Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Cl-].[Mg+2].[Cl-].N1C=CC=CC=1.ClC1[CH:28]=[CH:27][C:23]([C:24](Cl)=O)=[CH:22][CH:21]=1.Cl>ClCCl>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3](=[O:4])[C:5]1[CH:28]=[CH:27][C:23]([CH3:24])=[CH:22][CH:21]=1)[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)c1ccc(C)cc1
Reaction time: 0.25 h
Yield: 53.5 %

Procedure:
Ethyl acetoacetate (51.25 g, 390 mmol) was added dropwise to the stirred suspension of anhydrous magnesium chloride (37.54 g, 390 mmol) in dried dichloromethane (200 ml) over a period of 1 hour under argon atmosphere at 0° C. followed by pyridine (62.5 g, 788 mmol). After 15 minutes, 4-chlorobenzoylchloride (68.95 g, 394 mmol) was added dropwise and stirring was continued for 15 minutes at 0° C. and further stirred for 1.5 hours at 30° C. The resulting reaction mixture was neutralized with hydrochloric acid (6N, 235 ml) at 0–5° C., filtered and washed with water. The filtrate was extracted with diethylether (3×100 ml). The ether extract was washed with water, dried over anhydrous sodium sulphate and concentrated to dryness in vacuum. The obtained oil was taken in ammonium chloride (21 g in 200 ml water) solution containing ammonia (2 ml) and stirred at 30° C. for 20 minutes. The resulting solution was extracted with ethyl acetate (3×200 ml). Ethyl acetate extract was dried over anhydrous sodium sulphate, concentrated to yield the crude product, which was purified by column chromatography to yield the title compound as viscous oil (43 g, 48.2%). 1H-NMR (DMSO-d6): δ 1.15–1.18 (t, 3H), 4.08–4.13 (q, 2H), 4.20 (s, 2H), 7.61–7.64 (d, 2H), 7.94–7.97 (d, 2H). MS m/z: 227.1 (M+). Preparation 3 Synthesis of ethyl(4-methylthio)benzoylacetate
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].Cl.[CH3:7][NH:8][C:9]1([CH3:19])[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O>[CH3:5][O:4][C:2]([N:8]([CH3:7])[C:9]1([CH3:19])[CH2:14][C:13]([CH3:15])([CH3:16])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]1)=[O:3]
Reactant: CNC1(C)CC(C)(C)CC(C)(C)C1
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N(C)C1(C)CC(C)(C)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.7 %

Procedure:
Methyl chloroformate (0.97 g, 0.8 ml, 10.3 mmol) was added in one portion to a suspension of N,1,3,3,5,5-hexamethylcyclohexanamine hydrochloride (5-20) (1.13 g, 5.13 mmol) and Na2CO3 (1.63 g, 15.4 mmol) in THF (30 ml). The resulting mixture was stirred at room temperature for 6 h, and then it was diluted with water (50 ml) and extracted with ether (3*30ml). The combined organic phases were washed with 10% K2SO4, saline, dried over MgSO4, filtered and evaporated. The crude product was purified by flash chromatography, eluting with hexane-ethyl acetate mixture (6:1) to give 0.90 g (78%) of (15) as an oil.
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:9].[Na+:10]>CO>[Na+:10].[OH:9][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O-:7])=[O:8]
Reactant: [OH-]
Reactant: O=C1CCCCCO1
Agent: [Na+]
Solvent: CO
Product: O=C([O-])CCCCCO

Procedure:
To a solution of 20 mL (0.18 mmol) epsilon-caprolactone in 100 mL methanol is added 36 mL of 5N sodium hydroxide and the resulting mixture is heated at reflux for 8 hours. The solvent is evaporated and the residue is taken up in 200 mL ethanol. The precipitate is collected and the filtrate is evaporated. The residue is suspended in 50 mL ethanol and 300 mL ether is added. The precipitate is filtered off and combined with the earlier precipitate to obtain 6-hydroxyhexanoic acid sodium salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH:13]=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:31].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH:13]=[N:12][C:7]=3[C:8]([NH2:31])=[N:9][C:10]=2[CH:11]=1
Reactant: [NH4+]
Reactant: CC(C)Cn1cnc2cnc3cc(Br)ccc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: CC#N
Product: CC(C)Cn1cnc2c(N)nc3cc(Br)ccc3c21

