Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([C:6]([F:21])([F:20])[C:7]([F:19])([F:18])[C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[C:3]([OH:5])=[O:4].[CH3:23]O.S(=O)(=O)(O)O>O>[F:1][C:2]([F:22])([C:6]([F:20])([F:21])[C:7]([F:18])([F:19])[C:8]([F:17])([F:16])[C:9]([F:14])([F:15])[C:10]([F:13])([F:12])[F:11])[C:3]([O:5][CH3:23])=[O:4]
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Yield: 87 %

Procedure:
A 2-1, four-necked, round-bottomed flask equipped with stirrer, addition funnel, thermometer and reflux condenser, is charged with 728 g (2 mol) of dried perfluoroheptanoic acid, 160 g (5 mol) of methanol. The mixture is stirred and added dropwise 50 ml concentrated sulfuric acid and then heated to reflux for 4 hr. At the end of the reflux period the mixture is cooled to room temperature and poured into 2 l cold water. After separation of the phases, the lower organic phase is washed with water till pH neutral and dried over CaCl2. Distillation of the crude gives 658 g (87%) of methyl perfluoroheptanoate, bp 139° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N-:8][C:9](=[O:14])[CH:10]=[C:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:13][C:11]1([CH3:12])[C:4]2[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[NH:8][C:9](=[O:14])[CH2:10]1
Reactant: CC(C)=CC(=O)[N-]c1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC1(C)CC(=O)Nc2ccc(Br)cc21
Temperature: 130 °C
Reaction time: 1 h

Procedure:
To 1.0 g (3.9 mmol) of (4-bromophenyl) 3,3-dimethylacryloylamide heated to 130 degrees C. was added 0.526 g (3.94 mmol) of aluminum chloride over a period of 30 minutes. The reaction mixture was heated for an additional 30 minutes. The mixture was treated again with 0.079 g (0.592 mmol) of aluminum chloride and heated at 130 degrees C. for 1 hour and 40 minutes. The reaction mixture was extracted with 20 ml ether and the combined organics washed with 20 ml water, 20 ml brine and dried (MgSO4). Solvent was removed in-vacuo and the residue purified by flash chromatography (SiO2 ; 20% ethyl acetate in hexanes) to give the title compound as a light yellow solid.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1.Br[CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37]>>[F:37][C:31]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=1[O:29][CH2:28][CH2:27][CH2:26][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1
Reactant: Fc1ccc(F)c(OCCCBr)c1
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(O)cc2)C(O)C1
Product: O=C(OCc1ccccc1)N1CCC(c2ccc(OCCCOc3cc(F)ccc3F)cc2)C(O)C1

Procedure:
Analogously to Method I, 1.20 g of benzyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 1.00 g of 2-(3-bromopropoxy)-1,4-difluorobenzene (Example 142d) are reacted. The title compound is obtained as a colourless oil. Rf=0.24 (1:1 EtOAc-heptane). Rt=3.29.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1([CH3:28])[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[C:19]2[CH2:18][CH:17]([C:25]([OH:27])=[O:26])[CH2:16][C:15]1=2.[CH2:29](I)[CH2:30][CH2:31][CH2:32][CH3:33].Cl>O1CCCC1>[CH3:24][C:20]1([CH3:23])[CH2:21][CH2:22][C:14]([CH3:28])([CH3:13])[C:15]2[CH2:16][C:17]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([C:25]([OH:27])=[O:26])[CH2:18][C:19]1=2
Reactant: CCCCCI
Reactant: CC1(C)CCC(C)(C)C2=C1CC(C(=O)O)C2
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCCC1(C(=O)O)CC2=C(C1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.7 %

Procedure:
13.6 g of diisopropylamine were dissolved in 200 ml of THF (tetrahydrofuran) abs. and treated dropwise at −10° with 84 ml of butyl lithium (1.6 molar in hexane). After 15 minutes of stirring at 0° C., a solution of 12 g of 4,4,7,7-tetramethyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carboxylic acid in 40 ml of THF was dropped in. The reaction mixture was stirred for one hour at room temperature, cooled again to 0° C. and treated dropwise with a solution of 26.4 g of pentyl iodide in 30 ml of THF. After stirring for 90 minutes at room temperature, the reaction mixture was poured onto ice/water, acidified with 3N HCl and extracted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4 and evaporated to yield a pale yellow, partially crystalline oil. Flash chromatography (SiO2, hexane/ethyl acetate=6:1) and crystallization from pentane yielded 12.9 g of 4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carboxylic acid as white crystals, m.p. 57-58° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>>[Cl:18][C:15]1[CH:14]=[C:13]2[C:12](=[CH:17][CH:16]=1)[NH:11][C:8](=[O:10])[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[C:19]2[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=C(O)Cc1ccccc1
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)c1-c1ccccc1
Yield: 53 %

