](=[O:3])[CH3:2]
Reactant: COc1cccc(Br)c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(C)=O)c(Br)c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 83.4 %

Procedure:
Acetyl chloride (3.56 mL, 0.06 mol) is added dropwise to a stirred suspension of 3-bromoanisole (9.35 g, 0.05 mol) and AlCl3 (8.00 g, 0.06 mol) in dichloromethane (50 mL) at 0° C. under argon. The resulting mixture is stirred at 0° C. for 40 min and then at room temperature for 1 h, and diluted with H2O (100 mL) and 2 N HCl (35 mL), and extracted with ethyl acetate (2×100 mL and 50 mL). The extract is washed (brine) and dried. After solvent removal at reduced pressure, the residue is purified on silica gel (12.5% to 14.3% ethyl acetate/hexane) to give 9.55 g (83%) of 2 as a colorless liquid. IR 2964, 1688, 1596, 1252 cm−1; 1H NMR (CDCl3) δ 2.66 (s, 3H, CH3CO), 3.88 (s, 3H, CH3O), 6.91 (dd, J=8.4 Hz, 2.4 Hz, 1H, 5-PhH), 7.19 (d, J=2.4 Hz, 1H, 3-PhH), 7.63 ppm (d, J=8.4 Hz, 1H, 6-PhH).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[NH:29]N.Cl>>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[N:29]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Reactant: Cc1ccc(C)c(NN)c1
Agent: Cl
Product: Cc1ccc(C)c(-n2nccc2-c2nn(-c3ccccc3)ccc2=O)c1
Yield: 74 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and 2,5-dimethyl-phenylhydrazine×HCl according to the method described for Example 1 in 74% yield. MS: M=343.2 (M+H)+
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:20](=[O:22])[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])(=O)=O.C(O)(=O)C>O>[C:1]([O:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:20](=[O:22])[CH2:21][Cl:26])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)C(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)C(=O)CCl
Temperature: 40 °C
Reaction time: 5.5 h
Yield: 93.1 %

Procedure:
A mixture of ethyl 2-(2-benzoyloxyethoxyimino)-3-oxobutyrate (syn isomer) (28 g.), sulfuryl chloride (13.5 g.) and acetic acid (30 ml.) was stirred at 40° C. for 10 minutes and at room temperature for 5.5 hours. After adding water (200 ml.) to the resultant solution, the mixture was extracted with methylene chloride. The extract was washed with water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate, and then concentrated in vacuo to give ethyl 2-(2-benzoyloxyethoxyimino)-4-chloro-3-oxobutyrate (syn isomer) (29 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:20]1[C:21](O)=[CH:22][C:23]3[O:27][CH2:26][CH2:25][C:24]=3[CH:28]=1)([CH2:18][OH:19])[C:5](=[O:17])[N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].ClC1C=CC(Cl)=C2C=1C(C1C(O)=CC3OCOC=3C=1)(CO)C(=O)N2CCCCC>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:18][O:19][C:21]3[CH:22]=[C:23]4[C:24](=[CH:28][C:20]1=3)[CH2:25][CH2:26][O:27]4)[C:5](=[O:17])[N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)OCC3)c2c(Cl)cccc21
Agent: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2c(Cl)ccc(Cl)c21
Product: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2c(Cl)cccc21
Yield: 63 %

Procedure:
Following the procedure as described in EXAMPLE 1.22, and making non-critical variations using ethyl [4-chloro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate to replace 4,7-dichloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained in 63% yield as a colorless solid: MS (ES+) m/z 400.8 (M+1).
Reaction SMILES: [CH2:1]([O:4][C@H:5]([C@@H:25]([O:38][CH2:39][CH:40]=[CH2:41])[C@H:26]([O:34][CH2:35][CH:36]=[CH2:37])[C:27](=O)[CH2:28][O:29][CH2:30][CH:31]=[CH2:32])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=2)[CH:9]=1)=O)[CH:2]=[CH2:3].C([O-])=O.[NH4+].[BH3-]C#[N:48].[Na+]>CO>[CH2:35]([O:34][C@H:26]1[C@H:25]([O:38][CH2:39][CH:40]=[CH2:41])[C@@H:5]([O:4][CH2:1][CH:2]=[CH2:3])[C@H:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=3)[CH:9]=2)[NH:48][C@@H:27]1[CH2:28][O:29][CH2:30][CH:31]=[CH2:32])[CH:36]=[CH2:37]
Reactant: [BH3-]C#N
Reactant: C=CCOCC(=O)[C@@H](OCC=C)[C@H](OCC=C)[C@@H](OCC=C)C(=O)c1ccc(Cl)c(Cc2ccc(OCC)cc2)c1
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: C=CCOC[C@H]1N[C@@H](c2ccc(Cl)c(Cc3ccc(OCC)cc3)c2)[C@H](OCC=C)[C@@H](OCC=C)[C@@H]1OCC=C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.2 %