Procedure:
The method described in Part J of Example 365 was used to oxidize and aminate 7-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (18.7 g, 58.4 mmol). 3-Chloroperoxybenzoic acid (22.1 g of 50% pure material, 129 mmol) was added in five portions during the oxidation step, and the amination with ammonium hydroxide (146 mL) and p-toluenesulfonyl chloride (16.6 g, 87.6 mmol) proceeded overnight. The crude product was obtained as an oil, which was treated with acetonitrile to form a precipitate. The precipitate was isolated by filtration, washed with a small amount of acetonitrile, and recrystallized from acetonitrile to provide 4 g of 7-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine as off-white needeles, mp 218-220° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13]C(=O)OC(C)(C)C)=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[O:6])=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)NC2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(C(=O)NC2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
To a vial was added tert-butyl 4-(cyclopropylcarbamoyl)phenylcarbamate (326 mg, 1.18 mmol) and TFA (2 mL). The solution was stirred at 25° C. for 1 hour. The solution was concentrated in vacuo to give the crude product mixture which was purified by passing through a SCX column (2 g), eluting with the 2N ammonia in methanol to yield the pure product 4-amino-N-cyclopropylbenzamide (210 mg, 100%). LC/MS, m/z 177.05 (M+1). HPLC Rt, 0.63 min. Waters Sunfire C18 column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: C(OC([N:8]1[CH:12]([C:13]([OH:15])=O)[CH2:11][S:10][CH:9]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=O)(C)(C)C.[ClH:22].[NH2:23][C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:26][S:27][CH3:28]>>[ClH:22].[ClH:22].[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:9]2[NH:8][CH:12]([C:13]([NH:23][C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:26][S:27][CH3:28])=[O:15])[CH2:11][S:10]2)[CH:17]=1
Reactant: CSCC[C@H](N)C(N)=O
Reactant: CC(C)(C)OC(=O)N1C(C(=O)O)CSC1c1cccnc1
Agent: Cl
Product: CSCC[C@H](NC(=O)C1CSC(c2cccnc2)N1)C(N)=O

Procedure:
N-tert-Butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid and L-methioninamide hydrochloride were used as the starting materials and treated in the same manner as in Example 4 to give [2-(3-pyridyl)thiazolidine-4-carbonyl]-L-methioninamide dihydrochloride. Melting point 131° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([OH:15])([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.[CH3:17][N:18]1[CH2:22]C[C@H:20](O)[CH2:19]1>C1(C)C=CC=CC=1>[CH3:17][N:18]1[CH2:19][CH2:20][C@H:1]([O:2][C:3](=[O:16])[C:4]([OH:15])([C:5]2[S:6][CH:7]=[CH:8][CH:9]=2)[C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:22]1
Reactant: CN1CC[C@H](O)C1
Reactant: COC(=O)C(O)(c1cccs1)c1cccs1
Solvent: Cc1ccccc1
Product: CN1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)C1
Yield: 24.9 %

