Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[OH:16][C@@H:17]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]1.Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CN(C=O)C>[CH2:34]([O:33][C:31]([CH2:30][O:16][C@@H:17]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]1)=[O:32])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)CO[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of sodium bis(trimethylsilyl)amide in THF (58.7 mL, 58.75 mmol) was added dropwise to a stirred solution of (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (10 g, 53.41 mmol) in DMF (100 mL) over a period of 10 minutes under nitrogen. The resulting solution was stirred at ambient temperature for 10 minutes. Ethyl bromoacetate (8.92 g, 53.41 mmol) was added dropwise over 10 minutes (exotherm. Temperature kept below 30° C. using a cold water bath) and the reaction was stirred at ambient temperature for 20 hours.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]2[CH:12]=[C:11]([C:13](O)=[O:14])[CH:10]=[CH:9][N:8]2[C:16]=1[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:37][NH2:38].O>C1COCC1>[C:1]([C:5]1[N:6]=[C:7]2[CH:12]=[C:11]([C:13]([NH:37][NH2:38])=[O:14])[CH:10]=[CH:9][N:8]2[C:16]=1[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)c1nc2cc(C(=O)O)ccn2c1CC1CCCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1nc2cc(C(=O)NN)ccn2c1CC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
2-tert-Butyl-3-cyclohexylmethylimidazo[1,2-a]pyridine-7-carboxylic acid (500 mg, 1.59 mmol) was suspended in THF (5.0 mL), and the suspension was stirred at room temperature for 1 hour after adding carbonyldiimidazole (CDI) (280 mg, 1.73 mmol). The reaction mixture was stirred at room temperature for 1 hour after adding hydrazine monohydrate (0.240 mL, 4.80 mmol). Water was added to the reaction mixture. The precipitated solid was collected by filteration, and dried under reduced pressure to give 2-tert-butyl-3-cyclohexylmethylimidazo[1,2-a]pyridine-7-carbohydrazide (331 mg, yield 79%).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=2)=O)[CH2:3][CH2:2]1.O.NN.[OH-].[K+]>C(O)CO>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:4][CH:1]2[CH2:2][CH2:3]2)=[CH:7][CH:8]=1
Reactant: O=C(c1ccc(Br)cc1)C1CC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Brc1ccc(CC2CC2)cc1
Yield: 49.2 %

Procedure:
4-Bromophenyl cyclopropyl ketone (5.63 g), hydrazine monohydrate (2.5 ml) and potassium hydroxide (3.33 g) were added to ethylene glycol (25 ml) and the mixture heated to reflux for 1 hour. The reaction mixture was cooled and partitioned between water (20 ml) and ethyl acetate (30 ml) and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (30 ml) and the combined organic phases were washed with 2M hydrochloric acid (15 ml) and water (15 ml) then dried (MgSO4) and evaporated. The residue was purified by chromatography on a Mega Bond Elut column, eluting with hexane to give 1-bromo-4-(cyclopropylmethyl)benzene (2.6 g); 1H NMR (CDCl3): 0.2 (m, 2 H), 0.55 (m, 2 H), 2.50 (d, 2 H), 7.14 (d, 2 H), 7.41 (d, 2 H); mass spectrum (EI+) 210 (M.)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]([CH2:13][CH2:14][CH2:15][O:16][C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[S:19][N:18]=2)[CH3:12])=[CH:5][CH:4]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[NH:2]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][N:11]([CH2:13][CH2:14][CH2:15][O:16][C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[S:19][N:18]=2)[CH3:12])=[CH:7][CH:8]=1)[C:28]([CH3:29])=[O:30]
Reactant: CN(CCCOc1nsc(-c2ccccc2)n1)CCc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(CCN(C)CCCOc2nsc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
300 mg of 3-{3-[N-(2-(4-aminophenyl)-ethyl)-N-methylamino]-propyloxy}-5-phenyl-1,2,4-thiadiazole (for preparation, see Example 62) were dissolved in 4 ml pyridine. 1 ml of acetic acid anhydride was added to the solution and the reaction mixture was stirred for 2 hours at room temperature. For workup, it was poured over ice and the mixture made alkaline by adding sodium carbonate solution. Then extraction was performed with ethyl acetate, the organic phase was separated, and concentrated to dryness. The crude oily title compound obtained was purified by medium-pressure chromatography over fine-grained silica gel (Lichroprep Si 60®) using 95:5 ethyl acetate/methanol as the eluent. 0.12 g of the title compound were obtained as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:14][N:15]([CH3:17])[CH3:16])[N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.Cl[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:19][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8](=[N:14][N:15]([CH3:17])[CH3:16])[N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:22][CH:23]=1
Reactant: ClCOc1ccc(Cl)cc1
Reactant: CN(C)N=C(c1ccccc1O)n1ccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)N=C(c1ccccc1OCOc1ccc(Cl)cc1)n1ccnc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.7 %

