Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH:4]1[CH2:9][C:8]([CH:10]=O)=[CH:7][CH2:6][CH2:5]1)([O-:3])=[O:2].C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].Cl>N1C=CC=CC=1>[N+:1]([CH:4]1[CH2:9][C:8]([CH:10]=[CH:13][C:14]([OH:16])=[O:15])=[CH:7][CH2:6][CH2:5]1)([O-:3])=[O:2]
Reactant: O=C(O)CC(=O)O
Reactant: O=CC1=CCCC([N+](=O)[O-])C1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)C=CC1=CCCC([N+](=O)[O-])C1
Temperature: 60 °C

Procedure:
To a solution of 5-nitro-cyclohex-1-enecarbaldehyde (18 g, 0.116 mol) in pyridine (36 ml) was added malonic acid (41 g, 0.394 mol). The resulting suspension was heated to 60° C. for about 7 hours. After cooling to a temperature between 15° C. and 20° C., 6N HCl (72 ml) was slowly added into the reaction mixture to adjust the pH to between 1.5 and 2 while maintaining the temperature between 20° C. and 25° C. The mixture was then extracted with methylene chloride three times (1×180 ml, 2×90 ml). The combined extracts were washed with 1N HCl (48 ml), water (48 MI) and concentrated to a volume of 36 ml. The concentrate suspension was cooled to 0° C. and 5° C. for 1 hour. Light yellow solid was obtained after filtration and drying under vacuum. Yield: 10 g, 60%. Mp 158-160° C. 1HNMR (400 MHz, DMSO-d6): δ 2.10-2.33 (m, 4H), 2.73 (m, 2H), 4.96 (m, 1H), 5.83 (d, J=20 Hz, 1H), 6.28 (s, 1H), 7.27 (d, J=20 Hz, 1H), 12.3 (s, 1H).
Reaction SMILES: CS(Cl)(=O)=O.O[C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH3:21])[C:12]3[C:17]([S:18][C:19]=2[CH:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3.C(N(CC)CC)C.[Cl:29][CH2:30]Cl>O>[Cl:29][CH2:30][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH3:21])[C:12]3[C:17]([S:18][C:19]=2[CH:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: ClCCl
Reactant: CN1c2ccccc2Sc2cc(O)ccc21
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CN1c2ccccc2Sc2cc(CCl)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
With ice-cooling, methanesulfonyl chloride (3.9 ml, 50 mmol) was added dropwise to a mixture of 3-hydroxy-10-methylphenothiazine (10.9 g, 45 mmol), triethylamine (8.2 ml, 59 mmol) and dichloromethane (80 ml), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and the reaction product was extracted with chloroform. The extract was washed with a saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in that order, dried over anhydrous magnesium sulfate, and concentrated under a reduced pressure to give the title compound (8.09 g, 30.9 mmol, 69%) as yellow crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[C:11](=[O:18])[C:10]([C:19]([NH:21][CH2:22][CH2:23][S:24][CH3:25])=[O:20])=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.Br[C:27]1[CH:32]=[CH:31][C:30]([C@@H:33]2[CH2:35][C@H:34]2[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)CC.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>[CH3:25][S:24][CH2:23][CH2:22][NH:21][C:19]([C:10]1[C:11](=[O:18])[C:12]2[C:17](=[N:16][CH:15]=[CH:14][CH:13]=2)[N:8]([C:4]2[CH:3]=[C:2]([C:27]3[CH:32]=[CH:31][C:30]([CH:33]4[CH2:35][CH:34]4[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:29][CH:28]=3)[CH:7]=[CH:6][CH:5]=2)[CH:9]=1)=[O:20]
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(Br)cc1
Reactant: CSCCNC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCO
Product: CCOC(=O)C1CC1c1ccc(-c2cccc(-n3cc(C(=O)NCCSC)c(=O)c4cccnc43)c2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of amide from step 1 (1 eq), ethyl 2-(trans)-(4-bromophenyl)cyclopropanecarboxylate from EXAMPLE 1, step 1 (1 eq), Na2CO3 (3.5 eq.; 2M in H2O), Pd(PPh3)4 (0.05 eq) in n-propanol (0.1M) was stirred at 80° C. for 3 h. The mixture was cooled to rt, quenched with brine and diluted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was triturated in ether/MeOH, isolated by filtration and washed with ether to afford the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]([OH:13])[CH2:12]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(O)C(Nc2ccccc2)C1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
In 20 ml of ethyl alcohol was dissolved 5 g (0.027 mole) of 1-t-butoxycarbonyl-3-epoxypyrrolidine, and 12.6 g (0.135 mole) of aniline was added thereto. The mixture was refluxed by heating for 20 hours. After the mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the residue was applied to silica gel column chromatography (the eluent used was a mixture of ethyl acetate:toluene=1:4) to obtain 4.85 g of 1-t-butoxycarbonyl-3-hydroxy-4-phenylaminopyrrolidine as yellowish brown crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[C:3]=1[CH3:15].CCN=C=NCCCN(C)C.[O:27]1[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:15][C:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:6][C:5]=2[CH:13]=[CH:14][C:2]=1[NH:1][C:32]([CH:29]1[CH2:30][CH2:31][O:27][CH2:28]1)=[O:33]
Reactant: O=C(O)C1CCOC1
Reactant: Cc1c(N)ccc2sc3ccccc3c12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(NC(=O)C2CCOC2)ccc2sc3ccccc3c12

