Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.S(=O)(=O)(O)O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:31])[C:21]([NH:23][C:24]([C:29]#N)([CH3:28])[CH:25]([CH3:27])[CH3:26])=[O:22])=[CH:16][CH:15]=1.[OH-:32].[Na+]>O.C(O)(=O)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:21]2[O:22][C:28](=[O:32])[C:24]([CH:25]([CH3:27])[CH3:26])([CH3:29])[N:23]=2)[CH3:31])=[CH:16][CH:15]=1
Reactant: [OH-]
Reactant: CC(C(=O)NC(C)(C#N)C(C)C)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC(C1=NC(C)(C(C)C)C(=O)O1)c1ccc(Cl)cc1
Yield: 99.6 %

Procedure:
450 ml of toluene, 45 g (0.44 mole) of concentrated sulfuric acid and 45 ml of glacial acetic acid were added to 126.7 g (0.45 mole) of 2-(4-chlorophenyl)-N-(1-cyano-1,2-dimethylpropyl)propanamide. The mixture was refluxed for 4 hours with heating, to give rise to a reaction. After the completion of the reaction, the reaction mixture was cooled and dropwise added to a solution of 18.2 g (0.45 moles) of sodium hydroxide dissolved in 300 ml of water. The organic layer was separated, then washed with a saturated aqueous sodium bicarbonate solution and water, and concentrated to obtain 125 g (0.448 mole) of 2-[1-(4-chlorophenyl)ethyl]-4-isopropyl-4-methyl-1,3-oxazol-5-one (yield=99.6%).
Reaction SMILES: [OH:1][CH:2]([CH:6]([S:21][CH2:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:3]([NH2:5])=[O:4].N1C=CC=CC=1.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)Cl>[C:37]([O:1][CH:2]([CH:6]([S:21][CH2:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:3]([NH2:5])=[O:4])(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2ccccc2C(SCC(=O)c2ccccc2)C(O)C(N)=O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(-c2ccccc2C(SCC(=O)c2ccccc2)C(OC(C)=O)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a mixture of 4.0 g (0.0116 mol) of rac.-(R, R*)-α-hydroxy-4-methoxyphenyl-β-[(2-oxo-2-phenylethyl) thio]benzenepropanamide, 130 mL of methylene chloride and 5 mL of pyridine cooled in an ice-bath was added dropwise a solution of 1.25 g (0.0126 mol) of acetyl chloride in 25 mL of methylene chloride. The mixture was stirred at this temperature for one hour and at room temperature for 17 hours. After dilution with water the aqueous suspension was extracted with methylene chloride. The methylene chloride solution was dried (MgSO4) and removal of the solvent gave a residue which was washed with hexane. The crude product was crystallized from ethyl acetate to give 4.1 g (93%) of rac.-(R,*R*)-α-(acetyloxy)-4-methoxyphenyl-β-[(2-oxo-2-phenylethyl)thio]benzeneprop anamide, mp 154°-155°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1.[C:13](=O)(O)[O-].[Na+]>CO.S(Cl)(Cl)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1
Reactant: O=C([O-])O
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1n[nH]c2ccccc12
Yield: 94 %

Procedure:
To a solution of 1H-indazole-3-carboxylic acid (5.0 g, 30.8 mmol) in methanol (50 mL), thionyl chloride (15 mL) was added dropwise at 0° C. After the addition, the mixture was heated to reflux and maintained at the temperature for 1.5 hours. Then the reaction mixture was concentrated to give a residue. To the residue was added saturated sodium bicarbonate (50 mL), and then extracted with ethyl acetate (50 mL×3). The organic phase was combined and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to give methyl 1H-indazole-3-carboxylate as a white solid (5.1 g, 94%). 1H NMR (300 MHz, d6-DMSO): δ 13.91 (s, 1H), 8.06 (d, J=8.2 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.44 (ddd, J=8.3 Hz, J=6.9 Hz, J=1.1 Hz, 1H), 7.30 (ddd, J=7.9 Hz, J=6.9 Hz, J=0.9 Hz, 1H), 3.92 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[C:24]4[CH2:23][CH2:22][C:21]5[N:20]=[C:19]([CH:25]([OH:28])CO)[CH:18]=[CH:17][C:16]=5[C:15]=4[O:14][N:13]=3)[C:8]=2[C:29]([F:32])([F:31])[F:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=O.[Na+].O>C1COCC1.C(OCC)(=O)C>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[C:24]4[CH2:23][CH2:22][C:21]5[N:20]=[C:19]([CH:25]=[O:28])[CH:18]=[CH:17][C:16]=5[C:15]=4[O:14][N:13]=3)[C:8]=2[C:29]([F:31])([F:32])[F:30])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCC(O)c1ccc2c(n1)CCc1c(-c3noc(-c4ccccc4)c3C(F)(F)F)noc1-2
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc2c(n1)CCc1c(-c3noc(-c4ccccc4)c3C(F)(F)F)noc1-2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 104.4 %