Procedure:
To a solution of the Compound No. 13 (0.20 g, 0.869 mmol) obtained in Example 13 in N,N-dimethylformamide (3 ml) were added α,4-dichloroanisole (0.175 g, 0.989 mmol) and potassium carbonate (0.17 g, 1.23 mmol), and the mixture was stirred at room temperature for 20 hr. Ethyl acetate was added to the reaction mixture, the mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give the object compound (0.202 g, 0.545 mmol, yield 63%).
Reaction SMILES: C[O:2][CH:3](OC)/[C:4](/[CH3:11])=[CH:5]\[C:6]([O:8][CH2:9][CH3:10])=[O:7]>C(OCC)(=O)C.[Pd]>[CH:3]([CH:4]([CH3:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:2]
Reactant: CCOC(=O)/C=C(/C)C(OC)OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(C)C=O
Yield: 47.4 %

Procedure:
A solution of ethyl 3-(dimethoxymethyl)-crotonate (73 g) in ethyl acetate (200 ml) was hydrogenated at 50 psi for 3 h in the presence of 10% palladium on charcoal (7 g). The solution was filtered, evaporated, and the residual oil treated with 0.25 M hydrogen chloride in 75% aqueous methanol for 2 h. To the reaction mixture was added ethyl acetate (300 ml) and water (150 ml). The organic phase was successively washed with sat. sodium bicarbonate solution (3×150 ml), water (100 ml) and dried over magnesium sulfate. The solution was concentrated in vacuo and the residual oil purified by chromatography on silica gel eluting with ethyl acetate-hexane (1:9) to give ethyl 3-formylbutyrate (26.5 g, 48%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(Br)cc1
Yield: 96 %

Procedure:
A solution of 4-bromoaniline (10 g, 58.13 mmol) in acetic anhydride (50 mL) was stirred for 20 minutes at room temperature, and then collected by filtration to give N-(4-bromophenyl)acetamide (12 g, 96%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[O-]CC.[Na+].Cl[C@@H:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[S:27][CH2:28][C:29]([OH:31])=[O:30].Cl>C(O)C.O>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][C@@H:22]2[CH2:26][CH2:25][CH2:24][C@H:23]2[S:27][CH2:28][C:29]([OH:31])=[O:30])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: O=C(O)CS[C@@H]1CCC[C@H]1Cl
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(S[C@@H]2CCC[C@H]2SCC(=O)O)cc(C(C)(C)C)c1O
Reaction time: 1.5 h

Procedure:
2.6-bis(1.1-Dimethylethyl)-4-mercaptophenol (0.73 g, 0.0031 mole) was added to freshly prepared sodium ethoxide [sodium (0.16 g, 0,007 mole)] in ethanol (10 ml). Once dissolved, the product of Example 4 (0.50 g, 0.0026 mole) was added and the reaction mixture was stirred for 90 minutes and poured into water (50 ml) containing 1N hydrochloric acid (25 ml). The mixture was extracted three times with 20 ml of diethyl ether, and the combined extracts were washed with water (20 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to an oil with a rotary evaporator. The product was purified by silica gel chromatography. The structure was supported by NMR and elemental analysis.
Reaction SMILES: O.CC(C)=[O:4].OS(O)(=O)=O.O=[Cr](=O)=O.[F:15][C:16](=[C:20]([F:22])[F:21])[CH2:17][CH2:18][OH:19]>CC(C)=O>[F:15][C:16](=[C:20]([F:22])[F:21])[CH2:17][C:18]([OH:4])=[O:19]
Reactant: OCCC(F)=C(F)F
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CC(F)=C(F)F

