Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[C:10]([C:12]1[C:13]([CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:14][C:15]([CH2:21][CH:22]([CH3:24])[CH3:23])=[C:16]([CH2:18][C:19]#[N:20])[CH:17]=1)#[N:11]>>[C:10]([C:12]1[C:13]([CH2:25][CH:26]([CH3:28])[CH3:27])=[C:14]([N+:6]([O-:9])=[O:7])[C:15]([CH2:21][CH:22]([CH3:23])[CH3:24])=[C:16]([CH2:18][C:19]#[N:20])[CH:17]=1)#[N:11]
Reactant: CC(C)Cc1cc(CC(C)C)c(CC#N)cc1C#N
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(C)Cc1c(C#N)cc(CC#N)c(CC(C)C)c1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
A round bottom flask is charged with 25 parts of 98% sulfuric acid and 25 parts of 20% fuming sulfuric acid and cooled to 0°; then, 20 parts of 90% fuming nitric acid is added. Twenty parts of 5-cyano-2,4-diisobutylbenzeneacetonitrile is added in portions, and the mixture is warmed to 50° with stirring. After two hours, the solution is poured onto ice and the precipitate of 5-cyano-2,4-diisobutyl-3-nitrobenzeneacetonitrile is collected and dried.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=CC=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].N1CCC(C2C3C(=C(C(N)=O)C=C(C4C=C[S:49]C=4)C=3)NC=2)CC1.C(N(CC)CC)C.ClCCCS(Cl)(=O)=O>>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:24]=[CH:25][S:49][CH:28]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:6])=[O:7]
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCNCC3)c[nH]c12
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: O=S(=O)(Cl)CCCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Yield: 37 %

Procedure:
The title compound was prepared according to the general procedure for intermediate 11. 3-(4-piperidinyl)-5-(3-thienyl)-1H-indole-7-carboxamide (220 mg, 0.67 mmol) was reacted with triethyl amine (0.4 mL, 2.68 mmol) and 3-chloropropylsulfonyl chloride (0.12 mL, 1.01 mmol) to give the title compound (117 mg, 37%)
Reaction SMILES: [CH2:1]([Cl:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([F:18])([F:17])[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.CC(OC)(C)C>C(#N)C>[Cl-:8].[CH2:1]([N+:14]1[CH:15]=[CH:16][C:11]([C:10]([F:18])([F:17])[F:9])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: FC(F)(F)c1ccncc1
Solvent: COC(C)(C)C
Solvent: CC#N
Product: FC(F)(F)c1cc[n+](Cc2ccccc2)cc1
Product: [Cl-]
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 7.59 mL (65.94 mmol) benzyl chloride in 10 mL of acetonitrile was added to a solution of 10.00 g (65.94 mmol) of 4-trifluoromethylpyridine in 40 mL of acetonitrile and the mixture was stirred for 2 hours at 80° C. Another 1.5 mL of benzyl chloride was added and the mixture was stirred for 22 hours at 80° C. The reaction mixture was cooled to RT and combined with MTBE. The precipitate was filtered off, washed with MTBE, dried in vacuo, and stored in the desiccator. Yield: 14.48 g (80% of theoretical); C13H11F3N.Cl (M=273.681); calc.: molpeak (M+H)+: 238; found: molpeak (M+H)+: 238.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]>>[CH3:15][C:14]([CH3:17])([CH3:16])[C:13]([O:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([O:10][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C:3]1([CH3:12])[CH3:11])=[O:18]
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)(C)C(=O)OC1CC(C)(C)N(OC(=O)C(C)(C)C)C(C)(C)C1
Yield: 67 %

Procedure:
Using 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine, prepared as described by: Paleos C. M. et al., loc. cit., and pivaloyl chloride in a procedure otherwise similar to the preparation of the compound 101 gives a 67% yield of the compound 108 which is obtained in the form of colourless crystal; melting point: 43–46° C. (pentane).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:27]=1[NH:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([N:28]([CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]2[C:37]([CH3:41])=[CH:38][CH:39]=[CH:40][C:26]=2[CH3:25])=[O:21])[C:9]2[C:10]([CH3:16])=[CH:11][CH:12]=[CH:13][C:14]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCNc1c(C)cccc1C
Reactant: Cc1cccc(C)c1N(CCCC(=O)O)C(=O)c1ccc(Cl)cc1
Product: CCOC(=O)CCCN(C(=O)CCCN(C(=O)c1ccc(Cl)cc1)c1c(C)cccc1C)c1c(C)cccc1C