Procedure:
To a solution of 1-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydroisoxazolo[5,4-f]quinolin-7-yl)ethane-1,2-diol (Preparation 54G, 0.030 g, 0.068 mmol) in THF (1 mL) at room temperature was added sodium periodate (0.022 g, 0.101 mmol) followed by water (0.05 mL). The reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (10 mL), and brine (10 mL). The combined aqueous layers were extracted with ethyl acetate (30 mL), dried over and anhydrous sodium sulfate and concentrated to give 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydroisoxazolo[5,4-f]quinoline-7-carbaldehyde (0.029 g, 0.071 mmol, quantitative yield) as a tan solid. The compound had an HPLC ret. time=3.08 min. (condition A); LC/MS M+1=412.1.
Reaction SMILES: [CH3:1][C:2]12[CH2:12][CH:11]1[C:10]1[C:9]([O:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=3)=[CH:8][CH:7]=[CH:6][C:5]=1[O:4][CH2:3]2.O.[Cl-].[NH4+].ON>O1CCCC1.[Fe]>[CH3:1][C:2]12[CH2:12][CH:11]1[C:10]1[C:9]([O:13][C:14]3[N:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=3)=[CH:8][CH:7]=[CH:6][C:5]=1[O:4][CH2:3]2
Reactant: CC12COc3cccc(Oc4ccc([N+](=O)[O-])cn4)c3C1C2
Agent: [Fe]
Agent: NO
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CC12COc3cccc(Oc4ccc(N)cn4)c3C1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
To a solution of 2-[(1a-methyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-7-yl)oxy]-5-nitropyridine (Intermediate 126, 250 mg) in tetrahydrofuran (6 ml)/water (3 ml) were added iron (234 mg, 4.19 mmol) and ammonium chloride (224 mg, 4.19 mmol). The reaction mixture was stirred at room temperature overnight at which time UPLC showed partial formation of the target compound with some hydroxyl-amine intermediate, therefore additional 3 equivalents of ammonium chloride and iron were added and the reaction was left stirring for an other 5 hours. The iron was then filtered off over a pad of celite and the solution was diluted with an aqueous saturated solution of NaHCO3 (100 ml) and ethyl acetate (200 ml). Two phases were separated and the aqueous layer was extracted with ethyl acetate. Organic layers were combined, dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography (Companion system, with a gradient from cyclohexane/ethyl acetate 8:2 to cyclohexane/ethyl acetate 1:1) to give the title compound as a light brown solid (150 mg).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH:11]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[F:28])[C:21]([CH3:30])([CH3:29])[C:20]1=[O:31])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[N:19]([CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH2:10][CH2:9][OH:8])[C:20](=[O:31])[C:21]2([CH3:30])[CH3:29]
Reactant: CC1(C)C(=O)N(C(CCO[Si](C)(C)C(C)(C)C)c2cccc(F)c2)c2c(F)cccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C)C(=O)N(C(CCO)c2cccc(F)c2)c2c(F)cccc21
Reaction time: 1 h
Yield: 97.2 %