Procedure:
2-Amino-1-methyldibenzothiophene (Method 10; 0.337 g, 1.58 mmol), 4-(dimethylamino)pyridine (0.213 g, 1.74 mmol), EDAC (0.334 g, 1.74 mmol) and tetrahydro-3-furoic acid (0.167 ml, 1.74 mmol) were stirred in DCM (20 ml) at reflux under an argon atmosphere for 64 h. The product was purified by flash chromatography eluting with DCM—5% methanol/DCM. Evaporation of the appropriate fractions gave the product as a white solid. NMR: 9.77 (brs, 1H), 8.44 (m, 1H), 8.04 (m, 1H), 7.82 (d, 1H), 7.52 (m, 2H), 7.36 (d, 1H), 4.00 (m, 1H), 3.76 (m, 3H), 3.27 (m, 1H), 2.68 (s, 3H), 2.15 (q, 2H); m/z 313.
Reaction SMILES: [Cl:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([NH2:6])=[C:4]([F:12])[CH:3]=1.[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2[CH2:19][CH2:20][CH2:21][CH2:22][C:14]1=2.O>C(O)(=O)C>[Cl:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([N:6]2[C:16](=[O:17])[C:15]3[CH2:19][CH2:20][CH2:21][CH2:22][C:14]=3[C:13]2=[O:18])=[C:4]([F:12])[CH:3]=1
Reactant: Nc1cc([N+](=O)[O-])c(Cl)cc1F
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Solvent: O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc([N+](=O)[O-])c(Cl)cc1F
Yield: 61.8 %

Procedure:
4-Chloro-2-fluoro-5-nitroaniline (19 g) and 3,4,5,6-tetrahydrophthalic anhydride (15.2 g) are dissolved in acetic acid (50 ml) and refluxed for 6 hours. After being allowed to cool, the resultant mixture is poured into water and extracted with toluene. The toluene layer is washed with water, an aqueous sodium hydrogen carbonate solution and water in order, dried and concentrated. The residue is crystallized from ethanol to give 20 g of N-(4-chloro-2-fluoro-5-nitrophenyl)-3,4,5,6-tetrahydrophthalimide. M.P., 157°-157.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]([CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C:11]2([CH3:20])[CH3:19])[CH:8]=[N:7][CH:6]=1)=[O:4].S(=O)(=O)(O)[OH:22].[OH-].[Na+]>O>[CH3:1][O:2][C:3]([C:5]1[N:9]([CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:22])[C:11]2([CH3:20])[CH3:19])[CH:8]=[N:7][CH:6]=1)=[O:4]
Reactant: O=S(=O)(O)O
Reactant: COC(=O)c1cncn1C1c2ccccc2CC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1cncn1C1c2ccccc2C(=O)C1(C)C
Yield: 60.2 %

