Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([OH:16])(=O)/[CH:6]=[CH:7]/[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[C:5]([Cl:3])(=[O:16])[CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCCC=CC(=O)Cl

Procedure:
Thionyl chloride (8 ml) was added to trans-2-decenoic acid (3.4 g, 0.02 mol) followed by refluxing on a hot water bath for 2 hours. An excessive thionyl chloride was evaporated in vacuo to give 2-decenoic acid chloride. Pyridine (1 ml) was added to a solution of N,N-dimethylaminoethanol (2.0 g, 0.022 mol) in tetrahydrofuran (30 ml) followed by dropping into a solution of 2-decenoic acid chloride in tetrahydrofuran (20 ml). The reaction solution was heated to reflux on a hot water bath for 3 hours, tetrahydrofuran was evaporated in vacuo, water and ethyl acetate were added to the residue to partition and an ethyl acetate layer was collected therefrom. The ethyl acetate layer was washed with water and evaporated followed by purifying by silica gel column chromatography (developer: chloroform) to give the aimed compound as a light brown oily product.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([CH2:10][N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:12][C:13](OC)=[O:14])=[CH:8][C:7]([Br:26])=[CH:6][N:5]=1.O>CS(C)=O>[Br:26][C:7]1[CH:6]=[N:5][C:4]2[NH:3][C:13](=[O:14])[CH2:12][N:11]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH2:10][C:9]=2[CH:8]=1
Reactant: COC(=O)CN(Cc1ccc(OC)cc1)Cc1cc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CN2CC(=O)Nc3ncc(Br)cc3C2)cc1
Reaction time: 8 h
Yield: 62.3 %

Procedure:
Sodium hydride (60% in oil, 140 mg, 3.40 mmol) was added to a solution of methyl 2-(((2-amino-5-bromopyridin-3-yl)methyl)(4-methoxybenzyl)amino)acetate (1.05 g, 2.66 mmol) in DMSO (17 mL) at room temperature. The reaction mixture was stirred overnight then diluted by addition of water (45 mL). After 2 hours stirring at room temperature, the reaction mixture was filtered. The resulting solid was dried under high vacuum to give the title compound as a yellow solid (600 mg, 63%)
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>O1CCCC1>[F:25][C:26]1[CH:27]=[C:28]([NH:32][C:33]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C=Nc1cccc(F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(F)c1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 3-fluorophenyl isocyanate (0.139 ml, 1.22 mmol), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 187 mg (60.1%) of the desired product as a solid.
Reaction SMILES: C([N:3](CC)CC)C.[OH:8][CH:9]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)/[CH:10]=[CH:11]/[C@H:12]1[CH2:17][CH2:16][CH2:15][C:14](=[O:18])[N:13]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26].ClC(OCC)=O.N>C(Cl)Cl.CCOC(C)=O>[OH:8][CH:9]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)/[CH:10]=[CH:11]/[C@H:12]1[CH2:17][CH2:16][CH2:15][C:14](=[O:18])[N:13]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH2:3])=[O:26]
Reactant: CCN(CC)CC
Reactant: O=C(O)CCCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Agent: CCOC(=O)Cl
Agent: N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC(=O)CCCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
Triethylamine (9 μL, 0.065 mmol) was added to a solution of 7-[(R)-2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acid (11.3 mg, 0.030 mmol) in CH2Cl2 (0.3 mL) at rt. After cooling to 0° C., ethyl chloroformate (3.2 μL, 0.033 mmol) was added. After 1 h at 0° C., a solution of ammonia (0.5 M in 1,4-dioxane, 0.3 mL, 0.15 mmol) was added and the reaction mixture was allowed to warm to rt. After 18 h at rt, the reaction mixture was diluted with EtOAc (10 mL) and washed with aqueous HCl (0.5 M, 3 mL), saturated aqueous NaHCO3 (5 mL) and brine (5 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→3% MeOH/CH2Cl2, gradient) afforded 3.5 mg (31%) of the title compound.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].O.[F:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[CH:25][CH:26]=1>O1CCCC1>[C:15]([O:14][C:12]([NH:7][C@H:6]([CH2:10][CH2:9][C:8]([C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([F:20])[CH:26]=1)=[O:11])[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Fc1cccc([Mg]Br)c1
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](CCC(=O)c1cccc(F)c1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (4.0 g) in tetrahydrofuran (100 mL), 3-fluorophenylmagnesium bromide (1.0 M solution in tetrahydrofuran; 17.1 mL) was added dropwise at −40° C. over 10 minutes, and the reaction solution was stirred at −40° C. to 0° C. for one hour. Water was added to the solution in small portions at 0° C., followed by extraction from the reaction solution with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 5.5 g of the title compound as a colorless oil. The property values of the compound are as follows.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([CH3:11])=[CH:6][C:5]=1[C:12]1[NH:16][N:15]([CH3:17])[C:14](=[O:18])[CH:13]=1.Cl[CH:20]([F:22])[F:21]>O.O1CCOCC1>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([CH3:11])=[CH:6][C:5]=1[C:12]1[CH:13]=[C:14]([O:18][CH:20]([F:22])[F:21])[N:15]([CH3:17])[N:16]=1
Reactant: FC(F)Cl
Reactant: Cc1cc(-c2cc(=O)n(C)[nH]2)c(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2cc(OC(F)F)n(C)n2)c(Cl)cc1Cl