Procedure:
A mechanically stirred 12 L glass reactor clad with a jacket cooled with tap water was charged with 100 mL of acetone and 100 mL of Jones reagent. A solution of 3,4,4-trifluoro-3-buten-1-ol (850 g, 6.75 mol) diluted to a total volume of 5.0 L in acetone was added simultaneously with 5.0 L of Jones reagent via a twin head peristaltic pump capable of a pump rate ca. 120 mL/min. A reaction temperature of 51°-54° C. was maintained by adjusting the pump rate and the tap water cooling flow. Following the addition (45 min), the mixture was allowed to cool to 35°-40° C. over 30-60 min. The reaction mixture was transferred to a separatory funnel and layers separated. The upper layer was washed once with brine and concentrated. The lower layer was diluted with water (500 mL) and extracted with dichloromethane (3L). The dichloromethane extract was combined with the above residue, washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave 613g (65%) of the desired product as a green oil.
Reaction SMILES: [Si:1]([O:8][C:9]([C:11]([F:27])([F:26])[C@H:12]([C@@H:14]([CH:16]([C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:17])[OH:15])[OH:13])=[O:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.[F:34][C:35]([F:48])([F:47])[S:36]([O:39]S(C(F)(F)F)(=O)=O)(=[O:38])=[O:37]>ClCCl>[Si:1]([O:8][C:9]([C:11]([F:26])([F:27])[C@:12]([O:39][S:36]([C:35]([F:48])([F:47])[F:34])(=[O:38])=[O:37])([C@@H:14]([CH:16]([C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:17])[OH:15])[OH:13])=[O:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)OC(=O)C(F)(F)[C@@H](O)[C@H](O)C(O)C(=O)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(=O)C(F)(F)[C@](O)(OS(=O)(=O)C(F)(F)F)[C@H](O)C(O)C(=O)c1ccccc1
Temperature: -20 °C
Reaction time: 0.67 h
Yield: 85.9 %

Procedure:
To a solution of 2.3 gm (5.9 mMol) 1-t-butyldimethylsilyloxy-5-benzoyl-2-deoxy-2,2-difluoroxylose in dichloromethane (100 mL) were added 7.2 mL (88.5 mMol) pyridine and the reaction mixture was cooled to -20° C. To this was then added a solution of 1.5 mL (8.9 mMol) trifluoromethanesulfonic anhydride in dichloromethane (20 mL) dropwise at such a rate as to maintain the temperature between -5° and -20° C. The reaction mixture was stirred for 40 minutes at -15° C. The reaction mixture was then allowed to warm to room temperature and was washed with saturated aqueous sodium bicarbonate. The remaining organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 2.8 gm (90%) of the desired compound as a yellow oil. FD-MS: m/e=463(M-57, loss of t-butyl).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.Br[CH2:14][C:15]1[CH:34]=[CH:33][C:18]2/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=3[O:22][CH2:23][C:17]=2[CH:16]=1>>[CH:1]1([C:4]2[N:5]([CH2:14][C:15]3[CH:34]=[CH:33][C:18]4/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=5[O:22][CH2:23][C:17]=4[CH:16]=3)[C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2[nH]c(C3CC3)nc2c1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(Cn3c(C4CC4)nc4ccccc43)cc2COc2cc(F)ccc21
Yield: 96.3 %

Procedure:
Using 2-cyclopropyl-1H-benzo[d]imidazole (Europeane Journal of Organic Chemistry, 2000, p 1229, 69 mg, 0.434 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (160 mg, 0.447 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (182 mg, 95%) was obtained.
Reaction SMILES: Cl.C(O[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])C.C([O-])(=O)C.[NH4+:18]>C(O)C>[N+:11]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:5]=1[NH2:18])([O-:13])=[O:12]
Reactant: CCOc1ccncc1[N+](=O)[O-]
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCO
Product: Nc1ccncc1[N+](=O)[O-]
Temperature: 4 °C
Yield: 118.2 %

Procedure:
A 50 ml 3-neck round bottom flask fitted with a condenser, thermometer and mechanical stirrer was charged with 3.0 g (14.66 mmol) of 4-ethoxy-3-nitropyridine hydrochloride, 6.1 g (79.9 mmol) of ammonium acetate and 6.7 ml of absolute ethanol. The reaction mixture was refluxed for approximately 24 hours and cooled to about 4° C. The pH of the solution was adjusted to 8.0 with base and the precipitated solid was collected by filtration. The product was rinsed with chilled ethanol and dried in vacuo at 50° C. to afford 2.41 g of 3-nitro-4-aminopyridine (and a small amount of ammonium acetate). The identity of the product was verified by NMR comparison to an authentic sample.
Reaction SMILES: [CH2:1]([N:3]([CH3:13])[C:4]1[CH:5]=[C:6]([OH:12])[C:7](=[CH:10][CH:11]=1)[CH:8]=O)[CH3:2].[NH2:14][CH2:15][C:16]([NH2:19])([CH3:18])[CH3:17]>>[CH2:1]([N:3]([C:4]1[CH:5]=[C:6]([OH:12])[C:7](=[CH:10][CH:11]=1)[CH:8]=[N:14][CH2:15][C:16]([CH3:18])([N:19]=[CH:8][C:7]1[C:6](=[CH:5][C:4]([N:3]([CH3:13])[CH2:1][CH3:2])=[CH:11][CH:10]=1)[OH:12])[CH3:17])[CH3:13])[CH3:2]
Reactant: CCN(C)c1ccc(C=O)c(O)c1
Reactant: CC(C)(N)CN
Product: CCN(C)c1ccc(C=NCC(C)(C)N=Cc2ccc(N(C)CC)cc2O)c(O)c1