Procedure:
A mixture of 30 g of 1-(2,2-dimethyl-indan-1-yl)-5-imidazolecarboxylic acid methyl ester, 150 ml of water and 17 g of sulfuric acid is heated to +80° C. Within a period of 1.5 hours an aqueous solution of 114 g of ammoniaperoxodisulfate is added dropwise. The reaction mixture is cooled to +7° C. and the pH-value is adjusted to pH 3 by addition of a 30% sodium hydroxide solution. The mixture is twice extracted with 200 ml of methylene chloride. The combined organic extracts are dried with sodium sulfate and concentrated to dryness. The residue is taken up with a small amount of methylene chloride and diluted with diethyl ether. The resulting suspension is filtered and the filtrate is concentrated and crystallized from a diethyl ether/hexane mixture affording 19 g of 1-(2,2-dimethyl-3-oxo-indan-1-yl)-5-imidazolecarboxylic acid methyl ester, mp. 104°-108° C.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[CH2:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][NH:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O>[CH3:16][C:3]1([CH2:2][N:18]2[CH2:19][CH2:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17]2)[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCc3ccccc3C1)O2

Procedure:
A suspension of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine (1.4 g), 1,2,3,4-tetrahydroisoquinoline (1.3 g), and potassium carbonate (1.4 g) in N,N-dimethylacetamide (10 mL) was refluxed under nitrogen gas for 15 hours. This reaction mixture was diluted with water and extracted with 2 portions of ethyl acetate. The pooled organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3:1) to provide 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1,2,3,4-tetrahydroisoquinolin-2-yl)methyl]-5-benzofuranamine. This product was dissolved in ethanol, followed by addition of 1 equivalent of oxalic acid solution in ethanol. This mixture was heated and the resulting solution was concentrated under reduced pressure. The crystals that separated out were collected to provide 1.5 g of the title compound. Yield 68%.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:10]([C:11]#[N:12])=[C:9]([NH:13][CH:14]2[CH2:16][CH2:15]2)[N:8]=[C:7]([NH:17][C:18]([C:21]#[N:22])([CH3:20])[CH3:19])[N:6]=1>CO>[C:21]([C:18]([NH:17][C:7]1[N:6]=[C:5]([O:2][CH3:1])[C:10]([C:11]#[N:12])=[C:9]([NH:13][CH:14]2[CH2:16][CH2:15]2)[N:8]=1)([CH3:20])[CH3:19])#[N:22]
Reactant: CC(C)(C#N)Nc1nc(Cl)c(C#N)c(NC2CC2)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(NC(C)(C)C#N)nc(NC2CC2)c1C#N
Reaction time: 16 h
Yield: 59.5 %

Procedure:
To a stirred solution of 0.8 gram of sodium methoxide in 100 ml of methanol was added portionwise 4.2 grams of 4-chloro-2-(1-cyano-1-methylethylamino)-6-cyclopropylamino-5-pyrimidinecarbonitrile. Upon complete addition, the reaction mixture was heated under reflux for 3.5 hours, then allowed to stand at room temperature for 16 hours. The methanol was removed by evaporation under reduced pressure. The residue was extracted with a mixture of water and methylene chloride. The methylene chloride layer was separated and dried over magnesium sulfate. The mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was recrystallized twice from carbon tetrachloride to give 2.4 grams of 2-(1-cyano-1-methylethylamino)-6-cyclopropylamino-4-methoxy-5-pyrimidinecarbonitrile; mp, 138°-140°.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21]([SH:23])[CH3:22].Cl>CN(C)C=O>[CH2:21]([S:23][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[CH3:22]
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Reactant: CCS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCSc1ccc(S(C)(=O)=O)cc1C(=O)O
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 4.58 mmol 2-fluoro-5-methanesulfonyl-benzoic acid (Example B4(b)) in 6 ml N,N-dimethylformamide were added 13.8 mol cesium carbonate and 9.25 mmol ethanethiol and the mixture was stirred at 90° C. for 30 min. The reaction mixture was then cooled to room temperature and acidified to pH1 by addition of hydrochloric acid before being extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford the title compound as a white solid which was used in the next step without further purification (yield 99%). MS (m/e): 259.0 ([M−H]−, 100%).
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]4([NH:21]C(=O)OCC5C=CC=CC=5)[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]4)[CH2:14][N:13]3[C:32](=[O:35])[C:33]=2[OH:34])=[O:9])=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[NH2:21][C:18]12[CH2:17][CH2:16][CH:15]([CH2:20][CH2:19]1)[CH2:14][N:13]1[C:32](=[O:35])[C:33]([OH:34])=[C:10]([C:8]([NH:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:37][CH:36]=3)=[O:9])[N:11]=[C:12]21
Reactant: [H][H]
Reactant: O=C(NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Yield: 72.8 %