Procedure:
Prepared as described in Intermediate I-5 from 0.98 g (0.00385 mol) of 2-Hydroxy-2,2-dithien-2-ylacetic acid methyl ester in 30 ml of toluene, 0.39 g (0.00385 mol) of (3S)-1-methylpyrrolidin-3-ol (Intermediate I-20) and 0.108 g (0.0027 mol) of HNa (60% dispersion in mineral oil). The yield was 0.31 g (25%) of the title product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]([CH3:14])[CH:8]=1.Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([C:25]([OH:27])=[O:26])=[CH:18][C:17]=1[S:28]([NH2:31])(=[O:30])=[O:29].Cl>O>[N+:22]([C:21]1[CH:20]=[C:19]([CH:18]=[C:17]([S:28](=[O:30])(=[O:29])[NH2:31])[C:16]=1[O:13][C:12]1[CH:7]=[CH:8][C:9]([CH3:14])=[CH:10][CH:11]=1)[C:25]([OH:27])=[O:26])([O-:24])=[O:23]
Reactant: Cc1ccc(O)cc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(Oc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)cc1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
124 g (0.9 mol) of potassium carbonate are dissolved in 800 ml of water. To this solution, there are added portionwise 1.6 mols of p-cresol and subsequently 112 g (0.4 mol) of 2-chloro-3-nitro-5-carboxy-benzenesulphonamide and the solution is heated to 85° C. The whole is stirred for 16 hours at this temperature, cooled to 25°-30° C and acidified with concentrated hydrochloric acid to pH 1. The oil which thereupon separates is isolated from the aqueous phase and subjected to steam distillation. Alternatively, it is also possible to adjust to pH-value of 8-9, to extract the excess phenol with ethyl acetate and then to acidify the aqueous phase. After having separated in this manner the excess p-cresol, the product crystallises upon cooling. By recrystallisation from acetone/H2O, the 3-nitro-4-(4'-methylphenoxy)-5-sulphamoylbenzoic acid melting at 236° C is obtained.
Reaction SMILES: [CH2:1]([C:3]1([CH3:18])[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:17])=[O:16])=[CH:11][CH:10]=2)[O:4]1)[CH3:2].FC(F)(F)C(O[I:24](C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.II.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH2:1]([C:3]1([CH3:18])[C:7](=[O:8])[C:6]([I:24])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:17])=[O:16])=[CH:11][CH:10]=2)[O:4]1)[CH3:2]
Reactant: CCC1(C)OC(c2ccc(S(C)=O)cc2)=CC1=O
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCC1(C)OC(c2ccc(S(C)=O)cc2)=C(I)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 162.1 %

Procedure:
8.2 g of 2-ethyl-2-methyl-5-{4-(methylsulfinyl)phenyl}-3(2H)-furanone in 200 ml carbon tetrachloride and 200 ml chloroform was mixed with 6.8 g of [bis(trifluoroacetoxy)iodo]benzene (BTI) and 4.1 g of iodine. The mixture was stirred at room temperature for 6 hours, followed by quenching the reaction by adding saturated aqueous sodium thiosulfate until the characteristic color of iodine disappeared. The quenched solution was extracted with 300 ml water and dichloromethane (200 ml×3). The organic layer was concentrated in vacuo and the resulting residue was purified by column chromatography (hexane/ethylacetate=1:1) to give 10.0 g of 2-ethyl-4-iodo-2-methyl-5-{4-(methylsulfinyl)phenyl}-3(2H)-furanone. NMR: δ0.89 (t, J=7.5 Hz, 3H), 1.51 (s, 3H), 1.93 (m, 2H), 2.73 (s, 3H), 7.81 (d, J=8.7 Hz, 2H), 8.38 (d, J=8.7 Hz, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH2:18][S:19][CH3:20])[C:3]([NH:5][C:6]1[S:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][C:7]=1[CH3:17])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>O1CCOCC1>[CH3:1][CH:2]([CH2:18][S:19][CH3:20])[C:3]([NH:5][C:6]1[S:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][C:7]=1[CH3:17])=[S:30]
Reactant: CSCC(C)C(=O)Nc1sc(-c2cccnc2)nc1C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CSCC(C)C(=S)Nc1sc(-c2cccnc2)nc1C
Temperature: 130 °C