Procedure:
from phenylacetic acid and (2-amino-5-chloro-phenyl)-phenyl-methanone according to general procedure 2. Yield 53%.
Reaction SMILES: [F:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[NH:7][NH2:8].[C:11]([CH2:13][C:14](Cl)=[O:15])#[N:12]>O1CCCC1>[NH2:12][C:11]1[N:7]([C:6]2[C:5]([CH3:9])=[C:4]([CH3:10])[S:3][C:2]=2[F:1])[N:8]=[C:14]([OH:15])[CH:13]=1
Reactant: N#CCC(=O)Cl
Reactant: Cc1sc(F)c(NN)c1C
Solvent: C1CCOC1
Product: Cc1sc(F)c(-n2nc(O)cc2N)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Then, the obtained hydrazine derivative was dissolved in 50 mL of tetrahydrofuran, and to this solution, 5.1 g of cyanoacetyl chloride was added, followed by stirring at room temperature for 2 hours. Then, the solvent was distilled off under reduced pressure, the residue was dissolved in 50 mL of 1-propanol, and 3.1 g of methanesulfonic acid was added, followed by reflux with heating for 3 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, followed by neutralization with sodium hydrogen carbonate to a pH of 7, and extraction with ethyl acetate was carried out. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 5.5 g of 5-amino-1-(2-fluoro-4-methyl-5-methylthiophenyl)-3-hydroxypyrazole in the form of yellow crystals (melting point: 230-232° C.).
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][C:4](=[CH2:8])[C:5]([OH:7])=[O:6].[C:10]([OH:13])(=[S:12])[CH3:11]>>[CH3:1][CH:2]([CH3:9])[CH2:3][CH:4]([CH2:8][S:12][C:10](=[O:13])[CH3:11])[C:5]([OH:7])=[O:6]
Reactant: CC(O)=S
Reactant: C=C(CC(C)C)C(=O)O
Product: CC(=O)SCC(CC(C)C)C(=O)O
Temperature: 95 °C

Procedure:
A mixture of 4-methyl-2-methylenepentanoic acid (5.0 g) and thioacetic acid (25 mL) was heated at 95° C. under argon for 3 days. The excess thioacetic acid was evaporated and the residual oil was dissolved in ethyl acetate (40 mL) and extracted with saturated NaHCO3 (3×40 mL). The combined NaHCO3 extracts were combined and acidified at 0° C. to pH 2 with 1M HCl. The aqueous layer was extracted with CH2Cl2 (3×40 mL), the combined organic phases were dried (MgSO4) and evaporated to give 3.0 g of 4-methyl-2-acetylthiomethyl-pentanoic acid; 1H NMR (80 MHz, CDCL3) δ 0.95 (d, J=8.0, 6H), 1.20-1.90 (m, 4H), 2.35 (s, 3H), 2.50-3.20 (m, 3H), 6.7 (br s, 1H).
Reaction SMILES: [N+:1]([C:4]1[C:12](F)=[C:11]([F:14])[C:10]([F:15])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[OH-].[NH4+:17]>>[NH2:17][C:12]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH:9]=[C:10]([F:15])[C:11]=1[F:14])[C:6]([OH:8])=[O:7]
Reactant: [NH4+]
Reactant: O=C(O)c1cc(F)c(F)c(F)c1[N+](=O)[O-]
Agent: [OH-]
Product: Nc1c(F)c(F)cc(C(=O)O)c1[N+](=O)[O-]

Procedure:
1.4 g (6.3 mmol) of 2-nitro-3,4,5-trifluoro-benzoic acid was treated with ammonium hydroxide to produce 3-amino-4,5-difluoro-2-nitro-benzoic acid. LCMS: 219 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[C:4]([N+:16]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>C(O)C.[Zn]>[NH2:16][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[NH:8][CH2:9][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(C)CNc1ccc(F)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Product: COC(=O)C(C)CNc1ccc(F)cc1N
Temperature: 25 °C
Yield: 81 %