Procedure:
To a mixture of benzyl (2-((4-fluorobenzyl)carbamoyl)-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl)carbamate (300 mg, 0.59 mmol) in methanol (3 mL) was added 10% Pd/C (315 mg) and the mixture was stirred under balloon hydrogen atmosphere for 18 h. The mixture was then filtered through a pad of CELITE® and the pad washed with ethyl acetate. The filtrate was concentrated to afford the title compound (160 mg, 72% yield) as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ: 12.22 (s, 1H), 9.50 (brs, 1H), 7.35-7.41 (m, 2H), 7.19-7.22 (m, 2H), 4.54 (d, 2H, J=5.8 Hz), 4.01 (s, 2H), 2.42-2.48 (m, 3H), 2.08 (s, 2H), 1.98-2.03 (m, 2H), 1.84-1.90 (m, 2H), 1.70-1.78 (m, 2H). LCMS (M+H)=373.28.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25][NH2:26])=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1.CO>>[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25][N:26]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[CH:13][C:4]=4[N+:1]([O-:3])=[O:2])[C:9]3=[O:14])=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: NCc1ccc2c(c1)OCCO2
Solvent: CO
Product: O=c1c2cccc([N+](=O)[O-])c2ccn1Cc1ccc2c(c1)OCCO2

Procedure:
5-Nitro-isochromen-1-one (1.0 g, 0.0052 mol) and C-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methylamine (1.0 g, 0.0060 mol) were refluxed in methanol (40 mL, 1 mol) for 2 hours. The solvent was removed and the residue was purified via flash chromatography (40 g of silica gel, 0-30% EtOAc/Hexanes) to give a yellow solid.
Reaction SMILES: NN.[N+:3]([C:6]1[CH:7]=[C:8]([N:15]2[CH2:20][CH2:19][NH:18][CH:17]3[CH2:21][S:22](=[O:25])(=[O:24])[CH2:23][CH:16]23)[C:9]2O[CH:12]=[CH:11][C:10]=2[CH:14]=1)([O-])=O.CC#N.C1C[O:32]CC1>CCO.[Ni]>[O:25]=[S:22]1(=[O:24])[CH2:21][CH:17]2[CH:16]([N:15]([C:8]3[O:32][C:11]4[CH:12]=[CH:7][C:6]([NH2:3])=[CH:14][C:10]=4[CH:9]=3)[CH2:20][CH2:19][NH:18]2)[CH2:23]1
Reactant: O=[N+]([O-])c1cc(N2CCNC3CS(=O)(=O)CC32)c2occc2c1
Reactant: C1CCOC1
Agent: [Ni]
Agent: NN
Solvent: CC#N
Solvent: CCO
Product: Nc1ccc2oc(N3CCNC4CS(=O)(=O)CC43)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Raney-nickel (slurry in ethanol; 2 mL) and hydrazine (204 mL, 4.20 mmol) were added to 1-(5-nitro-1-benzofuran-7-yl)octahydrothieno[3,4-b]pyrazine 6,6-dioxide (0.354 g, 1.05 mmol; Intermediate 35) in a mixture of THF (20 mL) and EtOH (80 mL). The resulting mixture was stirred at room temperature overnight and then more Raney-nickel (slurry in ethanol; 2 mL) and hydrazine (204 mL, 4.20 mmol) were added and stirring was continued overnight. The mixture was filtered through Celite and the solvent was removed in vacuo to afford 0.338 g (quantitative). HPLC 90%, RT: 0.782 (System A; 10-97% MeCN over 3 min). 1H NMR (270 MHz, methanol-d4) δ ppm 2.79 (dd, J=12.49, 7.30 Hz, 1H) 2.90-3.25 (m, 4H) 3.43-3.64 (m, 3H) 3.91-3.94 (m, 1H) 5.01-5.07 (m, 1H) 6.33 (d, J=1.98 Hz, 1H) 6.61 (dd, J=12.99, 2.10 Hz, 2H) 7.62 (d, J=1.98 Hz, 1H). LC-MS 308 (M+H)+.
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=S)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:18]>C(O)C>[CH:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[NH:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N