Procedure:
To a microwave reaction vessel was added 2-methyl-N-(4-methyl-2-pyridin-3-yl-thiazol-5-yl)3-methylsulfanyl-propionamide (0.10 g, 0.32 mmol) in dioxane and Lawesson's reagent (0.19 g, 0.48 mmol). The vessel was capped and heated in a Biotage Initiator microwave reactor for 1 min at 130° C., with external IR-sensor temperature monitoring from the side. The reaction was concentrated to dryness and the crude material was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to give the desired product as a yellow semi solid (0.019 g, 18%): 1H NMR (300 MHz, CDCl3) δ 9.9 (m, 1H), 9.2 (d, 1H), 8.65 (d, 1H), 8.4 (m, 1H), 7.4 (m, 1H), 3.15 (m, 1H), 2.9 (m, 2H), 2.5 (s, 3H), 2.2 (s, 3H), 1.5 (d, 3H); ESIMS m/z 324.12 (M+1).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.ClCCl.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([OH:26])=O.[OH:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30]>O>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([NH:30][C:29]1[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=1[OH:27])=[O:26]
Reactant: Nc1ccccc1O
Reactant: O=C(O)Cc1ccccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1ccccc1Cl)Nc1ccccc1O
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a mixture of 1,1′-carbonyl diimidazole (12.45 g, 0.077 mol) and dichloromethane (50 ml) was added 2-chlorophenylacetic acid (12.5 g, 0.073 mol) in portions. The mixture was stirred for 1 h and 2-hydroxyaniline (7.99 g, 0.073 mol) was added in one portion. After stirring overnight, the reaction mixture was diluted with water and filtered to give the title compound (18.3 g after drying).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:7][C:6]=2[CH:14]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](=[O:12])(=[O:11])[NH2:13])=[N:7][C:6]=2[CH:14]=1)(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: NS(=O)(=O)c1nc2cc(O)ccc2s1
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCC(=O)Oc1ccc2sc(S(N)(=O)=O)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-hydroxy-2-benzothiazolesulfonamide (6.9 g., 0.03 mole), triethylamine (4.2 ml., 0.03 mole) and 4-dimethylaminopyridine (100 mg.) in dimethylformamide (30 ml.) is added lauroyl chloride (7 ml.) during a 1/2 hour period. The reaction mixture is stirred for 2 hours at room temperature, poured into ice water and hydrochloric acid, extracted into ether, washed with water, ammonium hydroxide (3 ml. diluted with water) dilute hydrochloric acid and dried over magnesium sulfate. The ether is evaporated at reduced pressure to give 2-sulfamoyl-5-benzothiazolyl dodecanoate.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[NH2:15][O:16][CH2:17][CH2:18][CH2:19][P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23].C(N(C(C)C)CC)(C)C>COCCOCCOC>[Cl:11][C:6]1[C:7]([NH:8][CH:9]=[O:10])=[C:2]([NH:15][O:16][CH2:17][CH2:18][CH2:19][P:20]([O:21][CH2:22][CH3:23])([O:24][CH2:25][CH3:26])=[O:27])[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=1
Reactant: CCOP(=O)(CCCON)OCC
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOCCOC
Product: CCOP(=O)(CCCONc1nc(NC=O)nc(Cl)c1NC=O)OCC
Temperature: 100 °C
Yield: 44.5 %

Procedure:
A mixture of 4,6-dichloro-2,5-diformamidopyrimidine (1.48 g, 6.3 mmol), diethyl 3-(aminooxy)propylphosphonate (1.33 g, 6.3 mmol), diisopropylethylamine (2.19 ml, 12.6 mmol) in diglyme (20 ml) was heated at 100° C. for 11/2 hours. After cooling, the solvent was removed under reduced pressure. The residue was chromatographed on silica gel (dichloromethane-methanol (97:3) as eluant) to give the title compound as a yellow foam (1.15 g, 58% based on recovered pyrimidine). 1H NMR: δH ((CD3)2SO+D2O) 1.21 (6H, t, J=7Hz, (OCH2CH3)2), 1.65-2.00 (4H, m, CH2CH2P), 3.85-4.05 (6H, m, N--OCH2, (OCH2CH3)2), 7.90+8.15 (1H, 5-NHCHO), 9.25 (2-NHCHO) Found: C, 38.12; H, 5.15; N, 16.25%. C13H21N5O6PCl requires: C, 38.10; H, 5.17; N, 17.09%.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[C:10]1([CH3:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[N+:1]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH3:16])([O-:4])=[O:2]
Reactant: Cc1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1ccccc1[N+](=O)[O-]

Procedure:
In a process for the manufacture of a nirotoluene compound by reacting toluene with an aqueous acid mixture comprising nitric acid and sulfuric acid under conditions sufficient to effect nitration thereof and form a nitrotoluene compound and a spent aqueous acid fraction and then recovering the nitrotoluene compound from the spent aqueous acid fraction, the improvement for refining the spent aqueous acid fraction which comprises the following steps:
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[C-:19]#[N:20].[Na+]>CN(C=O)C>[C:19]([C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:20]
Reactant: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1C#N
Temperature: 0 °C
Yield: 82.7 %

