Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[C:17]([OH:19])[C:16]([O:20][CH3:21])=[CH:15][C:14]=2[CH:22]([CH2:26][CH3:27])[C:23](=O)[CH3:24])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:28][NH2:29]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:13]3[CH:18]=[C:17]([OH:19])[C:16]([O:20][CH3:21])=[CH:15][C:14]=3[CH:22]([CH2:26][CH3:27])[C:23]([CH3:24])=[N:29][N:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NN
Reactant: CCC(C(C)=O)c1cc(OC)c(O)cc1C(=O)c1ccc(OC)c(OC)c1
Product: CCC1C(C)=NN=C(c2ccc(OC)c(OC)c2)c2cc(O)c(OC)cc21

Procedure:
Annulation of 3-{2-[(3,4-dimethoxy-phenyl)carbonyl]-4-hydroxy-5-methoxyphenyl}pentan-2-one by reaction with hydrazine to yield 1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7-methoxy-8-hydroxy-5H-2,3-benzodiazepine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[OH-].[Na+].Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].Cl>O>[CH2:13]([O:12][C:10]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NCCCCO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
4-Amino-1-butanol (5 g) was dissolved in water (50 ml) and cooled to 0° C. The solution was added with 1 N aqueous sodium hydroxide (56.1 ml) and then with benzyl chloroformate (8 ml) and stirred at room temperature for 23 hours. 5 N aqueous sodium hydroxide (22.4 ml) and benzyl chloroformate (16 ml) were further added to the mixture, and stirring was continued for 2 hours. The reaction system was cooled to 0° C. and adjusted to pH 4 with 5 N hydrochloric acid, and the organic substances were extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the precipitated crystals were washed with diethyl ether to obtain 4-benzyloxycarbonylamino-1-butanol (8.15 g, 65%).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Cl[C@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9]>CN1CCCC1=O>[C:1]([S:3][C@@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: O=C(O)[C@H](Cl)Cc1ccccc1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(=O)S[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 24 h
Yield: 94.4 %

Procedure:
Potassium thioacetate (93 mg, 0.81 mmol) was added to a solution of 100 mg (0.54 mmol) of (2R)-2-chloro-3-phenylpropionic acid in 2 ml of N-methyl-2-pyrrolidone at room temperature, and the mixture was stirred for 24 hours. The work-up procedure in the same manner as in Example 18 of the reaction mixture was followed to give 114 mg (0.51 mmol, yield 94%) of the desired (2S)-2-acetylthio-3-phenylpropionic acid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH2:13]([OH:18])[CH2:14][CH2:15][C:16]#[CH:17]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:10][C:9]([F:12])([F:11])[O:8][C:4]1[CH:3]=[C:2]([C:17]#[C:16][CH2:15][CH2:14][CH2:13][OH:18])[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCCO
Reactant: FC(F)(F)Oc1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: OCCCC#Cc1cccc(OC(F)(F)F)c1

Procedure:
In analogy to the procedure described in example 1 a], 1-iodo-3-trifluoromethoxy-benzene was reacted with 4-pentyn-1-ol in the presence of Pd(PPh3)4 and cuprous iodide to give the title compound as red oil.
Reaction SMILES: Cl.[CH3:2][O:3][N:4]1[CH2:9][CH2:8][C:7]([NH:13][CH3:14])([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1.S(Cl)(Cl)=O.[CH3:19]O>>[CH3:19][O:11][C:10]([C:7]1([NH:13][CH3:14])[CH2:8][CH2:9][N:4]([O:3][CH3:2])[CH2:5][CH2:6]1)=[O:12]
Reactant: CNC1(C(=O)O)CCN(OC)CC1
Reactant: CO
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CNC1(C(=O)OC)CCN(OC)CC1

