Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:19](N)=[NH:20].[OH-].[Na+]>>[CH3:14][O:13][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[O:11][CH3:12])[N:1]=[CH:19][NH:20][C:4]2=[O:5]
Reactant: N=CN
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cc2nc[nH]c(=O)c2cc1OC
Temperature: 140 °C
Yield: 75.4 %

Procedure:
A mixture of 2-amino-4,5-dimethoxybenzoic acid (1.0 g, 5.08 mmol) and formamidine acetate (4.50 g, 43.3 mmol) was disposed in a 50 mL ball. The solid mixture was heated at 140° C. in a silicone bath for eight hours. During heating, the fusion of solids happened, and then the resolidification of the reaction environment. The mixture was left cooling, and then a NaOH solution was added to it (0.33 mol.L−1) until pH was adjusted to 8. The grayish pink solid was collected through filtering in a Büchner funnel, washed with water (3×10 mL), and dried in vacuum to provide the desired compound (0.79 g, 3.83 mmol, 76%), which was used without purification in the next stage: m.p. 296-298° C. (Lit. (Bridges et al., J. Med. Chem. 1996, 39, 267), m.p. 295-298° C.).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].Cl.[CH3:27]O>>[CH3:27][O:10][C:9](=[O:11])[C:8]1[CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=1
Reactant: CO
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: Cl
Product: CCCCNc1cc(C(=O)OC)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 5 h

Procedure:
A mixture of 3-n-butylamino-4-phenoxy-5-sulphamyl-benzoic acid (3 g) and methanol (60 ml) was saturated with gaseous hydrogen chloride. The reaction mixture was allowed to warm during the saturation. After cooling and standing for 5 hours, the reaction mixture was evaporated in vacuo, and the residue was recrystallized from methanol (12 ml), whereby the methyl-3-n-butylamino-4-phenoxy-5-sulphamyl-benzoate was obtained with a melting point of 148° C.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>>[Br:1][C:2]1[O:6][C:5]([C:7]([Cl:12])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Br)o1
Product: O=C(Cl)c1ccc(Br)o1
Temperature: 90 °C

Procedure:
A mixture of 5-bromo-2-furancarboxylic acid (7.17 g, 37.54 mmol) and thionyl chloride (55 ml) is heated at 90° C. overnight. After the mixture has cooled to room temperature, the solvent is removed in vacuo, and the residue is washed with heptane. 5-Bromofuran-2-carbonyl chloride is obtained as a pale beige solid.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](=[O:28])[C:14]2[CH:19]=[CH:18][C:17]([O:20]CC3C=CC=CC=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C1CCCCC1>[OH-].[OH-].[Pd+2].C(O)C>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](=[O:28])[C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(OC(=O)c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCCCC1
Solvent: CCO
Product: CCCCCc1ccc(OC(=O)c2ccc(O)cc2)cc1
Yield: 93.2 %

Procedure:
15.6 g (41.5 mmol) of 4-benzyloxy-benzoic acid 4-pentyl-phenyl ester, 25 mL of cyclohexane and 0.78 g of palladium hydroxide/carbon were added to 100 mL of dehydrated ethanol and refluxed for 10 hours in the presence of argon. The resulting reaction mixture was filtered and the filtrate was concentrated. The residue was recrystallized from toluene to obtain 11.0 g of a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:8][CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCOCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(Tetrahydro-2H-pyran-4-yl)methanol (29.9 mg, 0.257 mmol) was dissolved in dichloromethane (DCM) (4 mL). To this solution was added triethylamine (0.108 mL, 0.772 mmol). The reaction was cooled to 0° C., methanesulfonyl chloride (0.03 mL, 0.386 mmol) added and the reaction left to stir overnight, allowing the reaction to warm to 20° C. The reaction was concentrated in vacuo. The product was partitioned between ethyl acetate (20 mL) and aqueous saturated sodium bicarbonate (20 mL). The organic phase was dried and concentrated in vacuo, before being used in the next reaction with no further purification or characterisation, 49 mg.
Reaction SMILES: [CH3:1][C:2]([O-:5])([CH3:4])[CH3:3].[K+].[CH:7]1([C:10](Cl)=[O:11])[CH2:9][CH2:8]1.C(=O)([O-])O.[Na+]>COC(C)(C)C>[C:2]([O:5][C:10]([CH:7]1[CH2:9][CH2:8]1)=[O:11])([CH3:4])([CH3:3])[CH3:1]
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)C1CC1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
219.1 g (1.91 mol, 1 eq.) potassium tert-butylate were suspended in 2.5 L tert-butyl methyl ether and cooled to 0-5° C. 200 g (1 eq.) cyclopropanecarbonyl chloride were added over 60 min, maintaining the temperature between 0-5° C. (ice-ethanol bath cooling). In-line FTIR reaction monitoring indicates a feed controlled reaction. The reaction mixture was stirred 30 min at 0-5° C. and 1 L of 5% aq. sodium hydrogencarbonate solution was added. The aqueous phase was separated and extracted with 500 ml tert-butyl methyl ether. The organic phases were washed with 500 ml half saturated aq. sodium chloride solution, combined and concentrated under reduced pressure (30° C./150 mbar) to provide 271 g of the title compound (91% yield corrected for 8% residual tert-butyl methyl ether).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[C:9]([N+:14]([O-])=O)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)([O-])=O.O.C.[H][H]>NC1C=CC=CC=1.[Pt]>[NH2:1][C:4]1[C:13]2[C:8](=[C:9]([NH2:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cccc2c([N+](=O)[O-])cccc12
Reactant: [H][H]
Agent: [Pt]
Solvent: O
Solvent: Nc1ccccc1
Product: Nc1cccc2c(N)cccc12
Temperature: 18 °C