Reactant: S=C(Nc1ccc(Cl)cc1)NC1CCCCC1
Solvent: CCO
Product: N=C(Nc1ccc(Cl)cc1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Cyclohexyl-3-(p-chlorophenyl)thiourea (2.0 g.) was dissolved in absolute ethyl alcohol saturated with ammonia (40 ml.). To this was added yellow mercuric oxide (1.7 g.) and the mixture stirred at room temperature for 16 hours. The mixture was then refluxed 15 minutes to coagulate the fine precipitate of mercuric sulphide, filtered and the clear filtrate evaporated to dryness. The residue was recrystallised from toluene to give 1-cyclohexyl-3-(p-chlorophenyl)guanidine, m.p. 187°-190°.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([S:9][CH:10]1[N:13]([CH:14](Cl)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C:12](=[O:29])[CH2:11]1)=[O:8].[C:30]1([P:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1C(C)=CC=CC=1C>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([S:9][CH:10]1[N:13]([C:14](=[P:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C:12](=[O:29])[CH2:11]1)=[O:8]
Reactant: COCCOCC(=O)SC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: COCCOCC(=O)SC1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 50 h
Yield: 43.2 %

Procedure:
A mixture of p-nitrobenzyl 2-[4-(2-methoxyethoxyacetylthio)-2-oxo-1-azetidinyl]-2-chloroacetate (761 mg.), triphenylphosphine (524 mg.; 2.00 mmoles) and 2.6-lutidine (0.235 ml.; 214 mg.; 2.00 mmoles) in tetrahydrofuran (7 ml.) was stirred under N2 atmosphere at room temperature for 50 hours. After filtration of the precipitate, the filtrate was evaporated to yield 1.39 g. of a crude oil. This oil was purified by column chromatography (SiO2 ; 30 g.; eluant-ethyl acetate) yielding title product (494 mg.; 0.736 mmole; yield 42.3% based on starting ester) as a brownish oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(#N)C>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of 0.34 g (2.0 mmol, 1.0 eq.) of 1-(chloromethyl)-4-nitrobenzene in 20 mL of acetonitrile was added 0.83 g (6.0 mmol, 3.0 eq.) of potassium carbonate and 0.4 mL (4.0 mmol, 2.0 eq.) of piperidine. The reaction mixture was heated at reflux for 16 h. The reaction mixture was allowed to cool to room temperature, filtered and the solvent removed in vacuo. The resulting residue was purified by preparative TLC to give 0.31 g (1.4 mmol, 70%) of 1-(4-nitrobenzyl)piperidine (I-27).
Reaction SMILES: [CH:1]([P:3](=[O:14])([O-:13])[O:4][CH2:5][CH:6]([CH2:11][CH3:12])[CH2:7][CH2:8][CH2:9][CH3:10])=[CH2:2].[CH2:15]([NH2:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[H-].[Na+].O>C(OCC)(=O)C>[CH2:11]([CH:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:5][O:4][P:3]([CH2:1][CH2:2][NH:33][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:13])[O:14][CH2:5][CH:6]([CH2:11][CH3:12])[CH2:7][CH2:8][CH2:9][CH3:10])[CH3:12]
Reactant: C=CP(=O)([O-])OCC(CC)CCCC
Reactant: CCCCCCCCCCCCCCCCCCN
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCNCCP(=O)(OCC(CC)CCCC)OCC(CC)CCCC
Temperature: 140 °C
Reaction time: 6 h