Procedure:
Synthesis and working up are carried out as in Example 9, starting from 500 mg (2.79 mmol) of 4-(ethylmethylamino)salicylaldehyde and 117 mg (1.33 mmol) of 1,2-diamino-2-methylpropane.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:11](=[O:19])[NH:12][C:13]4[N:14]([N:16]=[CH:17][N:18]=4)[C:15]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].[Na].[CH3:21]I>COCCOCCOC>[CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:11](=[O:19])[N:12]([CH3:21])[C:13]4[N:14]([N:16]=[CH:17][N:18]=4)[C:15]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c1ncc1c(=O)[nH]c3ncnn3c12
Reactant: CI
Agent: [Na]
Solvent: COCCOCCOC
Product: CCn1ncc2c1ncc1c(=O)n(C)c3ncnn3c12
Reaction time: 0.5 h

Procedure:
2.6 g. of 8-ethyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one (0.01 mol.) are treated with 0.3 g. of sodium in 50 ml. of diethyleneglycol dimethyl ether at reflux temperature with stirring for 30 minutes. After this time, the temperature is lowered to 60° and 3 g. of methyl iodide are added. Stirring and heating is continued for 12 hours. The precipitate of sodium iodide is filtered off and the solvent distilled from the mother liquor. The remaining 8ethyl-4-methyl-4Hpyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin5(8H)-one is recrystallized from butanol, yield 2 g. (75%); m.p. 208°-210°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[C:5]([OH:16])=[CH:6][C:7]=1[S:8]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)(=[O:10])=[O:9].C([O:20][C:21](=[O:25])[CH:22](Cl)Cl)C.C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC.O>[CH3:1][C:2]1[C:7]([S:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)(=[O:10])=[O:9])=[CH:6][C:5]2[O:16][CH:22]([C:21]([OH:25])=[O:20])[O:17][C:4]=2[CH:3]=1
Reactant: Cc1cc(O)c(O)cc1S(=O)(=O)c1cccs1
Reactant: CCOC(=O)C(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc2c(cc1S(=O)(=O)c1cccs1)OC(C(=O)O)O2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a manner analogous to that described in Example 4, 30.0 g (111 mmol) of 4-methyl-5-(2-thienylsulphonyl)-1,2-benzenediol, 17.4 g (111 mmol) of dichloroacetic acid ethyl ester and 76.7 g (555 mmol) of potassium carbonate in 300 ml of 1,2-dimethoxyethane are boiled under reflux. After 18 hours, the reaction mixture is poured into water, stirred for one hour at room temperature and then adjusted to pH 1-2 by means of hydrochloric acid. Some of the 1,2-dimethoxyethane is distilled off in vacuo and the mixture remaining is extracted with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated by evaporation in a rotary evaporator. The resulting dark-red oil is chromatographed over silica gel. As eluant, a mixture of chloroform/methanol/concentrated ammonia in a ratio of 40:10:1 is used until elution of the starting diol, then an analogous mixture in a ratio of 12:5:1 is used. The uniform fractions are combined and concentrated almost completely by evaporation. Ice/water is added to the residue and the pH is adjusted to 1-2 with concentrated hydrochloric acid. The acidic solution is extracted with ethyl acetate. The combined organic phases are washed, dried and concentrated by evaporation. The residue is boiled in diisopropyl ether and the black sludge formed is removed by decanting. The clear solution is concentrated to a large extent and the substance which has crystallised out is filtered off with suction. The crystals are recrystallised from 1,2-dichloroethane, yielding 5-methyl-6-(2-thienylsulphonyl)-1,3-benzodioxole-2-carboxylic acid in the form of white crystals having a melting point of 162.5°-164.5°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=1[NH2:8].[CH3:11][O:12][CH2:13][CH2:14][C:15](O)=O.[OH-].[Na+]>CO>[CH3:11][O:12][CH2:13][CH2:14][C:15]1[NH:1][C:2]2[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=2[N:8]=1
Reactant: Cc1cc(O)cc(N)c1N
Reactant: COCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCc1nc2c(C)cc(O)cc2[nH]1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
0.65 g (4.70 mmol) 3,4-diamino-5-methylphenol were placed in a little methanol and 0.94 mL (10.00 mmol) 3-methoxypropionic acid was added. First the methanol was distilled off and then the mixture was stirred for 2 h at 140° C. The reaction mixture was taken up in DMF/MeOH and purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with an aqueous 4M NaOH solution and extracted with ethyl acetate. The organic phase was dried and evaporated down i.vac. and dried.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[N:10]=[C:9]([NH:15][C:16]([NH:18][S:19]([C:22]2[CH:27]=[C:26]([NH2:28])[CH:25]=[CH:24][C:23]=2[C:29]([N:31]([CH3:33])[CH3:32])=[O:30])(=[O:21])=[O:20])=[O:17])[N:8]=1>CC(N(C)C)=O>[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[N:10]=[C:9]([NH:15][C:16]([NH:18][S:19]([C:22]2[CH:27]=[C:26]([NH:28][C:1](=[O:3])[CH3:2])[CH:25]=[CH:24][C:23]=2[C:29]([N:31]([CH3:33])[CH3:32])=[O:30])(=[O:21])=[O:20])=[O:17])[N:8]=1
Reactant: CC(=O)Cl
Reactant: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cc(N)ccc2C(=O)N(C)C)n1
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cc(NC(C)=O)ccc2C(=O)N(C)C)n1