Procedure:
28.8 g (720 mmol) of sodium hydroxide dissolved in 240 ml of water were added to a solution of 37 g (144 mmol) of 5-(2,4-dichloro-5-methylphenyl)-1,2-dihydro-2-methyl-3H-pyrazol-3-one in 390 ml of dioxane. Chlorodifluoromethane was subsequently passed in at 60-65° C. in the course of 4 hours, whereupon the reaction solution was stirred into 1 l of water. It was then extracted using methyl tert-butyl ether. The organic phase was dried over magnesium sulfate, filtered and then concentrated. The crude product was purified by means of column chromatography on silica gel (eluent: diethyl ether). Yield: 35.1 g.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11]1>>[OH:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[C:11]2/[C:10](=[O:15])[CH2:14][CH2:13][CH2:12]/2)=[CH:4][CH:3]=1
Reactant: O=C1CCCC1
Reactant: O=Cc1ccc(O)cc1
Product: O=C1CCC/C1=C\c1ccc(O)cc1

Procedure:
The procedure was similar to that in Example 4 by reacting 4-hydroxybenzaldehyde with the morpholine enamine of cyclopentanone to give 2-(E)-[(4-hydroxy) benzylidene]cyclopentanone. The melting point of this intermediate compound was determined to be 188°-190° C. A subsequent Mannich reaction yielded the 2-Dimethylaminomethyl-5-(E)-[(4-hydroxy) benzylidene] cyclopentanone hydrochloride. The melting point of the product was determined to be 174°-175° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[C:16](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:11][C:10](=[O:12])[N:9]([CH3:16])[C:8]2=[O:13])=[CH:4][CH:3]=1
Reactant: O=C1CN(Cc2ccc(Br)cc2)C(=O)N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)CN(Cc2ccc(Br)cc2)C1=O
Temperature: 50 °C
Reaction time: 48 h
Yield: 83.2 %

Procedure:
1-(4-Bromobenzyl)imidazolidine-2,4-dione (1B4) (1.86 mmol, 500 mg) was dissolved in DMF (7 ml) and potassium carbonate (5.57 mmol, 770 mg) and iodomethane (1B5) (1.86 mmol, 0.116 ml, 264 mg) were added and the reaction mixture was stirred at 50° C. under nitrogen. The reaction was monitored by TLC and after 48 h of heating some starting material remained. An additional 2 equivalents of iodomethane (3.72 mmol, 0.232 ml, 528 mg) was added and the mixture stirred at 75° C. under nitrogen overnight. The reaction mixture was cooled to room temperature, filtrated and concentrated, then purified on silica eluting with heptane/EtOAc/EtOH 5/4/1 to give 1-(4-bromobenzyl)-3-methylimidazolidine-2,4-dione (1B6) 438 mg, (83%); 1H NMR (400 MHz, CDCl3) 7.51 (d, 2H) 7.15 (d, 2H) 4.53 (s, 2H) 3.74 (s, 2H) 3.06 (s, 3H).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[N:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[N:20][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:22][CH:23]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(S(C)(=O)=O)nc3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(Nc3ccc(S(C)(=O)=O)nc3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
N-tert-Butyl-2-(6-(methylsulfonyl)pyridin-3-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (97 mg, 187 μmol) was dissolved in dichloromethane (2.88 mL) and treated with trifluoroacetic acid (426 mg, 288 μL, 3.74 mmol). The mixture was stirred at room temperature for 16 h. The mixture was concentrated then re-dissolved in dichloromethane (3 mL), methanol (1.5 mL) and ammonium hydroxide (0.5 mL) and the mixture stirred at room temperature for 1 h. The mixture was concentrated in vacuo then triturated with water and filtered. The solid obtained was washed with ether then dried to give N-tert-butyl-2-(6-(methylsulfonyl)pyridin-3-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (71 mg, 183 μmol, 98%) as a yellow solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.51 (s, 1H), 10.26 (s, 1H), 8.99 (d, J=2.5, 1 H), 8.37 (dd, J=8.4, 2.7, 1 H), 8.14 (s, 1H), 8.11 (s, 1H), 7.92 (d, J=8.7, 1 H), 7.62 (s, 1H), 3.21 (s, 3H), 1.45 (s, 9H); MS (EI/CI) m/z: 389.2 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH3:14])=[CH:8][CH:7]=1)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:28][S:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)(=[O:31])=[O:30].[H-].[Na+]>CN(C)C=O.O>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH3:14])=[CH:8][CH:7]=1)[C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([S:29]([CH3:28])(=[O:31])=[O:30])=[CH:40][CH:39]=1)[CH3:2]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CCOC(=O)Cc1ccc(OCC)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)c1ccc(S(C)(=O)=O)cc1)c1ccc(OCC)cc1
Yield: 96.2 %