Procedure:
Analogously to Example 1, using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyric acid and ethyl 4-(2,6-dimethylanilino)butyrate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyryl]-4-(2,6-dimethylanilino)butyrate (M.P. 95° to 97°), the saponification of which and the processing of the reaction product yields N-[N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyryl]-4-(2,6-dimethylanilino)butyric acid (M.P. 129° to 131°).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].CS(C)=O.C(=O)([O-])[O-].[K+].[K+].[NH2:21][C@@H:22]([CH3:25])[CH2:23][OH:24]>O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:21][C@@H:22]([CH3:25])[CH2:23][OH:24])([O-:10])=[O:9]
Reactant: C[C@H](N)CO
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@@H](CO)Nc1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 104.5 %

Procedure:
A 200-mL round bottomed flask equipped with a magnetic stir bar was charged with 1-fluoro-2-nitrobenzene (8.25 g, 58.5 mmol), DMSO (29 mL), potassium carbonate (8.89 g, 64.3 mmol), and (S)-2-aminopropane-1-ol (4.83 g, 64.3 mmol). The mixture was heated to 60° C. for 6 h and then cooled to room temperature. The reaction mixture was diluted with water (60 mL). The mixture was stirred for several minutes, then extracted with ethyl acetate (ca. 200-250 mL). The ethyl acetate extract was washed thrice with 5 wt % aqueous sodium chloride (3×50 mL) and concentrated under reduced pressure to afford crude (S)-2-(2-nitrophenylamino)propane-1-ol (12.0 g, 105%) as a bright orange syrup. MS (ESI, pos. ion) m/z 197 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH:10]([OH:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[N:15][OH:16])[CH:10]([OH:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(O)C(=O)c1ccc(F)c(F)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(O)C(=NO)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a well stirred solution of 1-(3,4-difluorophenyl)-2-hydroxy-propan-1-one (5.5 g, 29.6 mmol) in MeOH (200 mL) was added hydroxylamine hydrochloride (2.6 g, 38.4 mmol) and sodium acetate (8.1 g, 59.2 mmol) and the turbid solution was stirred overnight at room temperature. The solvent was evaporated and the residue was extracted with CH2Cl2. The organic layer was washed with sat. NaHCO3, separated, dried over NaSO4 and then filtered. The solvent was removed in vacuo to obtain 1-(3,4-Difluorophenyl)-2-hydroxy-propan-1-one-oxime as an orangish yellow oil (5.3 g, 97%). It was used in the next step without purification.
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[C:29]4[O:28][CH2:27][CH2:26][NH:25][CH2:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)[N:15]=2)=[CH:10][C:7]=1[C:8]#[N:9])[CH3:4].C(N(CC)C(C)C)(C)C.Br[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>C(#N)C>[C:8]([C:7]1[CH:10]=[C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[C:29]4[O:28][CH2:27][CH2:26][N:25]([CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)[N:15]=2)[CH:12]=[CH:13][C:6]=1[O:5][CH:3]([CH3:2])[CH3:4])#[N:9]
Reactant: CCOC(=O)CCBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3OCCNC4)no2)cc1C#N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CCN1CCOc2c(cccc2-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)C1
Temperature: 80 °C
Yield: 38.5 %