Procedure:
To a solution of methyl 3-(4-fluoro-2-nitrophenylamino)-2-methylpropanoate (14.0 g, 54.6 mmol) in ethanol (250 mL) were added zinc powder (14.2 g, 218 mmol) and saturated ammonium chloride (28.4 mL) at 0° C. Once addition was completed, the reaction mixture was stirred at reflux for 1 hour. Then the mixture was cooled to room temperature, filtered, and washed with ethanol (200 mL). The organic phase was concentrated in vacuo, dissolved in water (250 mL), and extracted with ethyl acetate (200 mL*3). The combined organic layers was separated, dried over anhydrous sodium sulfate, and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to afford methyl 3-(2-amino-4-fluorophenylamino)-2-methylpropanoate as a black solid (10.0 g, 81%).
Reaction SMILES: [CH3:1][C:2]([O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)([CH3:12])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[N:5]1.C(OCC)(=O)C.[H][H]>C(O)C>[CH3:12][C:2]([O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)([CH3:1])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH2:9])=[N:5]1
Reactant: CC(C)(Cn1ccc([N+](=O)[O-])n1)OC[C@H]1CO1
Reactant: [H][H]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(Cn1ccc(N)n1)OC[C@H]1CO1
Yield: 103.1 %

Procedure:
A mixture of 1-[2-methyl-2-((R)-1-oxiranylmethoxy)-propyl]-3-nitro-1H-pyrazole (0.3 g, 1.24 mmol), and ethyl acetate (15 mL), ethanol (15 mL) was subjected to the H-Cube (Thales Nano) at 1 mL/min at 10° C., 10 psi hydrogen. The first time through not completely reduced. Resubjected and complete reduction of nitro group by NMR. Solvent was removed under reduced pressure to afford 1-[2-methyl-2-((R)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3ylamine as an oil (0.27 g, 100%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH2:21])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS[C:24]1[NH:28][C:27](=[O:29])[CH2:26][N:25]=1.[OH-].[Na+]>C(O)C>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH:21][C:24]2[NH:28][C:27](=[O:29])[CH2:26][N:25]=2)=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSC1=NCC(=O)N1
Reactant: NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CN=C(NCc2cccc3cc(S(=O)(=O)c4ccccc4)ccc23)N1

Procedure:
A mixture of C-(6-Benzenesulfonyl-naphthalen-1-yl)-methylamine, 2-methylsulfanyl-3,5-dihydro-imidazol-4-one (prepared by the method reported by Chen et al., WO9736859) and sodium hydroxide in ethanol is heated to reflux, then concentrated under reduced pressure, diluted with ethyl acetate, and washed with aqueous sodium carbonate. The organic phase is dried (magnesium sulfate) and concentrated under reduced pressure to give 2-[(6-benzenesulfonyl-naphthalen-1-ylmethyl)-amino]-3,5-dihydro-imidazol-4-one.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH2:8][OH:9])=[C:5]([CH3:7])[N:6]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].O>ClCCl>[Br:1][C:2]1[S:3][C:4]([CH2:8][O:9][S:18]([CH3:17])(=[O:20])=[O:19])=[C:5]([CH3:7])[N:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(Br)sc1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1nc(Br)sc1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 67.2 %

Procedure:
To an ice-cold solution of (2-Bromo-4-methyl-thiazol-5-yl)-methanol (3.2 g, 15.6 mmol) and triethylamine (3.2 mL, 23.4 mmol) in dichloromethane (80 mL) is slowly added a solution of methanesulfonyl chloride (2.1 g, 18.7 mmol) in dichloromethane (20 mL). The mixture is kept at this temperature for 45 minutes and afterwards allowed to warm to room temperature. Water (30 mL) is added after 3 hours and the mixture is extracted with ethylacetate. The organic phase is separated and dried over MgSO4. The organic solvent is removed under reduced pressure to give 3.0 g of Methanesulfonic acid 2-bromo-4-methyl-thiazol-5-ylmethyl ester, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[F:16][C:17]1[CH:18]=[C:19]([CH:28]=[C:29]([F:32])[C:30]=1[F:31])[CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:23]2[N:22]=[C:21]([CH2:20][C:19]3[CH:18]=[C:17]([F:16])[C:30]([F:31])=[C:29]([F:32])[CH:28]=3)[CH:26]=[CH:25][N:24]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: Fc1cc(Cc2ccnc(Cl)n2)cc(F)c1F
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nccc(Cc3cc(F)c(F)c(F)c3)n2)ccc1-n1cnc(C)c1
Yield: 54 %

Procedure:
The title compound was prepared in analogous manner as described in example 1e) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 4-(3,4,5-trifluoro-benzyl)-2-chloro-pyrimidine. It was obtained as a pale-brown solid in 54% yield.
Reaction SMILES: C([C:6]1[O:7][C:8]2[CH:16]=[C:15](O)[CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[CH:11]=1)(OCC)=O.CC1C=CC2C(=CC=CC=2)N=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CC(C)=O>[O:12]=[C:10]1[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[O:7][CH:6]=[CH:11]1
Reactant: CCOC(=O)c1cc(=O)c2ccc(O)cc2o1
Agent: Cc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: O=c1ccoc2ccccc12