Procedure:
To a suspension of 1-methoxy-4-methylamino-piperidine-4-carboxylic acid hydrochloride salt (2.08 g, 9.26 mmol) in methanol (20 ml) at 0-5° C. was added thionyl chloride (2.41 ml, 3.97 g, 33.40 mmol) and the reaction mixture was heated at reflux for 7 days. After cooling, the mixture was concentrated, the residue diluted with ice water and neutralised with aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (4×), the combined organic layers washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (gradient ethyl acetate→ethyl acetate/methanol 20:1). Yield: 76 mg of 1-methoxy-4-methylamino-piperidine-4-carboxylic acid methyl ester (title compound P5.4) as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])=[CH:6][C:5]([CH3:20])=[CH:4][N:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].C1(C)C(C)=CC=CC=1>N1C=CC=CC=1>[CH3:20][C:5]1[CH:6]=[C:7]2[N:8]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:16]([O-:18])=[O:17])[S:22][C:2]2=[N:3][CH:4]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1cnc(Cl)c(NC(=O)c2ccccc2[N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1C
Product: Cc1cnc2sc(-c3ccccc3[N+](=O)[O-])nc2c1
Temperature: 140 °C
Reaction time: 20 h
Yield: 75.4 %

Procedure:
A mixture of N-(2-chloro-5-methylpyridin-3-yl)-2-nitrobenzamide (5.0 g, 17.1 mmol) and P2S5 (7.6 g, 34.2 mmol) in pyridine (50 mL) and p -xylene (200 mL) was stirred at 140° C. for 20 h. The hot solution was transferred to another flask and the solvent was removed in vacuo. The residue was purified by recrystallization from EtOH to afford 6-methyl-2-(2-nitrophenyl)thiazolo[5,4-b]pyridine as a yellow solid (3.5 g, yield: 75%).
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.O1CCCC1.[Br:10][C:11]1[N:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[H-].[Na+]>O>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:1][O:2][CH3:3])=[CH:15][N:16]=1
Reactant: Oc1ccc(Br)nc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1ccc(Br)nc1

Procedure:
Methoxymethyl chloride (73 ml) was added to a tetrahydrofuran (1.3 L) solution of the obtained 6-bromo-3-pyridinol (129 g), and sodium hydride (30% liquid paraffin added) (32 g) was added at an inner temperature not to be over −10° C. Water was added, extracted with ethyl acetate, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=9/1 to 8/1) to obtain the entitled compound (105 g) as a colorless oil.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([Cl:10])[CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(OCC)C>CS(C)=O.Cl>[Cl:10][C:4]1[CH:5]=[C:6]([CH:9]=[C:2]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)[CH:3]=1)[C:7]#[N:8]
Reactant: CN1CCNCC1
Reactant: N#Cc1cc(F)cc(Cl)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOCC
Product: CN1CCN(c2cc(Cl)cc(C#N)c2)CC1
Temperature: 80 °C
Yield: 92.8 %

Procedure:
5-Fluoro-3-chloro-benzonitrile (Ig, 6.4 mmol) was dissolved in DMSO (20 ml) followed by addition OfK2CO3 (1.3 g, 9.6 mmol) and 1-methyl piperazine (1.4 ml, 12.8 mmol). The reaction mixture was heated at 80° C. for 20 hours. Diethyl ether was added to the crude material (10 ml) then acidified with IN HCl. A precipitate was filtered off from the crude reaction mixture to give 3-chloro-5-(4-methyl-ρiρerazin-1-yl)-benzonitrile (1.4 g, 93% yield) as a white solid (LC/MS: Rt 1.83 [M+H]+ 236, acidic method).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)[CH3:17]
Reactant: c1ccc2c(c1)CCNC2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
To a solution of 1,2,3,4-tetra-hydroisoquinoline (2.664 g, 20 mmol) and ethyl bromoacetate (3.647 g, 22 mmol) in N,N-dimethylformamide (23 mL), was added Cs2CO3 (7.168 g, 22 mmol) under N2. The mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure, and the remaining residue was subjected to silica gel chromatography, eluting with ethyl acetate/hexanes (33:66) to afford Intermediate 199(a) (3.39 g, 15.5 mmol) as yellow oil in 77% yield.
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([N:8]2[C:4](=[O:5])[CH:3]=[CH:2][C:1]2=[O:7])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccccc1
Reactant: O=C1C=CC(=O)O1
Product: O=C1C=CC(=O)N1c1ccccc1