Procedure:
60 g (0.275 mol) of 1,5-dinitro naphthalene were suspended, in a 700 ml stirrer autoclave, in 340 ml of aniline and treated with 18 g of water-moist, 1%-strength catalyst of platinum and activated charcoal corresponding to 8 g of dry catalyst. Hydrogenation was carried out at 50° C. and a hydrogen pressure of 10 bars, as was described in Example 1. The hydrogen uptake was finished after 2 hours. The catalyst was separated off by filtration at 80° C. and the aniline subsequently removed by water-vapour distillation. The distillation residue was cooled to 18° C. and the precipitated crystallate filtered off and dried. In this way 40 g (92% of the theory) of 1,5-diamino naphthalene of m.p. 188°-189° C. were obtained.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:13][CH2:14][CH3:15])[NH:8][C:9]=1[C:10]([OH:12])=[O:11])([CH3:4])[CH3:3].Cl.[CH2:17](O)[CH3:18]>>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:13][CH2:14][CH3:15])[NH:8][C:9]=1[C:10]([O:12][CH2:17][CH3:18])=[O:11])([CH3:4])[CH3:3]
Reactant: CCO
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)O)[nH]1
Agent: Cl
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Temperature: 35 °C
Yield: 82 %

Procedure:
3.0 grams of 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid (formula III) from Example 4, and 30 ml of ethanol were added into 100 ml three-necked flask, anhydrous hydrogen chloride gas was supplied while the temperature was maintained at 30-40° C. until the reaction completed. The reaction mixture was then allowed to cool to ambient temperature, the solvent was evaporated, 30 ml of ethyl acetate and 30 ml of water were added, and the mixture was adjusted to basic using sodium bicarbonate. The organic layer was separated and the aqueous layer was further extracted with 10 ml×3 of ethyl acetate. The organic portion was washed once with saturated saline solution, dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated to give 2.8 grams of ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylate, resulting in a yield of 82%.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]([C:30]2([CH:36]=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH2:31]2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[C:24]([C:30]5([CH:36]=[O:37])[CH:31]=[CH:32][CH:33]=[CH:34][CH2:35]5)[CH:25]=[CH:26][C:27]=4[O:28][CH3:29])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1ccc(C2(C=O)C=CC=CC2)cc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: CC#N
Product: COc1ccc(C2(C=O)C=CC=CC2)cc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2 benzisoxazole (2.01 g; 9.13 mmol), K2CO2 (2.0 g), and 1-[3-(3-chloropropoxy)-4-methoxy-phenyl]phenyl -methanone (3.93 g; 11.3 mmol) and acetonitrile (50 ml) was heated at reflux for 4 hours. At the end of the reaction, the solvent was evaporated and the residue was partitioned between water (150 ml) and dichloromethane (400 ml). The dichloromethane solution was washed with water and brine (100 ml), dried over MgSO4, then concentrated to an oil. The purification was done by flash chromatography over a silica gel column (SiO2, 40 g; eluted with dichloromethane, 300 ml; 1% methanol in dichloromethane, 850 ml). The material thus obtained as a colorless oil solidified on standing. Recrystallization from ethanol (150 ml) gave 1-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-4-methoxyphenyl]-phenylmethanone as white crystals, 3.07 g (63%), m.p.=140°-141° C.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].[CH2:18](O)[CH3:19]>>[F:5][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8]([O:10][CH2:18][CH3:19])=[O:9]
Reactant: CCO
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1F
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Under ice-cooling, thionyl chloride (8.02 mL) was added dropwise to ethanol (200 mL), and 2-fluoro-5-nitrobenzoic acid (13.81 g) was added. This mixture was stirred at 80° C. for 4 hrs. and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (15.77 g) as a pale-yellow oil.
Reaction SMILES: O.NN.[Cl:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][N:12]2C(=O)C3=CC=CC=C3C2=O)=[CH:7][CH:6]=1.Cl>C(O)C>[Cl:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(Cl)nc1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1ccc(Cl)nc1
Temperature: 20 °C
Yield: 91.2 %