Procedure:
A mixture of 1.5g (6.41 mmoles) of 2-carboethoxy-7- hydroxy-4-oxo-4H-1-benzopyran, 1.82g (6.41 mmoles) of 2-3-chloromethylphenoxy)methylquinoline and 0.886 g of potassium carbonate in 12 ml of dimethylformamide and 96 ml of acetone is refluxed for 2 days, cooled, concentrated in vacuo and the residue taken up in water and is extracted into ethyl acetate. The solution is concentrated and the crude product is recrystallized from ethyl acetate to give 0.585g of 2-carboethoxy-7-(3-quinolin-2-ylmethoxy)benzyloxy)-4-oxo-4H-1-benzopyran as a pale yellow solid having an m.p. of 123°-24° C.
Reaction SMILES: C(Cl)(=O)CCCCC.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:13][CH:14]([CH2:25][CH2:26][CH3:27])[CH:15]([OH:24])[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O.Cl.[NH2:29][OH:30]>C(O)C.N1C=CC=CC=1.CCCCCCC.C(O)C.O>[Cl:13][CH:14]([CH2:25][CH2:26][CH3:27])[CH:15]([OH:24])[C:16](=[N:29][OH:30])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCC(Cl)C(O)C(=O)c1ccccc1
Reactant: NO
Agent: CCCCCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Solvent: CCO
Solvent: c1ccncc1
Solvent: CCCCCCC
Product: CCCC(Cl)C(O)C(=NO)c1ccccc1

Procedure:
o-chloropheol and caproylchloride are converted in a wellknown mode to ester which with aluminium chloride, according to Fries, is rearranged by one-hour heating to 120° C. to 3-chloro-2-hydroxy-caprophenone, between 78° C. and 80° C. in flash point (ethanol/water, n-heptane). 22.6 g (0.1 Mol) of ketone are boiled three hours, along with reflux cooling, together with 15.2 (0.22 Mol) of hydroxylamine hydrochloride in 150 ml of absolute ethanol and 25 ml of pyridine. An oily residue is left, following evaporation of the solvent under vacuum conditions. The oxime, 102° C. to 103° C. in flash point, is obtained from treatment with ethanol/water and recrystallisation from n-heptane.
Reaction SMILES: [C:1]([O:9][CH:10]([C@@H:13]1[CH2:17][C@@H:16]([O:18]C(=O)C)[C@H:15]([N:22]2[C:26]3[N:27]=[C:28]([NH2:32])[NH:29][C:30](=[O:31])[C:25]=3[S:24][C:23]2=[O:33])[O:14]1)[CH2:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CC(O)=O>CO>[C:1]([O:9][CH:10]([C@@H:13]1[CH2:17][C@@H:16]([OH:18])[C@H:15]([N:22]2[C:26]3[N:27]=[C:28]([NH2:32])[NH:29][C:30](=[O:31])[C:25]=3[S:24][C:23]2=[O:33])[O:14]1)[CH2:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(OC(=O)c1ccccc1)[C@@H]1C[C@@H](OC(C)=O)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: CCC(OC(=O)c1ccccc1)[C@@H]1C[C@@H](O)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of 1-[(2S,4R,5R)-4-acetoxy-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl]propyl benzoate (compound 26c, 4.98 g, 10.5 mmol) in methanol (105 mL) was added K2CO3 (1.38 g, 10.0 mmol). After being stirred at room temperature for 1 hour, the reaction was adjusted to pH 7.0 with HOAc (1.2 g, 20.0 mmol), concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 1:200 methanol in DCM) to afford 4.5 g of 1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl benzoate (compound 26d) as a light brown solid. MS obsd. (ESI+) [(M+H)+]: 433.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH2:6][CH2:5]2.[Br:13]Br>C(O)(=O)C>[Br:13][CH:6]1[CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[O:8][C:7]1=[O:12]
Reactant: O=C1CCc2cc(F)ccc2O1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C1Oc2ccc(F)cc2CC1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a solution of 6-fluorochromanone 99.6 g, 0.6 mol) in 500 ml of acetic acid, 96.0 g (0.6 mol) of bromine were added in dropwise at a rate so as to maintain a reaction temperature at 25° C. After stirring the reactants for 2.0 hours at 25° C., the reaction mixture was poured into 1.2 liter of cracked ice with stirring. Resulting precipitate was subsequently filtered, washed with water and then dried on air to give 140 g (95.2%) of the desired compound.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH:9]2[CH2:13][CH2:12][CH2:11][O:10]2)[C:5]([NH2:6])=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.O1CCOCC1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][C:34]([C:37]([OH:40])([CH3:39])[CH3:38])=[N:35][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.C(Cl)Cl.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>[NH2:6][C:5]1[C:7]([CH:9]2[CH2:13][CH2:12][CH2:11][O:10]2)=[CH:8][C:2]([C:31]2[CH:32]=[N:33][C:34]([C:37]([OH:40])([CH3:39])[CH3:38])=[N:35][CH:36]=2)=[CH:3][C:4]=1[N+:14]([O-:16])=[O:15]
Reactant: CC(C)(O)c1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1c(C2CCCO2)cc(Br)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(O)c1ncc(-c2cc(C3CCCO3)c(N)c([N+](=O)[O-])c2)cn1
Yield: 78.8 %