Procedure:
499 mg of 4-ethoxyphenylacetic acid ethyl ester, 480 mg of carbonyldiimidazole, and 0.5 g of 4-methanesulfonyl benzoic acid were dissolved in 10 ml of dimethy formamide, and 119 mg of sodium hydride were slowly added dropwise to the solution and the mixture was reacted at the room temperature for 12 hours. Afterwards, water was added to dilute the resultant, followed by extraction with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate to give 0.9 g of the titled compound as a light yellow liquid (yield 92%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Cl[Si:10]([CH3:13])([CH3:12])[CH3:11]>C[Si](C)(C)N[Si](C)(C)C>[I:1][C:2]1[CH:3]=[N:4][C:5]([O:8][Si:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=c1ncc(I)c[nH]1
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: C[Si](C)(C)Oc1ncc(I)cn1

Procedure:
A suspension of 15.06 g (67.83 mmol) of 5-iodo-2(1H)-pyrimidinone was refluxed in 40 ml of hexamethyldisilazane and 2 ml of chlorotrimethylsilane for 1 hour. The excess reagent was removed in vacuo to yield a yellow oil 5-iodo-2-trimethylsilyloxypyrimidine, which was dissolved with 30 ml of dry degassed triethylamine. To this solution was added 11.5 ml (81.37 mmol) of trimethylsilylacetylene, 0.32 g (2.5 mol%) of CuI and 0.48 g (1 mol %) of (O3P)2PdCl2. The reaction mixture was stirred under nitrogen, at room temperature, for 3 days and diluted with 100 ml of dry THF. The mixture was filtered under dry nitrogen; the precipitate washed several times with dry THF and the filtrate was concentrated to a residue. The latter was treated with methanol to give a white crystalline, chromatographically homogeneous material 5-(2-Trimethylsilyl)ethynyl-2(1H)-pyrimidinone (9.99 g, 76.6%). Analytically pure material could be obtained by recrystallization from methanol; mp 203°-206° C.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([N+:13]([O-:15])=[O:14])[C:7]=1Cl)(=[O:5])=[O:4].[H-].[Na+].[OH2:20]>>[CH3:1][N:2]([CH3:17])[S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([N+:13]([O-:15])=[O:14])[C:7]=1[OH:20])(=[O:5])=[O:4]
Reactant: O
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: [H-]
Agent: [Na+]
Product: CN(C)S(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Temperature: 35 °C
Reaction time: 16 h
Yield: 92.8 %

Procedure:
A mixture of N,N-dimethyl-2,6-dichloro-3-nitrobenzenesulfonamide (2.64 g, 8.83 mmol), 60% sodium hydride (1.06 g, 26.5 mmol) and water (191 mg, 10.6 mmol) was heated to 35° C. while kept under argon atmosphere for 16 hours. The solvent was evaporated. when The reaction was almost complete as indicated by 1H NMR. The residue was diluted with ethyl acetate and washed with 1N aq. HCl. The solvent was concentrated to give the crude material. Column chromatography on silica gel, eluting with ethyl acetate/hexane/acetic acid (40/58/2, v/v/v), gave the desired product (2.3 g, 93%). EI-MS (m/z)279.5 (M−).
Reaction SMILES: [C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][NH:16][C:17]2[CH:29]=[CH:28][C:20]3[O:21][C:22]([CH3:27])([CH3:26])[O:23][C:24](=[O:25])[C:19]=3[CH:18]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:32]1([CH2:37][CH2:38][C:39](Cl)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:37][CH2:38][C:39]([N:16]([CH2:15][C:14]2[CH:30]=[CH:31][C:11]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:12][CH:13]=2)[C:17]2[CH:29]=[CH:28][C:20]3[O:21][C:22]([CH3:26])([CH3:27])[O:23][C:24](=[O:25])[C:19]=3[CH:18]=2)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CCCCCCCCC#Cc1ccc(CNc2ccc3c(c2)C(=O)OC(C)(C)O3)cc1
Reactant: O=C(Cl)CCC1CCCC1
Product: CCCCCCCCC#Cc1ccc(CN(C(=O)CCC2CCCC2)c2ccc3c(c2)C(=O)OC(C)(C)O3)cc1