Procedure:
Aniline, a primary aromatic amine, is a hazardous carcinogenic liquid. It is difficult to handle aniline safely during reactive extrusion, which is the most economical way to produce imides on a large scale. Often maleic anhydride is reacted with aniline to obtain the N-phenylmaleimide monomer, which is then copolymerized with other monomers in solution or emulsion polymerization processes.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.Br.Br.[C:24]12[CH2:31][NH:30][CH2:29][C:28]=1[CH2:27][NH:26][CH2:25]2.N12CCCN=C1CCCCC2>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:26]2[CH2:27][C:28]3[CH2:29][NH:30][CH2:31][C:24]=3[CH2:25]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: C1NCC2=C1CNC2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Nc1c(F)c(N2CC3=C(CNC3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
0.4 g of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.8 g of 3,7-diazabicyclo[3.3.0]oct-1(5)-ene dihydrobromide and 0.6 ml of 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU) were suspended in 40 ml of acetonitrile and the suspension was refluxed in 100° C. oil bath for 7 hours. The reaction mixture was kept overnight at room temperature. The produced precipitate was filtered and washed with methanol. 0.3 g of the titled compound was obtained (yield 57%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.Br[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.[I-].[K+]>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:3][CH:4]=1)=[CH2:7]
Reactant: C=Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=Cc1ccc(OCC(=O)OC(C)(C)C)cc1
Yield: 93.1 %

Procedure:
In a 1500 ml sulfonation flask, 135.6 g (1.13 mol) of 4-hydroxystyrene and 220.2 g (1.13 mol) of tert-butyl bromoacetate are dissolved in 800 ml of acetone and to the solution are added 195.0 g (1.41 mol) of potassium carbonate and 0.8 g of potassium iodide. The resultant suspension is stirred for 4 hours at 60° C. bath temperature. After cooling, the inorganic salts are removed by filtration and the filtrate is concentrated. The oily residue is taken up in 1000 ml of diethyl ether, washed twice with 800 ml of 1.0N sodium hydroxide solution and then three times with 1000 ml of water. The organic phase is separated, dried over magnesium sulfate and concentrated, giving 246.5 g of the desired product as a clear oil (93.2 %).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][C:8]([NH:11][C:12](=[O:15])[CH:13]=[CH2:14])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.[OH-].O1CCOCC1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([NH:11][C:12](=[O:15])[CH2:13][CH2:14][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)([CH3:9])[CH3:10])=[CH:16][CH:17]=1
Reactant: C=CC(=O)NC(C)(C)COc1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(COc1ccc(Cl)cc1)NC(=O)CCn1ccnc1
Temperature: 95 °C

Procedure:
A mixture of N-[2-(4-chlorophenoxy)-1,1dimethylethyl]acrylamide (4.5 g), imidazole (1.24 g), benzyltrimethylanmonium hydroxide (0.62 ml of a 40% solution in methanol, Triton®B) and 1,4-dioxane (40 ml) was heated at 95° C. for 7 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. This solution was extracted with SM hydrochloric acid. The combined acid extracts were basified with 10M sodium hydroxide solution and extracted with dichloromethane to give N-[2-(4-chlorophenoxy)-1,1-dimethylethyl]-3-(imidazol-1-yl)propionamide.
Reaction SMILES: C([Mg]Br)C.I[C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1.[CH2:30]([Sn:34](Cl)([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH3:33]>C1COCC1>[CH2:39]([Sn:34]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:35][CH2:36][CH2:37][CH3:38])[C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH2:40][CH2:41][CH3:42]
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 2 h
Yield: 126.3 %