Procedure:
To a solution of 2-[(1-methylethyl)oxy]-5-[3-(2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)-1,2,4-oxadiazol-5-yl]benzonitrile hydrochloride (Example 32) (90 mg, 0.218 mmol) in acetonitrile (10 ml) was added N,N-diisopropylethylamine (0.076 ml, 0.436 mmol) followed by ethyl 3-bromopropanoate (0.056 ml, 0.436 mmol). The reaction mixture was heated at 80° C. overnight. A further 1 equivalent of N,N-diisopropylethylamine and ethyl 3-bromopropanoate were added and heating continued overnight. The reaction mixture was cooled and evaporated. Purification of the residue by column chromatography on silica, eluting with 60-70% ethyl acetate in cyclohexane to give the title compound as a brown oil (40 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:13][CH3:14])[C:9]([F:12])([F:11])[F:10])=[N:6][CH:7]=1.[F:15][CH:16]([F:43])[C:17]([N:19]1[C@H:23]([CH2:24][F:25])[C@@H:22]([C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[O:21]C1(C)C)=[O:18].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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:15][CH:16]([F:43])[C:17]([NH:19][C@H:23]([CH2:24][F:25])[C@H:22]([OH:21])[C:26]1[CH:27]=[CH:28][C:29]([C:2]2[CH:7]=[N:6][C:5]([CH:8]([NH:13][CH3:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=2)=[CH:30][CH:31]=1)=[O:18]
Reactant: CNC(c1ccc(Br)cn1)C(F)(F)F
Reactant: CC1(C)O[C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@@H](CF)N1C(=O)C(F)F
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CNC(c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1)C(F)(F)F
Temperature: 80 °C
Yield: 98.8 %

Procedure:
To a stirred solution of [1-(5-Bromo-pyridin-2-yl)-2,2,2-trifluoro-ethyl]-methyl-amine (0.075 g, 0.279 mmol) and 2,2-Difluoro-1-{(4S,5R)-4-fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidin-3-yl}-ethanone (0.115 g, 0.279 mmol) in toluene:ethanol:water (3:3:3 mL) is added Na2CO3 (0.073 g, 0.697 mmol) at room temperature. Resulting reaction mixture is degassed with nitrogen for 30 minutes followed by addition of Pd(PPh3)4 (0.032 g, 0.028 mmol) and heated to 80° C. for 3 h. The reaction mixture is concentrated in vacuo then is diluted with water and extracted with ethyl acetate. Organic layer is dried over sodium sulphate and evaporated in vacuum. The crude material is purified by Combi-flash eluting in 20% ethyl acetate in hexane afford the title compound (0.120 g). 1H-NMR (400 MHz, DMSO) δ: 1.52 (s, 3H), 1.60 (s, 3H), 2.25 (d, J=5.76 Hz, 3H), 3.01-3.05 (m, 1H), 4.44-4.48 (m, 1H), 4.56-4.58 (m, 0.5H), 4.67-4.72 (m, 1H), 4.81-4.88 (m, 0.5H), 4.90-5.00 (m, 1H), 5.27 (d, J=3.68 Hz, 1H), 6.65 (t, J=52.36 Hz, 1H), 7.60 (d, J=8.24 Hz, 2H), 7.98-8.00 (dd, J1=2.04 Hz, J2=8.2 Hz, 1H), 8.06 (d, J=8.24 Hz, 1H), 8.15 (d, J=8.32, 2H), 8.73 (d, J=1.8 Hz, 1H). LC-MS (m/z): [M−H]=476.0.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[N+:9]([O-])[C:8]([C:13]#[N:14])=[CH:7][CH:6]=2.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:6]1[C:5]2[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:9]=[C:8]([C:13]#[N:14])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2ccc(C#N)[n+]([O-])c2c1
Product: Cc1ccc2c(Cl)cc(C#N)nc2c1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
A mixture of 7-methylquinoline-2-carbonitrile 1-oxide (11.5 g, 63 mmol) and phosphorus oxychloride (47 mL, 500 mmol) was heated at 100° C. for 10 min then at 200° C. for 20 min. The reaction mixture was poured into crushed ice and the precipitate was filtered. The crude material was then purified by flash chromatography on silica gel (eluting solvent: 3% acetone in dichloromethane) to provide the title compound. 1HNMR (400 MHz, acetone-d6): δ 8.25 (d, 1H), 8.10 (s, 1H), 8.00 (d, 1H), 7.82 (dd, 1H), 2.65 (s, 3H).
Reaction SMILES: C([NH:3][C@@H:4]1[C:27](=[O:28])[N:6]2[C:7]([C:24]([O-:26])=[O:25])=[C:8]([CH2:11][N+:12]([CH3:23])([CH3:22])[CH2:13][C:14]3[NH:15][CH:16]=[C:17]([OH:21])[C:18](=[O:20])[CH:19]=3)[CH2:9][S:10][C@H:5]12)=O.[ClH:29].C(OCC)(=O)C>C(O)=O>[ClH:29].[ClH:29].[NH2:3][C@@H:4]1[C:27](=[O:28])[N:6]2[C:7]([C:24]([O-:26])=[O:25])=[C:8]([CH2:11][N+:12]([CH3:23])([CH3:22])[CH2:13][C:14]3[NH:15][CH:16]=[C:17]([OH:21])[C:18](=[O:20])[CH:19]=3)[CH2:9][S:10][C@H:5]12
Reactant: C[N+](C)(CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC=O)[C@H]2SC1)Cc1cc(=O)c(O)c[nH]1
Agent: Cl
Solvent: O=CO
Solvent: CCOC(C)=O
Product: C[N+](C)(CC1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1)Cc1cc(=O)c(O)c[nH]1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a cooled solution of 7β-formamido-3-[N,N-dimethyl-N-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)methyl}ammonio]methyl-3-cephem-4-carboxylate (4.084 g) in formic acid (8.1 ml) was added dropwise conc. hydrochloric acid (2.5 ml). The mixture was warmed to room temperature and stirred for 2.5 hours. The mixture was added dropwise to ethyl acetate (400 ml) and the supernatant was decanted. The residual oil was dissolved in methanol (50 ml) and the solution was poured into ethyl acetate (600 ml). The resulting precipitates were collected by filtration, washed with ethyl acetate and diisopropyl ether and dried in vacuo. The powder was dissolved in cold water (28 ml) and chromatographed on Diaion HP-20 (28 ml) at 5° C., and the elution was carried out with water. To the eluate (30 ml) was added dropwise cold isopropyl alcohol (19 ml) under cooling and the mixture was stirred at 5° C. for an hour. The resultant crystal was collected by filtration washed with a cooled mixture of isopropyl alcohol and water (10:1) and cold isopropyl alcohol, and dried in vacuo to give 7β-amino-3-[N,N-dimethyl-N-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)methyl}ammonio]methyl-3-cephem-4carboxylate dihydrochloride (728 mg).
Reaction SMILES: [O:1]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[CH2:22]([Sn](=O)CCCC)[CH2:23][CH2:24]C.C(Br)C=C>C1C=CC=CC=1.[Br-].C([N+](CC)(CC)CC)C>[CH2:24]([O:6][C@H:5]1[C@@H:7]([OH:8])[C@@H:9]([CH2:11][OH:12])[O:10][C@@H:2]([O:1][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[C@@H:3]1[OH:4])[CH:23]=[CH2:22]
Reactant: CCCC[Sn](=O)CCCC
Reactant: COC(=O)CCCCCO[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Solvent: C=CCBr
Solvent: c1ccccc1
Product: C=CCO[C@H]1[C@@H](O)[C@@H](CO)O[C@@H](OCCCCCC(=O)OC)[C@@H]1O
Temperature: 25 °C
Reaction time: 36 h
Yield: 71.7 %