Procedure:
Hydrazine hydrate (2.00 ml, 0.04 mol) was added at ambient temperature (20° C.) to a solution of N-(6-chloro-3-pyridylmethyl) phthalimide (10.70 g, 0.039 mol) in ethanol (150 ml), and the resulting solution was heated under reflux for 4 hours before being cooled to ambient temperature (20° C.). 25% w/v aqueous hydrochloric acid (60 ml) was added directly and the resulting mixture was heated under reflux for 1 hour. The reaction mixture was then cooled to ambient temperature (20° C.), filtered and evaporated under reduced pressure. The resulting concentrated mixture was filtered and the filtrate was cooled, with ice/salt bath cooling, and solid potassium hydroxide was added with stirring until the mixture became basic. The reaction mixture was then extracted with diethylether (5×150 ml). The combined ether extracts were dried using magnesium sulphate and evaporated under reduced pressure to give the product, 6-chloro-3-pyridylmethylamine as a brown oil (5.07 g, 90.6%).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([O:8][CH2:9][CH3:10])(=[O:7])[CH:5]=[CH2:6]>CCO>[CH2:1]([NH:3][CH2:6][CH2:5][C:4]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCN
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: CCNCCC(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of ethylamine (70% in water, 5.8 mL) in EtOH (30 mL) was added to a suspension of ethyl acrylate (2.0 g) in EtOH (20 mL) at 0° C. and the mixture was stirred at RT for 30 mins. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on amino silica gel to afford the sub-title compound (2.4 g) as a pale yellow oil; 1H NMR (300 MHz, CDCl3); 4.13 (2H, q), 2.88 (2H, t), 2.66 (2H, q), 2.52 (2H, t), 1.24 (2H, t), 1.11 (3H, t).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]([NH:15][C@@H:16]([CH2:24][NH:25]C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([O-])(O)=O.[Na+]>ClCCl.FC(F)(F)C(O)=O>[C:1]12([CH2:11][O:12][C:13]([NH:15][C@@H:16]([CH2:24][NH2:25])[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[O:14])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CC(C)(C)OC(=O)NC[C@H](NC(=O)OCC12CC3CC(CC(C3)C1)C2)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCC12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Yield: 93.7 %

Procedure:
A solution of 8.7 g (19.22 mmol) of (13.10) in 180 ml of trifluoroacetic acid dichloromethane=1/1 is added, after 1 min, to 1.5 ml of an ice-cold solution of NaHCO3. The solution is extracted 3 times with dichloromethane and the dichloromethane phase is then dried over sodium sulfate. 6.35 g (94%) of (13.11) are obtained as a colorless solid after filtering and removing the solvent in vacuo.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2].[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].N1CCCCC1>C(O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[C:24]3[S:20][C:21](=[O:26])[NH:22][C:23]3=[O:25])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: O=C1CSC(=O)N1
Reactant: CCc1ccc(CCOc2ccc(C=O)cc2)nc1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)nc1
Yield: 64.2 %