Procedure:
1-[3-{[tert-butyl(dimethyl)silyl]oxy}-1-(3-fluorophenyl)propyl]-7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (0.80 g, 1.8 mmol) was dissolved in tetrahydrofuran and tetrabutyl ammonium fluoride (1.0 M in THF, 5.3 mL, 5.3 mmol) was added and the mixture was stirred for 1 hour. Reaction was quenched with saturated aqueous ammonium chloride then saturated sodium bicarbonate was added, diluted with ether, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 5-50% ethyl acetate in hexane) to afford 0.58 g (97%) racemic 7-fluoro-1-[1-(3-fluorophenyl)-3-hydroxypropyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one that was resolved by chiral HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[N:9]([CH:19]2[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]2)[C:8]1=[O:27].Br[CH2:34][C:35]#[N:36].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:34][C:35]#[N:36])[CH:14]=2)[N:9]([CH:19]2[CH2:20][CH2:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24]2)[C:8]1=[O:27]
Reactant: COc1ccc(Cn2c(=O)c3cc(O)ccc3n(C3CCS(=O)(=O)CC3)c2=O)cc1OC
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3cc(OCC#N)ccc3n(C3CCS(=O)(=O)CC3)c2=O)cc1OC
Yield: 72.1 %

Procedure:
A mixture of 0.055 g of the compound obtained in Step 18.2, 0.017 g of bromoacetonitrile and 0.078 g of Cs2CO3 in 2 ml of DMF is irradiated in a microwave field for 15 minutes at 100° C. The reaction mixture is evaporated under reduced pressure. The residue is taken up in DCM, washed with water, dried over Na2SO4 and filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with an MeOH/DCM mixture from (0.5/99.5, v/v) to (5/95, v/v), to give 0.043 g of the expected product.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([CH:19]=O)[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO.C1COCC1>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([CH2:19][N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: O=Cc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: c1cc2nc(N3CCN(C4CC4)CC3)sc2cc1CN1CCOCC1
Temperature: 63 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
To a solution of 2-(4-cyclopropylpiperazin-1-yl)benzothiazole-6-carboxaldehyde (500 mg, 1.7 mmol) in MeOH (14 mL) and THF (28 mL) was added morpholine (296 mg, 3.4 mmol), acetic acid (22 mg, 0.4 mmol) and NaCNBH3 (158 mg, 2.7 mmol). The mixture was stirred at 63° C. overnight. Then the resulting mixture was concentrated under reduced pressure and the residue was diluted with dichloromethane (15 mL). The mixture was washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 306 mg (31%) of 2-(4-cyclopropylpiperazin-1-yl)-6-(morpholin-4-ylmethyl)benzothiazole as a trifluoroacetate salt.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([CH2:13][CH2:14][CH2:15][C:16]([NH:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])=[O:17])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]([C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[N:3]=1.N1C=CC=CC=1.[CH3:41][C:42]([CH3:47])([CH3:46])[C:43](Cl)=[O:44]>>[O:21]([CH2:20][CH2:19][NH:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13][C:5]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:4]([C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[N:3]=[C:2]([NH:1][C:43](=[O:44])[C:42]([CH3:47])([CH3:46])[CH3:41])[S:6]1)[Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:24])[CH3:23]
Reactant: CC(C)(C)C(=O)N1N=C(N)SC1(CCCC(=O)NCCO[Si](C)(C)C(C)(C)C)c1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)NC1=NN(C(=O)C(C)(C)C)C(CCCC(=O)NCCO[Si](C)(C)C(C)(C)C)(c2ccccc2)S1
Yield: 85.2 %

Procedure:
In the same manner as that in Step 3 of Reference Example 20, from the optically active 4-[5-amino-3-(2,2-dimethylpropionyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl]-N-[2-(tert-butyldimethylsiloxy)ethyl]butanamide (0.0683 g, 0.135 mmol) obtained in Step 6 mentioned above, pyridine (131 μL, 1.62 mmol) and trimethylacetyl chloride (0.166 mL, 1.35 mmol), optically active N-[2-(tert-butyl-dimethylsiloxy)ethyl]-4-[3-(2,2-dimethylpropionyl)-5-(2,2-dimethylpropionylamino)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl]butanamide (68.0 mg, 83%) was obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:12](O)[CH2:13][OH:14].C(OCC)(OCC)OCC>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:10]([O:9][C:7]([CH:3]1[CH2:4][CH2:5][CH2:6][C:2]21[O:14][CH2:13][CH2:12][O:1]2)=[O:8])[CH3:11]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCCC12OCCO2
Yield: 128.1 %