Procedure:
Compound 2 was prepared from 1 according to the literature procedure (J. Carbohydr. Chem. 8 (1989) 145) as follows Compound 1 of Example 1 (20.0 g) was refluxed in anhydrous benzene (500 mL) containing 3Å molecular sieves (20 g) for 1 h followed by the addition of di-n-butyltin oxide (24.0 g) and the refluxing was continued for 4 more h. To this tetraethylammonium bromide (7.0 g) and allyl bromide (80 mL) were added and refluxed for another 1 h followed by stirring at room temperature for 36 h. The reaction mixture was evaporated to dryness and the product was extracted with CH2Cl2, washed with 10% aqueous KF solution, ice cold 1M hydrochloric acid (HCl) and saturated sodium bicarbonate (NaHCO3) solution. Chromatography of the crude product on a column of Silica gel using ethyl acetate-hexane-ethanol =10:10:1 as eluant gave the titled compound 2 (16.2 g). [ α]D25 -3.5±2° (c 0.96, CHCl3). 1H n.m.r. (CDCl3 +D2O<5%) ∂: 5.97 (m, --CH=C), 5.35, 5.30, 5.24 and 5.20 (m, CH2 =C), 4.23 (m, O--CH2 --C=, H-1, J1,2 =7.5 Hz), 4.05 (d, J=3.5 Hz, H-4), 3.96-3.80 and 3.50-3.40 (m, O--CH2 --C, H-6a,b, H-5), 3.72 (dd, J=7.5, 9.5 Hz, H-2), 3.36 (dd, J=3.5, 9.5 Hz, H-3), 2.32 (t, J=7.0 Hz, CH2COO), 1.64 and 1.40 ((6 H, hydrogens of pentyl group). 13C n.m.r.(CD3OD) ∂: 176.0, 136.7, 117.3, 105.1 (C-1), 82.6 (C-3), 76.6 (C-5), 71.94, 71.89, 70.6, 67.6 (C-4 ), 62.7 (C-6), 52.0, 34.9, 30.5, 26.8, 25.9. Anal. Calcd for C16H28O8 ·H2O: C, 52.46; H, 8.20. Found: 52.84; H, 7.93.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[N+:23]([O-:25])=[O:24])=[CH:10][CH:9]=1.[OH2:26]>C(#N)C>[F:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[N+:23]([O-:25])=[O:24])(=[O:1])=[O:26])=[CH:12][CH:13]=1
Reactant: O
Reactant: O=S([O-])OO
Reactant: O=[N+]([O-])c1cc(Br)ccc1CSc1ccc(F)cc1
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cc(Br)ccc1CS(=O)(=O)c1ccc(F)cc1
Reaction time: 5 h