Procedure:
A solution of 6.6 g of 5-chloro-1-(4-bromophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester in 30 ml of DMF with 2 g of sodium cyanide was heated at approximately 95° C. for 3 hours. The reaction mixture was poured into ice water and the precipitated solid was collected by filtration. The product was recrystallized from 3 A alcohol to afford 5.3 g of 5-cyano-1-(4-bromophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester. MP=104°-105° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19](=O)[CH2:20]Br)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.[CH:23]1[N:27]=[C:26]([NH2:28])[S:25][CH:24]=1>CCO>[CH2:17]([S:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:4]=[C:3]([C:19]3[N:28]=[C:26]4[N:27]([CH:20]=3)[CH:23]=[CH:24][S:25]4)[C:2]([NH2:1])=[N:7][CH:6]=2)[CH2:9][CH2:10]1)(=[O:16])=[O:15])[CH3:18]
Reactant: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)CBr)n2)CC1
Reactant: Nc1nccs1
Solvent: CCO
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3cn4ccsc4n3)n2)CC1
Temperature: 25 °C
Yield: 156.7 %

Procedure:
1-[3-amino-6-(4-ethylsulfonylpiperazin-1-yl)pyrazin-2-yl]-2-bromo-ethanone (35 mg, 0.08922 mmol) was suspended in EtOH (2 mL) and 2 aminothiazole (8.935 mg, 0.08922 mmol) was added. The mixture was heated at reflux for 4 hours and then allowed to cool to ambient temperature. The solution was filtered through a 0.45 μnm PTFE filter and the solvent removed under a stream of nitrogen. The resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound (55 mg, 10% Yield). 1H NMR (400.0 MHz, DMSO) d 1.14 (t, J=7.3 Hz, 3H), 3.01 (q, J=7.4 Hz, 2H), 3.21-3.23 (m, 4H), 3.34-3.36 (m, 4H), 7.28 (d, J=4.4 Hz, 1H), 7.67 (s, 1H), 7.89 (d, J=4.4 Hz, 1H) and 8.23 (s, 1H) ppm; MS (ES+) 394.0
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32][C:33]1[C:42]([OH:43])=[CH:41][CH:40]=[C:39]2[C:34]=1[CH:35]=[CH:36][N:37]=[CH:38]2.[C:44]([N:51]1[CH2:56][CH2:55][CH:54](O)[CH2:53][CH2:52]1)([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45].C(N(CC)CC)C>ClCCl>[C:47]([O:46][C:44]([N:51]1[CH2:56][CH2:55][CH:54]([O:43][C:42]2[C:33]([Br:32])=[C:34]3[C:39](=[CH:40][CH:41]=2)[CH:38]=[N:37][CH:36]=[CH:35]3)[CH2:53][CH2:52]1)=[O:45])([CH3:50])([CH3:48])[CH3:49]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc2cnccc2c1Br
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnccc3c2Br)CC1
Reaction time: 0.25 h
Yield: 59 %