Procedure:
The title compound was prepared following the procedure B using 6-[(4-dec-1-ynylbenzyl)amino]-2,2-dimethyl-4H-1,3-benzodioxin-4-one and 3-cyclopentylpropanoyl chloride (purification by flash chromatography on SiO2 EtOAc/c-Hex 20/80) as a colorless oil (97%). 1H NMR (CDCl3) δ: 7.68 (d, J=2.3 Hz, 1H), 7.30 (d, J=7.7 Hz, 2H), 7.09 (d, J=7.7 Hz, 2H), 7.06-6.99 (m, 1H), 6.90 (d, J=8.7 Hz, 1H), 4.85 (s, 2H), 2.39 (t, J=7.2 Hz, 2H), 2.13-2.01 (m, 2H), 1.75 (s, 6H), 1.70-1.20 (m, 21H), 1.04-0.83 (m, 5H). HPLC, Rt: 6.6 min (purity: 99.7%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2].Br[C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>>[CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH:11][C:22]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=2[C:31]([F:32])([F:34])[F:33])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)c(Br)c1
Reactant: CCOC(Cn1nc(-c2cccnc2)cc1N)OCC
Product: CCOC(Cn1nc(-c2cccnc2)cc1Nc1cc([N+](=O)[O-])ccc1C(F)(F)F)OCC

Procedure:
Analogously to Example 13A/Step 1, 1.50 g (5.43 mmol) of the compound of Example 4A and 1.47 g (5.43 mmol) of 2-bromo-4-nitro-1-(trifluoromethyl)benzene gave 2.03 g (75% of theory) of the title compound.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH3:11][N:12]([CH3:17])[CH:13]=[CH:14][C:15]#[N:16].[OH-].[Na+]>ClCCCl>[C:15]([C:14](=[CH:13][N:12]([CH3:17])[CH3:11])[CH:3]=[O:4])#[N:16]
Reactant: CN(C)C=O
Reactant: CN(C)C=CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=C(C#N)C=O
Temperature: 25 °C

Procedure:
36 ml. (0.465 mole) Of N,N-dimethylformamide were stirred at 0° and 36 ml. (0.392 mole) of phosphorus oxychloride were added dropwise (a salt/ice bath was used in order to keep the reaction mixture at 0°). To the stirring semi-solid, faintly colored reaction mixture was added 300 ml. of 1,2-dichloroethane. Upon warming to room temperature by means of a water bath (25°), a clear solution resulted which was cooled to -7° with an ice/salt bath. A solution of 30 ml. (0.293 mole) of β-dimethylaminoacrylonitrile in 90 ml. of 1,2-dichloroethane was added dropwise keeping the temperature between -4° to -7°. The addition required about 1 hour. The cooling bath was removed and the clear amber reaction mixture allowed to come to room temperature. The reaction mixture was transferred to a 2 liter, round bottomed flask and the solvent removed in vacuo leaving a semi-solid orange colored residue. A 100 g. of ice was added to the residue which gradually dissolved with evolution of heat. The solution was transferred to a beaker and the pH adjusted to 8.4 by adding carefully 2N sodium hydroxide (815 ml. were required) to the stirred solution at 15°-20°. The resulting solution was extracted with ethyl acetate in a liquid-liquid extractor overnight. The ethyl acetate extract was cooled, the crystals which had separated were filtered off, washed with cold ethyl acetate and dried in vacuo, affording crude 2-cyano-3-dimethylaminoacrolein, as deep yellow prisms, m.p. 143°-144°. This material was dissolved in 500 ml. of hot water, treated with 2 g. of norite, the solvent removed in vacuo and the residue crystallized from absolute ethanol, producing the pure product in the form of light yellow prisms, m.p. 143°-144°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:21])[CH:11]=[C:12]([CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][NH2:23].CO>ClCCl>[CH2:1]([O:8][C:9]1[C:10](=[O:21])[CH:11]=[C:12]([CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[N:23]([CH3:22])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=c1cc(C(O)C(F)(F)F)occ1OCc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: Cn1cc(OCc2ccccc2)c(=O)cc1C(O)C(F)(F)F
Reaction time: 1 h
Yield: 77 %