Procedure:
A suspension of oxone (3.55 g) in water (8 ml) was added to a solution of (4-bromo-2-nitrophenyl)methyl 4-fluorophenyl sulfide (Intermediate 66) (0.52 g) in acetonitrile (10 ml). The mixture was stirred for 5 h filtered and the residue was washed with ethyl acetate. The biphasic filtrate was separated, the aqueous layer was re-extracted with ethyl acetate (2×50 ml) and the combined organic extracts were washed with aqueous sodium metabisulphite (5%, 100 ml) and brine. The dried (MgSO4) extracts were concentrated under vacuum to give the title compound (0.56 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: Nc1ccc(S(=O)(=O)O)cn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Nc1ncc(S(=O)(=O)O)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 1 h

Procedure:
6-Aminopyridine-3-sulfonic acid (20 g) in concentrated H2SO4 (80 mL) was heated at 50° C. until it was completely dissolved. To this solution was added fuming HNO3 dropwise over 20 minutes. The rate of addition was kept slow so that the internal temperature did not exceed 55° C. After the addition was complete, the reaction mixture was heated at 50° C. for 1 hour. After it cooled to room temperature, it was poured into 150 g of ice. The mixture was stirred for another 1 hour. The whole flask was cooled to 0° C., and was kept at 0° C. for another 2 hours. The solid was collected by filtration. The solid was washed with cold 1:1 water/ethanol (20 mL), followed by diethyl ether (10 mL). The solid was dried in a vacuum oven overnight to give the title compound.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].C(#N)C.Cl[C:9]([O:11][CH3:12])=[O:10].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][CH2:21][CH3:22])=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24]>O>[CH2:21]([S:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:2]([NH:3][C:9]([O:11][CH3:12])=[O:10])=[S:1])=[C:15]([N+:23]([O-:25])=[O:24])[CH:16]=1)[CH3:22]
Reactant: COC(=O)Cl
Reactant: N#C[S-]
Reactant: CCSc1ccc(N)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCSc1ccc(NC(=S)NC(=O)OC)c([N+](=O)[O-])c1
Temperature: 10 °C
Reaction time: 2 h
Yield: 39.2 %