Procedure:
3.75 mL (4.15 g, 23.8 mmol) of diethyl azo dicarboxylate were added to 12.7 g (19.9 mmol) of polymer-bound triphenylphosphine (PS—PPh3, approx. 1.6 mmol/g, Argonaut) in 250 mL of dichloromethane at 0° C. and stirred for 15 min. 4.45 g (19.9 mmol) 5-bromo isoquinoline-6-ol (9), 4.0 g (19.9 mmol) Boc-(4-hydroxy)piperidine and 4.1 mL (3.0 g, 29.8 mmol) triethyl amine were added. The mixture was shaken for 16 h. The polymer was removed by filtration through Celite and the solvents were distilled off. 20 mL dichloromethane were added and the precipitate was isolated by filtration. The crude product (8 g) was purified by flash chromatography using ethyl acetate/n-heptane as eluent to give 4.78 g (60%) of compound 11.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:20]([C@H:28]3CCN3C)[CH2:19][CH2:18][O:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:35]1([C:40]([O-:42])=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36]1>>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C@H:20]([CH:28]3[O:41][C:40](=[O:42])[N:35]4[CH2:39][CH2:38][CH2:37][CH:36]34)[CH2:19][CH2:18][O:17]2)[CH3:14])[CH:4]=[C:3]([C:2]([F:34])([F:33])[F:1])[CH:8]=1
Reactant: C[C@@H](O[C@H]1OCC[C@@H]([C@H]2CCN2C)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C([O-])N1CCCC1
Product: C[C@@H](O[C@H]1OCC[C@@H](C2OC(=O)N3CCCC23)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Prepared from (2R or S)-2-[(R or S)-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)hydroxymethyl]-1-pyrrolidinecarboxylate (Example 41, Isomer B) according to the method of Example 42.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[O:12](C(C(F)(F)F)=O)[C:13]([C:15]([F:18])([F:17])[F:16])=O>ClCl>[F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][C:13](=[O:12])[C:15]([F:18])([F:17])[F:16]
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: ClCl
Product: O=C(Nc1cc([N+](=O)[O-])ccc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Fluoro-5-nitroaniline (7.0 g, 45 mmol) was dissolved in CH2 Cl2 (200 mL) and Et3 N (7.0 mL, 49 mmol) was added. Then (CF3 CO)2O (7.5 mL, 11.3 g, 54 mmol) in 25 mL of CH2 Cl2 was added dropwise at 0° C., and the mixture was stirred for 24 h at room temperature. The reaction mixture was washed with water (3×300 mL) and saturated aq. NaHCO3 (300 mL). The organic layer was separated, and an aqueous layer was extracted with CH2 Cl2 (2×100 mL). Combined organic solutions were dried over Na2 SO4, evaporated, and the title compound was isolated as a light beige solid with m.p. 112-113° C.; yield—10.5 g (93%). 1H NMR (CDCl3, 300 MHz, ppm): δ=7.35 (t, JHH=3JHF=9.2, 1H, H-3), 8.14 (ddd, 4JHH=2.8, 4JHF=4.2, 3JHH=9.2, 1H, H-4), 8.22 (br s, NH), 9.18 (dd, 3JHH=2.9, 4JHF=6.4, 1H, H-6); 13C NMR (CDCl3, 75.5 MHz, ppm): δ=115.1 (q, 1JCF=289, CF3), 116.1 (d, 2JCF=22, C-3), 117.8 (d, 3JCF=2.3, C-4/6), 122.3 (d, 3JCF=9.5, C-6/4), 124.6 (d, 2JCF=12.7, C-1), 144.5 (C-5), 154.4 (q, 2JCF=42, CO), 155.8 (d, 1JCF=256, C-2); EI-MS: m/z (rel. int., %)=223 (100) [M—HCO]+, 154 (21), 126 (18), 99 (17).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=O)[CH:7]=[C:8]([F:10])[CH:9]=1)=O.C([O-])(=O)C.[NH4+:28].O>C(O)(=O)C>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:12]2[NH:28][C:3](=[O:2])[C:5]3[N:6]([CH:7]=[C:8]([F:10])[CH:9]=3)[CH:11]=2)=[CH:15][CH:16]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: [NH4+]
Reactant: COC(=O)c1cc(F)cn1CC(=O)c1ccc(C(C)(C)C)cc1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(-c2cn3cc(F)cc3c(=O)[nH]2)cc1
Temperature: 25 °C

Procedure:
A solution of 52.4 mg (0.165 mmol) 1-[2-(4-tert-butyl-phenyl)-2-oxo-ethyl]-4-fluoro-1H-pyrrole-2-carboxylic acid methyl ester and 382 mg (4.95 mmol) ammonium acetate in 0.5 ml acetic acid is stirred for 18 hours at 110° C. The reaction mixture is allowed to cool to room temperature and excess water is added. The resulting precipitate is filtered off, washed with water and dried. It is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 3-(4-tert-butyl-phenyl)-7-fluoro-2H-pyrrolo[1,2-a]pyrazin-1-one as light brown crystals; HPLC/MS 2.88 min (B), [M+H] 285; 1H NMR (400 MHz, DMSO-d6) δ [ppm] 10.97 (s, 1H), 7.61 (s, 1H), 7.58 (d, J=8.5, 2H), 7.48 (m, 3H), 6.75 (d, J=1.6, 1H), 1.31 (s, 9H).