Procedure:
Mixed 4-bromo-2-nitro-6-tetrahydrofuran-2-yl-aniline (6a) (40.40 g, 92%, 129.5 mmol), 1,4-dioxane (260 mL, Sigma-Aldrich 360481), 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol (7) (41.05 g, 155.4 mmol), and aqueous 2.7 M Na2CO3 (143.9 mL, 388.5 mmol). A stream of nitrogen was bubbled through the stirring mixture for 1 hr, followed by addition of tetrakis(triphenylphosphine)palladium (0) (7.48 g, 6.47 mmol, Strem 462150). The reaction mixture was stirred at reflux for 2 hrs (HPLC showed complete reaction), allowed to cool, diluted with EtOAc, washed with water, saturated aqueous NH4Cl, brine, dried over MgSO4, and filtered through a short plug of Florisil® eluting with EtOAc. The filtrate was concentrated under reduced pressure giving a dark brown oil. Dissolved in CH2Cl2 and eluted through a short plug of silica gel with CH2Cl2 and then EtOAc. The desired fraction was concentrated on a rotary evaporator until a precipitate formed giving a thick brown slurry, which was triturated with MTBE. The solid was collected by filtration, washed with MTBE, and dried under high vacuum giving (8) as a yellow solid (35.14 g, 99+% HPLC purity,). LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 345.00 (2.69 min). 1H NMR (300 MHz, CDCl3) δ 8.88 (s, 2H), 8.36 (d, J=2.2 Hz, 1H), 7.56 (d, J=2.1 Hz, 1H), 7.09 (s, 2H), 4.92 (t, J=7.2 Hz, 1H), 4.62 (s, 1H), 4.20-4.11 (m, 1H), 4.03-3.94 (m, 1H), 2.39-2.26 (m, 1H), 2.23-2.08 (m, 3H), 1.64 (s, 6H) ppm. The filtrate was further concentrated and purified by ISCO silica gel chromatography eluting with 0 to 80% EtOAc/hexane giving a second crop of product (8) as an amber solid (4.46 g, 88% overall yield; 88% HPLC purity.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[C:41]([CH3:43])[N+:40]([O-:44])=[C:39]([CH3:45])[CH:38]=1>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:37]3[CH:42]=[C:41]([CH3:43])[N+:40]([O-:44])=[C:39]([CH3:45])[CH:38]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cc1cc(Br)cc(C)[n+]1[O-]
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc(C)[n+]1[O-]

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-bromo-2,6-dimethylpyridine-N-oxide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.185, m/z=459.1; 1H NMR (CDCl3) 1.11 (s, 3H), 1.18 (s, 3H), 1.57 (d, 3H), 2.20 (s, 2H), 2.22-2.35 (m, 2H), 2.38-2.49 (m, 1H), 2.72 (s, 6H), 2.91 (m, 1H), 5.70 (m, 1H), 7.08 (d, 2H), 7.31 (m, 3H), 7.37 (m, 4H), 7.43 (s, 2H).
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: O=[N+]([O-])O
Reactant: Cc1ccccc1
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: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19][CH:20]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)=[O:25])[C:21](O)=[O:22]>>[F:34][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=1)[CH2:27][NH:26][C:24](=[O:25])[CH:20]([CH3:19])[C:21]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:22]
Reactant: CC(C(=O)O)C(=O)NCc1cccc(F)c1
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Product: CC(C(=O)NCc1cccc(F)c1)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=446.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and 2-methyl-N-(3-fluoro-benzyl)-malonamic acid.