Procedure:
3 M Ethyl magnesium bromide in THF (5.0 ml, 15.0 mmol) was added dropwise to a solution of 4-iodo-1-trityl-1H-imidazole (4.44 g, 10.2 mmol) in THF (100 ml) at −78° C. After stirring for 2 h, tributyltin chloride (5.0 ml, 18.4 mmol) was added. After stirring for an additional 2 h, the solution was concentrated under reduced pressure. The residue was flash chromatographed with 19:1, 9:1, 17:3, and 4:1 hexane:ethyl acetate as the eluant to yield 7.72 g of impure 4-(tributylstannyl)-1-trityl-1H-imidazole as a yellow solid. Method [7] Retention time 10.89 min by HPLC (MH+ 601).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14]Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: CN(C)CCCl
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)CCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.3 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (610 mg) in N,N-dimethylformamide (20 mL) is added successively 2-dimethylaminoethyl chloride hydrochloride (1.08 g) and potassium carbonate (2.0 g), and the mixture is stirred at room temperature for 18 hours. To the reaction mixture is added ethyl acetate, and the mixture is washed with water and saturated brine and dried over anhydrous sodium sulfate. The resultant crude product is purified by column chromatography in silica gel (Solvent; chloroform:methanol=20:1→10:1) to give 4-[2-(dimethylamino)-ethoxy]benzaldehyde (640 mg, yield; 66%) as a pale yellow oil. MS (APCI) m/z: 194 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.S(Cl)(Cl)=O.[CH2:16](O)[CH3:17]>>[CH2:16]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[OH:11])[CH3:17]
Reactant: O=C(O)c1ccc(F)cc1O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(F)cc1O

Procedure:
To a solution of 4-fluoro-2-hydroxybenzoic acid (3.0 g) in ethanol (40 mL) was added thionyl chloride (5.61 mL) at 0° C., and this mixture was heated to reflux for 24 hours. This reaction mixture was concentrated, and this residue was poured into water, and this mixture was extracted with ethyl acetate. This organic layer was washed with water and brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-fluoro-2-hydroxybenzoic acid ethyl ester (3.5 g). To a solution of 4-fluoro-2-hydroxybenzoic acid ethyl ester (3.5 g) in dichloromethane (30 mL) were added N,N-diisopropylethylamine (5.0 g) and (chloromethyl)methyl ether (2.3 g) at 0° C., and this reaction mixture was stirred at room temperature overnight. This reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. This organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane) to give the title compound (2.8 g).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH3:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1[nH]c(=O)ccc1[N+](=O)[O-]
Product: Cc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 115 °C

Procedure:
A suspension of 6-methyl-5-nitro-1H-pyridin-2-one (Preparation 2, 3.53 g, 22.9 mmol) in phosphorous oxychloride (20 mL) was heated to 115° C. (oil bath temperature) for 3 h then allowed to cool to rt. The phosphorous oxychloride was removed in vacuo and the residue poured into iced water (100 mL). The mixture was quenched by addition of saturated sodium bicarbonate solution, then the aqueous mixture was extracted with ethyl acetate (3×100 mL). The combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to furnish the title compound as a brown solid. δH (CDCl3): 2.86 (3H, s), 7.36 (1H, d, 8.59 Hz), 8.27 (1H, d, 8.32 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][CH2:16][C:17]([CH3:22])([N+:19]([O-])=O)[CH3:18])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[C].[Pd]>[CH3:13][O:12][C:10](=[O:11])[C@H:9]([CH2:14][CH2:15][CH2:16][C:17]([CH3:22])([CH3:18])[NH2:19])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: COC(=O)[C@H](CCCC(C)(C)[N+](=O)[O-])NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](CCCC(C)(C)N)NC(=O)OC(C)(C)C
Yield: 80.8 %

Procedure:
Methyl (S)-2-t-butoxycarbonylamino-6-methyl-6-nitroheptanoate (300 mg, 0.94 mmol) was dissolved in methanol (10 ml) and 5% palladium-carbon (0.15 g, 50% wet) was added. The mixture was stirred at a hydrogen pressure of 20 atm and 80° C. for 24 h. Palladium-carbon was removed by filtration and methanol was evaporated by concentration under reduced pressure to give the objective compound (219 mg, yield 80.8%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1>CN(C)C=O>[CH:22]1([CH2:21][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH:11]([F:12])[F:13])[CH:5]=[O:6])[CH2:24][CH2:23]1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 104.8 %