Procedure:
A mixture of 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde (2.40 g), 2,4-thiazolidinedione (1.66 g), ethanol (40 ml) and piperidine (0.2 ml) was heated under reflux for 8 hours. The resulting crystals were recrystallized form ethyl acetate to give 2.14 g (64%) of 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzylidene}-2,4thiazolidinedione as colorles crystals. m.p.: 165.5°-167° C.
Reaction SMILES: CN1CCOCC1.N#N.[C:10]([NH:13][C@H:14]([C:30]([OH:32])=O)[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])(=[O:12])[CH3:11].C(N=C=NCCCN(C)C)C.[C:44]([O:48][C:49](=[O:73])[CH:50]([CH2:71][NH2:72])[CH2:51][C:52]1([C:57](=[O:70])[NH:58][C@H:59]2[CH2:64][CH2:63][C@@H:62]([C:65]([O:67][CH2:68][CH3:69])=[O:66])[CH2:61][CH2:60]2)[CH2:56][CH2:55][CH2:54][CH2:53]1)([CH3:47])([CH3:46])[CH3:45]>ClCCl>[C:44]([O:48][C:49](=[O:73])[CH:50]([CH:71]([C:30](=[O:32])[C@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[NH:13][C:10](=[O:12])[CH3:11])[NH2:72])[CH2:51][C:52]1([C:57](=[O:70])[NH:58][C@H:59]2[CH2:60][CH2:61][C@@H:62]([C:65]([O:67][CH2:68][CH3:69])=[O:66])[CH2:63][CH2:64]2)[CH2:56][CH2:55][CH2:54][CH2:53]1)([CH3:46])([CH3:45])[CH3:47]
Reactant: CC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(CN)C(=O)OC(C)(C)C)CCCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: N#N
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(C(=O)OC(C)(C)C)C(N)C(=O)[C@H](CCCCNC(=O)OCc3ccccc3)NC(C)=O)CCCC2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1-Hydrobenztriazole (207 mg, 1.53 mmole) and N-methylmorpholine (235 mg, 2.36 mmole) were added to a stirred solution of N2 -acetyl-N6 -benzyloxycarbonyl-L-lysine (456 mg, 1.41 mmole) in dry dichloromethane at 0° C., followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (361 mg). The solution was stirred at 0° C. for 20 minutes and 3-{1-[(cis-4-ethoxycarbonylcyclohexyl)-carbamoyl]cyclopentyl}-2-(aminomethyl)propanoic acid t-butyl ester (500 mg, 1.18 mmole) in dichloromethane (10 ml) was added in one portion and the reaction mixture allowed to warm to room temperature and stirred for 16 hours. The solution was concentrated under vacuum to a volume of 10 ml and partitioned between ethyl acetate and water. The organic phase was washed with water (2×50 ml), 2M hydrochloric acid (50 ml, 2×25 ml), sodium bicarbonate solution (2×25 ml) and brine and then dried (MgSO4) and the solvent evaporated. The residue was chromatographed on silica eluting with ethyl acetate to give the title compound (610 g, 71%). Found: C, 63.34; H, 8.61; N, 7.45. C39H60N4O9 (0.25 H2O) requires C, 63.48; H, 8.33; N, 7.59%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[Cl:9].[N+:10]([O-])([OH:12])=[O:11]>O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([Cl:8])=[CH:4][C:3]=1[Cl:9]
Reactant: O=[N+]([O-])O
Reactant: Clc1ccc(Cl)c(Cl)c1
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Reaction time: 1 h

Procedure:
2723 gm (15.0 mols) of 1,2,4-trichlorobenzene were added to 7350 gm (105 mols) of 90% fuming nitric acid at 40° C. over a 3 hour period. The reaction mixture was held at 40° C. for one hour and worked up by the addition of 3700 ml of H2O while maintaining a temperature of 55°-60° C., and separating the waste acid. Two additional washes with 2000 ml of hot (55° C.) water and 1000 ml of 10% sodium bicarbonate solution followed by a phase separation gave 3316 gm (14.64 mols) of crude 1,2,4-trichloro-5-nitrobenzene. An additional 33 gm product was recovered from the waste acid when cooled and filtered.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[O:16]([C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccccc1
Reactant: O=Cc1ccccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1Oc1ccccc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 2-fluorobenzaldehyde (0.5 ml) in dimethylformamide (5 ml), 676 mg of phenol and 993 mg of potassium carbonate were added, and the reaction solution was stirred overnight at 100° C. The reaction solution was cooled, then 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (98:2-50/50)) to afford the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]([CH3:14])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:14][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[C:5]1[CH2:3][NH:2][CH3:1]
Reactant: CNC(=O)c1cc2ccccc2n1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCc1cc2ccccc2n1C
Reaction time: 23 h
Yield: 92.9 %