Procedure:
0.13 ml of acetyl chloride is slowly added dropwise to a mixture of 0.64 g of N-[(4,6dimethoxypyrimidin-2-yl)aminocarbonyl]-5-amino-2-dimethylaminocarbonylbenzenesulfonamide and 10 ml of dimethylacetamide. After the end of reaction, the reaction mixture is concentrated under reduced pressure and the residue is washed with water and ethyl acetate, to give 0.45 g of the desired product in high purity (>92%, HPLC).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].F[C:15]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:16]=1[CH2:17][N:18]([CH3:29])[C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CS(C)=O>[CH2:21]([O:20][C:19]([N:18]([CH2:17][C:16]1[CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[CH:32]=[CH:33][C:15]=1[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH3:29])=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CN(Cc1cc([N+](=O)[O-])ccc1F)C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])cc1CN(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.7 %

Procedure:
To sodium hydride (60% dispersion) (1.885 g, 47.1 mmol), was added DMSO (20 mL). The mixture was stirred for 5 min, then diethyl malonate (7.15 mL, 47.1 mmol) was added. The reaction mixture was stirred at rt for 15 min to give a clear colorless solution. To this mixture was added a solution of benzyl 2-fluoro-5-nitrobenzyl(methyl)carbamate (3 g, 9.43 mmol) in DMSO (1 mL) dropwise. The orange reaction mixture was stirred at rt for 1 h, then at 65° C. for 3 h. The reaction mixture was cooled to rt, quenched with sat. NH4Cl. The mixture was diluted with EtOAc. The organic phase was washed with H2O (2×) and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (loaded in chloroform onto a 120 g column and eluted with a gradient from 0 to 30% ethyl acetate/hexanes) to give 10A (3.88 g, 8.46 mmol, 90% yield). MS (ESI) m/z: 458.9 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.[NH2:14][OH:15].Cl>CCO>[OH:15][NH:14][C:8](=[NH:9])[C:7]1[CH:10]=[CH:11][C:4]([O:3][C:2]([F:1])([F:12])[F:13])=[CH:5][CH:6]=1
Reactant: N#Cc1ccc(OC(F)(F)F)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: N=C(NO)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
To a solution of 4-(trifluoromethoxy)benzonitrile (2.0 g, 10.6 mmol) in EtOH (20 mL), TEA (53 g, 53.0 mmol) and NH2OH.HCl (3.6 g, 26.5 mmol) were added in sequence. The mixture was refluxed for 4 h, cooled to RT, and concentrated under reduced pressure. The residue was diluted with H2O (20 mL), and extracted with EtOAc (20 mL×3). The combined organic layers were washed with H2O (1×10 mL) and brine (1×10 mL), dried over Na2SO4, filtered and concentrated to afford the crude N-hydroxy-4-(trifluoromethoxy)benzimidamide (2.0 g, 85%), which was directly used for next reaction without further purification. MS (ES+) C8H7F3N2O2 requires: 220, found: 221 [M+H]+.