Procedure:
To a solution of compound from Step E (0.60 g, 1.03 mmol) in MeOH (12 ml) was added 4 Å MS followed by ammonium formate (0.13 g, 2.06 mmol). NaBH3CN (0.14 g, 2.3 mmol) was then added in one portion and the mixture stirred at room temperature for 1 hour 30 minutes. The reaction mixture was then filtered and concentrated. Purification by silica gel chromatography (10%-20% EtOAc/hexanes) afforded (2R,3R,4R,5S,6S)-3,4,5-tris-allyloxy-2-allyloxymethyl-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-piperidine (155 mg, 0.27 mmol, 27%). MS (ES+) [M+H]+=568.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][CH2:12][N:13]([CH3:22])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][CH2:8][S:7][C:6]=2[CH:23]=1.I.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](SC)=[NH:31].N>CCO.C(Cl)Cl.CO>[CH3:22][N:13]([CH2:12][CH2:11][N:10]1[CH2:9][CH2:8][S:7][C:6]2[CH:23]=[C:2]([NH:1][C:30]([C:26]3[S:25][CH:29]=[CH:28][CH:27]=3)=[NH:31])[CH:3]=[CH:4][C:5]1=2)[CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16]
Reactant: CSC(=N)c1cccs1
Reactant: CN(CCN1CCSc2cc(N)ccc21)CC(=O)OC(C)(C)C
Agent: I
Agent: N
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: CN(CCN1CCSc2cc(NC(=N)c3cccs3)ccc21)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
To a solution of tert-butyl 2-((2-(7-amino-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)(methyl)amino)acetate (850 mg, 2.52 mmol) in EtOH (25 mL) was added methyl thiophene-2-carbimidothioate hydroiodide (1.43 g, 5.04 mmol). The resulting suspension was stirred at room temperature for 17 hours (overnight). At this time, the suspension was diluted with 20 mL CH2Cl2 to give a dark yellow solution. Argon was then bubbled through this solution for 30 minutes. The solution was transferred to a separatory funnel containing saturated sodium bicarbonate solution (50 mL) and CH2Cl2 (100 mL) then extracted. After extraction, the organic layer was separated, dried (Na2SO4), filtered, and concentrated to give a dark residue. This residue was subjected to flash chromatography on silica gel using 2:98 MeOH:CH2Cl2 followed by 2.5:97.5 (2M NH3 in MeOH):CH2Cl2 to give a yellow-green residue (420 mg, 37.3%). Some impure fractions were collected (˜340 mg). 1H-NMR (CDCl3) δ 7.43-7.35 (m, 2H), 7.06 (pseudo t, J=4.8 Hz, 1H), 7.71 (brd, J=8.1 Hz, 2H), 6.65 (dd, J=1.8, 8.4 Hz, 1H), 4.91 (brs, 2H), 3.66-3.58 (m, 2H), 3.43 (t, J=7.2 Hz, 2H), 3.21 (s, 2H), 3.07-2.99 (m, 2H), 2.74 (t, J=7.5 Hz, 2H), 2.45 (s, 3H), 1.47 (s, 9H); ESI-MS (m/z, %): 447 (MH+, 100), 391 (50); HPLC purity: 99.7% a/a.
Reaction SMILES: [CH2:1]([C:5]1([CH2:23][CH3:24])[CH2:16][CH:15]=[CH:14][CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].Cl.[NH2:26][OH:27].Cl>O>[CH2:1]([C:5]([CH2:23][CH3:24])([CH2:16][CH:15]=[CH:14][CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][CH:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH2:7])[CH:6]=[N:26][OH:27])[CH2:2][CH2:3][CH3:4]
Reactant: NO
Reactant: CCCCC1(CC)C=NC(c2ccccc2)CC=CCCC=CC1
Agent: Cl
Solvent: O
Product: CCCCC(C=NO)(CC)CC=CCCC=CCC(N)c1ccccc1
Yield: 100 %

Procedure:
The procedure described in Example (1b) is repeated, except that 283.4 g (0.875 mol) of 3-n-butyl-3-ethyl-12-phenyl-1-aza-1,5,9-cyclododecatriene, 60.8 g (0.87 mol) of hydroxylamine hydrochloride, 50 ml of concentrated hydrochloric acid and 250 ml of water are used. Working up yields 310 g (0.87 mol) of 2-n-butyl-2-ethyl-11-phenyl-11-amino-undeca-4,8-dienal oxime; yield 99.5% of theory.