Procedure:
In each of four parallel synthesis tubes equipped with a magnetic stir bar was placed 5-benzyloxy-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-pyran-4-one (0.90 g, 3.0 mmol), and a 2M methylamine solution in MeOH (5.5 mL, 11 mmol). The resulting solution was heated to reflux. The reaction was completed in 60 min. The solutions from the four reaction tubes were combined, and evaporated to dryness to give a semi solid mixture. The mixture was taken up in dichloromethane (15 mL) to give a thick solution. On standing, a solid product precipitated out to give the first crop of the title compound (2.90 g, 77% yield, HPLC Method 1 (Example 24); RT=13.0 min, HPLC purity (peak percent area): 99.5% at λ=280 nm). 1H NMR (DMSO-d6+D2O) δ ppm: 7.64 (s, 1H), 7.37 (m, 5H), 6.49 (s, 1H), 5.38 (q, J=6.5 Hz, 1H), 4.97 (s, 2H), 3.69 (s, 3H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[C:23]([O:22][C:20]([N:17]1[CH2:16][CH2:15][CH:14]([CH2:13][N:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[S:2]([CH3:1])(=[O:4])=[O:3])[CH2:19][CH2:18]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(CN(c2ccccc2)S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
Methanesulfonyl chloride (0.77 mL, 1.13 g, 9.9 mmol) was added dropwise to a stirred, cooled (0° C.) solution of N-phenyl-1-t-butoxycarbonylpiperidine-4-methylamine (2.61 g, 9 mmol) and pyridine (1.09 mL, 1.07 g, 13.5 mmol) in dichloromethane (50 mL) and the mixture was stirred at room temperature for 16 h. The mixture was cooled in ice and 4-dimethylaminopyridine (220 mg, 1.8 mmol), pyridine (1.09 mL, 1.07 g, 13.5 mmol) and methanesulfonyl chloride (0.77 mL, 1.13 g, 9.9 mmol) were added. The mixture was stirred at room temperature for 24 h. The solvent was evaporated under reduced pressure, aqueous sodium hydrogen carbonate (saturated, 50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic fractions were washed with aqueous citric acid (10%, 2×50 mL), aqueous sodium hydrogen carbonate (saturated, 50 mL) and brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane (2:1, 30 mL) to give the title compound as a colorless solid (2.96 g, 89%), δH (250 MHz, CDCl3) 7.46-7.31 (5H, m), 4.06 (2H, m), 3.56 (2H, d, J 7.2 Hz), 2.85 (3H, s), 2.60 (2H, m), 1.71 (2H, m), 1.57 (1H, m), 1.43 (9H, s), and 1.05 (2H, m).
Reaction SMILES: [OH:1][NH:2][CH2:3][CH2:4][CH2:5][P:6](=[O:9])([OH:8])[OH:7].S(O)(O)(=O)=O.CS[C:17](=[NH:19])[NH2:18]>[OH-].[Na+].O>[OH:1][N:2]([CH2:3][CH2:4][CH2:5][P:6](=[O:8])([OH:7])[OH:9])[C:17]([NH2:19])=[NH:18]
Reactant: O=P(O)(O)CCCNO
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N=C(N)N(O)CCCP(=O)(O)O
Reaction time: 8 h
Yield: 47.1 %

Procedure:
A mixture of 3-(N-hydroxyamino)propylphosphonic acid (1.64 g.) in 1N aqueous sodium hydroxide solution (10 ml.) and S-methylisothiourea sulfate (1.40 g.) in water (5 ml.) was heated to reflux for 1.5 hours and allowed to stand overnight at ambient temperature to give crystalline precipitates, which was collected by filtration and washed with water and then with ethanol to give 3-(1-hydroxyguanidino)propylphosphonic acid (690 mg.), mp: 244°-247° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([NH:12][CH2:13][CH2:14][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][CH3:28])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].C(O)C.[OH-].[K+].Cl>O>[F:1][C:2]1[CH:11]=[C:10]([NH:12][CH2:13][CH2:14][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][CH3:28])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC)c(F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)c(F)c1

Procedure:
A mixture of 3.5 g of methyl 2-fluoro-4-hexadecylaminobenzoate, 40 ml of ethanol, 60 ml of water, and 3.8 g of potassium hydroxide is heated on a steam bath for 14 hours. The hot solution is acidified with concentrated hydrochloric acid. The reaction mixture is cooled and filtered. The colorless residue is recrystallized from chloroform-hexane to yield 2-fluoro-4-(hexadecylamino)benzoic acid as a white solid.