Procedure:
To a mixture of 3-hydroxy-4-difluoromethoxybenzaldehyde (19.55 g, 104 mmol) and potassium carbonate (21.56 g, 156 mmol) in dimethylformamide (150 mL) under an argon atmosphere at 60° C. was added bromomethylcyclopropane (15.13 mL, 156 mmol) and the mixture was stirred and heated at 65° C. After 1.5 h, the mixture was allowed to cool and was filtered. The filtrate was concentrated under reduced pressure and the residue was partitioned between ethylacetate and water and was extracted four times with ethyl acetate. The organic extract was washed twice with water and was dried (sodium sulfate). The solvent was removed in vacuo to provide an oil (26.4 g).
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][SH:3].Cl[CH2:6][C:7]([C:9](=[N:15][O:16][CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O>>[S:3]1[C:7]([C:9](=[N:15][O:16][CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][S:4][CH2:1][CH2:2]1
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Reactant: SCCS
Product: CCOC(=O)C(=NOC)C1=CSCCS1
Yield: 22.3 %

Procedure:
Ethane-1,2-dithiol (20.6 g.) was allowed to react with ethyl 2-chloroacetyl-2-methoxyiminoacetate (41.4 g.) in a similar manner to that of Example A-(i) to give ethyl 2-(2,3-dihydro-1,4-dithiin-6yl)-2-methoxyiminoacetate (syn isomer, 11 g.), white crystals, mp. 65° to 67° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:12](=[O:13])[CH2:11][C@H:10]1O>C(O)(=O)C.O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:12](=[O:13])[CH:11]=[CH:10]1
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Solvent: CC(=O)O
Solvent: O
Product: CCCCC[C@H](O)/C=C/[C@H]1C=CC(=O)[C@@H]1CCCCCCC(=O)O
Reaction time: 48 h

Procedure:
A 125 mg (0.3 mmol) portion of the prostaglandin E1 analogue of Example 3 (14-Phenyl-11α,15R-dihydroxy-9-oxoprost-10,13E-dien-1-oic acid) was stirred into 10 ml of acetic acid-water (2:1) at 50° C. under an inert atmosphere. Progress of the reaction was followed by thin layer chromatography. After 48 hours, the reaction mixture was extracted with ether. Ether layers obtained were combined and washed to neutrality with brine. Removal of the solvent yielded a yellow oil. The oil was azeotroped with toluene and chromatographed on 70 g SG-60, and eluted with benzene-ethanol (19:1) to yield 102 mg of the PGA1 analogue.
Reaction SMILES: [CH:1]1([C:7]([O:9]C)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:11][NH2:12]>CO>[CH:1]1([C:7]([NH:11][NH2:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1CCCCC1
Reactant: NN
Solvent: CO
Product: NNC(=O)C1CCCCC1
Temperature: 65 °C
Yield: 33.5 %

Procedure:
To a solution of methyl cyclohexane carboxylate (12 g, 83.9 mmol) in MeOH (50 mL) was added hydrazine (5.3 mL, 1.67 mol). The reaction mixture was heated at 65° C. overnight. The reaction mixture was cooled to room temperature and the resultant solid was collected by filtration and was dried in vacuo to give 4.0 g of cyclohexanecarboxylic acid hydrazide.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:10]([O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: N#Cc1ccc(O)cc1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCOc1ccc(C#N)cc1
Yield: 88 %

Procedure:
In 4000 ml of acetone was dissolved 500 g (4.2 moles) of p-hydroxybenzonitrile and 965 g (5.0 moles) of octyl bromide, 828 g (6.0 moles) of anhydrous potassium carbonate was added thereto, and the mixture was refluxed with heating for 30 hours. Then, the inorganic salt was filtered off from the reaction mixture, acetone was distilled under reduced pressure. To the residue was added 2000 ml of ether and the mixture was washed with 2N aqueous solution of sodium hydroxide, water, then saturated aqueous solution of sodium chloride. The resulting organic layer was dried with anhydrous magnesium sulfate, and ether was distilled under reduced pressure to give 855 g of p-octyloxybenzonitrile (yield: 88%).