Procedure:
A mixture of dry potassium thiocyanate (25.65 g.) and acetonitrile (320 ml.) was cooled to 10° C. and treated during 5 minutes with methyl chloroformate (25.0 g.). The mixture was stirred at room temperature for 2 hours. 1-Amino-4-ethylthio-2-nitrobenzene (22.45 g.) was then added to the mixture at 10°-15° C. The suspension was stirred for 3 hours at room temperature and allowed to stand overnight. It was then poured into water (1.6 liters) and the solid which precipitated was filtered off, washed with water and recrystallised from a mixture of methanol and ethanol, to give 4-ethylthio-1-(3-methoxycarbonyl-2-thioureido)-2-nitrobenzene (14.0 g.), m.p. 152° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=2)[C:4](=[O:5])[NH:3]1.ClC1C=C(N2C(=O)NNC2=O)C=C(Cl)C=1.CBr.[C:34](Cl)(=[O:36])[CH3:35]>CN(C)C=O.C(N(CC)CC)C>[CH3:1][N:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([Cl:15])[CH:14]=2)[C:4](=[O:5])[N:3]1[C:34](=[O:36])[CH3:35]
Reactant: Cn1[nH]c(=O)n(-c2cc(Cl)cc(Cl)c2)c1=O
Reactant: CC(=O)Cl
Agent: CBr
Agent: O=c1[nH][nH]c(=O)n1-c1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)n1c(=O)n(-c2cc(Cl)cc(Cl)c2)c(=O)n1C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a solution of 2.6 g of 1-methyl-4-(3',5'-dichlorophenyl) urazole, which had been prepared by reacting 4-(3',5'-dichlorophenyl) urazole and methyl bromide in an equimolar proportion, and 1.0 g of triethylamine in 10 ml of N,N-dimethylformamide was added 0.8 g of acetyl chloride in small increments at room temperature with agitation. After completing the addition, the reaction was carried out on a water bath for 2 hours with continued agitation. The solvent was removed by distillation into vacuo and the mass was poured in water to precipitate crystals which were recrystallized from ethanol to obtain 2.3 g of 1-methyl-2-acetyl-4-(3',5'-dichlorophenyl) urazole in a yield of 76%.
Reaction SMILES: CCN(CC)CC.[NH2:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[OH:16].Cl[CH2:18][C:19](Cl)=[O:20].[H-].[Na+]>C1COCC1>[Br:15][C:13]1[CH:12]=[CH:11][C:10]2[O:16][CH2:18][C:19](=[O:20])[NH:8][C:9]=2[CH:14]=1
Reactant: Nc1cc(Br)ccc1O
Reactant: O=C(Cl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1COc2ccc(Br)cc2N1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 72.2 %

Procedure:
NEt3 (2.4 mL, 17 mmol) was added to 2-amino-4-bromophenol (2.5 g, 13 mmol) in THF (80 mL). The reaction mixture was cooled to 0° C., chloroacetyl chloride (1.12 mL, 14 mmol) was added portionwise and then stirred at 0° C. for 10 minutes before being allowed to warm to r.t. and stirred for a further 2 h. The reaction mixture was cooled to 0° C. and NaH (1.05 g, 60% dispersion in oil, 26 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 20 minutes then at r.t. for 2 h before being quenched with water (20 mL). The solvent was removed in vacuo and the resulting mixture diluted with water (100 mL). The precipitate was filtered, washed with water (3×50 mL) and dried in vacuo to give the title compound (2.14 g, 70%) as a beige solid. δH (DMSO-d6) 10.81 (1H, br. s), 7.08 (1H, dd, J 8.5 Hz and J 2.3 Hz), 7.02 (1H, d, J 2.3 Hz), 6.92 (1H, d, J 8.5 Hz), 4.60 (2H, s).
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N>C1(C)C=CC=CC=1.CO.ClCCl>[C:13]1([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Ic1cccs1
Reactant: OB(O)c1ccccc1
Agent: N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1
Product: c1ccc(-c2cccs2)cc1
Temperature: 80 °C
Yield: 33.7 %

Procedure:
To a solution of 2-iodothiophene (2.8 ml, 25 mmol) and palladium tetrakistriphenylphosphine (866 mg, 0.75 mmol) in toluene (50 ml) under a nitrogen atmosphere was added aqueous sodium carbonate (2M, 25 ml) followed by a solution of phenylboronic acid (3.7 mg, 30 mmol) in methanol (12.5 ml). The vigorously stirred mixture was heated at 80° C. for 6 hours and then cooled to room temperature. Aqueous sodium carbonate (2M, 125 ml), dichloromethane (250 ml) and 0.88 ammonia solution (12 ml) were added to the reaction. The two phases were separated, and the aqueous phase extracted with dichloromethane (50 ml). The combined organic phases were washed with brine (80 ml), dried (MgSO4) and evaporated in vacuo to an oil. Purification by chromatography on silica gel eluting with hexane gave the title compound as a colourless oil (1.35 g, 36%) which solidified on standing. δH (CDCl3) 7.06-7.09 (1H, m, ArH), 7.25-7.31 (3H, m, ArH), 7.35-7.39 (2H, m, ArH, 7.60-7.62 (2H, m, ArH).