Procedure:
A 3-liter 3-necked roundbottom flask equipped with overhead stirring was charged with N,1-dimethyl-1H-indole-2-carboxamide (23.45 g, 124.58 mmole) and anhydrous THF (170 mL). The solution was stirred while a solution of LiAlH4 in TBF (1.0 M, 250 mL, 250 mmole) was added via syringe. Gas was evolved during the addition of the first 50 mL of LiAlH4 solution. When the addition was complete, the resulting light yellow solution was heated at gentle reflux. After 23 hr, the reaction was cooled in ice and quenched by the sequential dropwise addition of H2O (9.5 mL), 15% NaOH (9.5 mL), and H2O (28.5 mL). The mixture was stirred for 15 min, then was filtered through celite®, and the filter pad was washed thoroughly with THF. The filtrate was concentrated and the residue was flash chromatographed on silica gel (10% MeOH/CHCl3 containing 0.5% conc. NH4OH). The title compound (20.17 g, 93%) was obtained as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.56 (d, J=7.8 Hz, 1 H), 7.02-7.35 (m, 3 H), 6.38 (s, 1 H), 3.88 (s, 2 H), 3.75 (s, 3 H), 2.49 (s, 3 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14].O>CC(O)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:6][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: CC(C(=O)O)c1ccc(O)cc1
Solvent: CC(=O)O
Solvent: O
Product: CC(C(=O)O)c1ccc(O)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
2-(4-Hydroxy-phenyl)-propionic acid (788 mg, 1 mmol) in CH3COOH (10 ml) is added to 60% Nitric acid (552 mg, 1.11 mmol) at room temperature. The reaction mixture is stirred for 1 h. The iced water (50 ml) added to the reaction mixture. The mixture is extracted with ethyl acetate. The extracts are washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:37][CH2:38][C:39]([NH:41][CH:42]([CH3:44])[CH3:43])=[O:40]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH:37][CH2:38][C:39](=[O:40])[NH:41][CH:42]([CH3:44])[CH3:43])=[O:9]
Reactant: CC(C)NC(=O)CN
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NC(=O)CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Yield: 70 %

Procedure:
To a solution of 5-fluoro-2-nitrobenzoic acid (370 mg, 2.0 mmol) in anhydrous DMF (5 mL) was added 1-hydroxybenzotriazole hydrate (330 mg, 2.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (460 mg, 2.4 mmol) and 2-amino-N-isopropylacetamide (INTERMEDIATE I.1) (230 mg, 2.0 mmol). The resultant mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, the crude yellow residue dissolved in EtOAc (20 mL) and washed with dilute HCl (aq.) (3×5 mL), sat. NaHCO3 (aq.) (3×5 mL) and brine (1×5 mL). The organic layer was dried (Na2SO4), concentrated in vacuo and purified by chromatography on silica gel with MeOH:DCM (1:19, v/v) as eluent to afford 5-fluoro-N-(isopropylcarbamoylmethyl)-2-nitrobenzamide (INTERMEDIATE IV.1) (400 mg, 1.4 mmol, 70%) as yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[NH:8])[NH:4][N+:5]([O-:7])=[O:6].C(O)(=O)C.N[CH2:14][C:15]1[S:19][C:18]([Cl:20])=[N:17][CH:16]=1.[OH-].[Na+]>O>[CH3:1][O:2][C:3](=[N:4][N+:5]([O-:7])=[O:6])[NH:8][CH2:14][C:15]1[S:19][C:18]([Cl:20])=[N:17][CH:16]=1
Reactant: NCc1cnc(Cl)s1
Reactant: COC(=N)N[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
O-methyl-N-nitroisourea (3.0 g, 0.0252 mol), acetic acid (1.5 ml, 0.0262 mol, 10.4 equivalents), and 5-(aminomethyl)-2-chlorothiazole (93% purity, 4.4 g, 0.0275 mol, 1.09 equivalents) were added to water (55 ml) in this order at 24° C. The reaction mixture was adjusted to pH 7 with 30% aqueous sodium hydroxide solution. The mixture was stirred at room temperature for 2 hours and then extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide 2.9 g (46.0% yield) of O-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.