Procedure:
A mixture of 2-ethylhexyl vinylphosphonate (49.90 g), octadecylamine (40.43 g) and sodium hydride 0.10 g was stirred at 140° C. for 6 hours. Water (100 ml) and ethyl acetate (200 ml) were added. The organic phase was separated, dried with sodium sulfate, filtered and the solvent evaporated under reduced pressure to give di(2-ethylhexyl)[2-(octadecylamino)ethyl]phosphonate, as colourless liquid nD40 =1.4541.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:9]([O:16][NH2:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH2:9]([O:16][N:17]=[CH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCCCC=O
Reactant: NOCc1ccccc1
Solvent: C1CCOC1
Product: CCCCCCC=NOCc1ccccc1
Reaction time: 0.33 h
Yield: 91 %

Procedure:
To a 10 mL round bottom flask equipped with a stifling bar and purged with N2 was added heptanal (343 mg, 420 μL, 3.0 mmol) followed by O-benzylhydroxylamine (369 mg, 349 μL, 3.0 mmol). An immediate evolution of heat occurred with formation of a cloudy solution. The solution was stirred at room temperature during four minutes before 3 mL of dry THF was added. Stirring continued for 20 min, at which time the TLC (hexanes/ethyl acetate, 85:15) indicated completion of reaction. The volatiles were removed under reduced pressure, and the crude material was purified by column chromatography on silica gel using hexanes/ethyl acetate (95:5) as eluent to give 599 mg (91%) of clear oil: Rf=0.48 and 0.51 (two isomers) (hexanes/ethyl acetate, 95:5, v/v); 1H NMR (CDCl3) δ 7.43 (t, 3J=6.3 Hz, 0.6H), 7.36-7.31 (m, 4H), 7.30-7.26 (m, 1H), 6.66 (t, 3J=5.3 Hz, 0.4H), 5.09 (s, 0.8H), 5.04 (s, 1.2H), 2.37-2.33 (m, 0.8H), 2.19-2.15 (m, 1.2H), 1.48-1.42 (m, 2H), 1.34-1.23 (m, 6H), and 0.86 (t, 3J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH3:17])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:25][C:26]1[CH:35]=[CH:34][C:29]([C:30](=O)[CH2:31]Br)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([CH:31]=[C:30]([C:29]3[CH:34]=[CH:35][C:26]([O:25][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:27][CH:28]=3)[C:15]=2[CH2:16][CH3:17])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1ccc(OCc2ccccc2)cn1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)cn2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Yield: 78.7 %

Procedure:
5-Benzyloxy-2-n-propylpyridine (50.15 g, 221 mmol) and 4-benzyloxyphenacylbromide (67.34 g, 221 mmol) was dissolved in 400 ml of dry acetone under a nitrogen atmosphere. The mixture was heated to reflux for 5 days. The reaction was cooled to room temperature and the solvent was removed. The remaining quaternary salt was suspended in 250 ml of water and 250 ml of diethyl ether and filtered off. The dried salt was suspended in 600 ml of water and sodium hydrogen carbonate (74 g, 884 mmol) was added. The mixture was refluxed for 3 days. The resulting precipitate was filtered off, washed with water and dried to afford 75.38 g (78%) of 6-benzyloxy-2-(4-benzyloxyphenyl)-1-ethylindolizine as brown crystals. 1H-NMR (DMSO-d6, 200 MHz) δ: 1.10 (t, 3H); 2.79 (q, 2H); 5.02 (s, 2H); 5.12 (s, 2H); 6.52 (dd, 1H); 7.08 (d, 2H); 7.29-7.51 (m, 14H); 7.96 (s, 1H).