Procedure:
A mixture of ethyl 2-oxocyclopentanecarboxylate (Aldrich, 10.0 g, 64.0 mmol), ethylene glycol (18 mL, 323 mmol), triethyl orthoformate (21 mL, 126 mmol) and p-toluenesulfonic acid monohydrate (0.61 g, 3.21 mmol) in toluene (150 mL) was heated under reflux with removing distillate with a Dean-Stark apparatus for 1 h. The mixture was cooled and poured into NaHCO3 solution, and the organic layer was separated. The aqueous layer was extracted with diethyl ether, and the combined organic layers were washed with NaCl solution and dried over Na2SO4. Filtration and concentration gave 16.41 g of 2, as a pale yellow oil, which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[H][H]>O1CCCC1.[Pd]>[CH3:1][CH:2]([CH2:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH2:3][CH2:4][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(CC(=O)c1ccccc1)CC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(CCc1ccccc1)CC(C)(C)C

Procedure:
A solution of 116.5 grams of 3,5,5-Trimethylhexanoylbenzene in 1500 mL of tetrahydrofuran with 9.9 grams of 10% palladium on carbon (as a catalyst) was stirred at 23° C. in an atmosphere of hydrogen at 275 kPa for 17 hours. The mixture was filtered through Celite™ diatomaceous earth filter agent to remove the catalyst. The filtrate was concentrated in vacuo to give 3,5,5-trimethylhexylbenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:13])[CH2:10][CH2:11][NH2:12])=[CH:4][N:3]=1.[N+:14]([CH:17]=[C:18](SC)[S:19][CH3:20])([O-:16])=[O:15]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:13])[CH2:10][CH2:11][NH:12][C:18]([S:19][CH3:20])=[CH:17][N+:14]([O-:16])=[O:15])=[CH:4][N:3]=1
Reactant: CN(CCN)Cc1ccc(Cl)nc1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: CSC(=C[N+](=O)[O-])NCCN(C)Cc1ccc(Cl)nc1
Yield: 56.7 %

Procedure:
A mixture of N-(2-chloro-5-pyridylmethyl)-N-methylethylenediamine (2.0 g), 1-nitro-2,2-bis(methylthio)ethylene (1.7 g) and ethanol (40 ml) was refluxed for 5 hours with stirring. The reaction mixture was concentrated to about half of its volume, and cooled. The precipitated crystals were collected by filtration, washed with a small amount of ethanol, and dried to give the desired N-(2-chloro-5-pyridylmethyl)-N-methyl-N'-(1-methylthio-2-nitrovinyl)ethylenediamine (1.8 g) having a melting point of 93° to 95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:23](=[O:24])[N:22]([CH:25]([F:27])[F:26])[C:21]([CH3:28])=[N:20]2)=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](O)=[O:12])=[CH:7][CH:6]=1.S(Cl)([Cl:31])=O>>[Cl:1][C:2]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:23](=[O:24])[N:22]([CH:25]([F:27])[F:26])[C:21]([CH3:28])=[N:20]2)=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([Cl:31])=[O:12])=[CH:7][CH:6]=1
Reactant: Cc1nn(-c2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc2F)c(=O)n1C(F)F
Reactant: O=S(Cl)Cl
Product: Cc1nn(-c2cc(Oc3ccc(C(=O)Cl)cc3)c(Cl)cc2F)c(=O)n1C(F)F

Procedure:
A stirred solution of 1.7 g (0.0041 mole) of 4-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]phenylcarboxylic acid in 75 mL of thionyl chloride was heated at reflux for four hours. The excess thionyl chloride was removed by distillation under reduced pressure to yield 4-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]-phenylcarboxylic acid chloride as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]([CH2:17][CH2:18]O)[CH:7]=[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:5]2=[O:25].P(Cl)(Cl)([Cl:28])=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]([CH2:17][CH2:18][Cl:28])[CH:7]=[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:5]2=[O:25]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cn(CCO)c2cc(-n3cccc3)c(F)cc2c1=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(CCCl)c2cc(-n3cccc3)c(F)cc2c1=O
Reaction time: 2 h

Procedure:
3.5 g (0.01 mol) of ethyl 6-fluoro-7-(pyrrol-1-yl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate are suspended in 30 ml chloroform, 3 ml of Cl3PO are added, the mixture is kept at room temperature for 2 hours and evaporated to dryness, the residue is redissolved in chloroform, the resulting solution is washed with a sodium bicarbonate solution and then with water and evaporated, and the precipitate is recrystallized from dimethylformamide to give 3.3 g of a solid melting at 254°-256° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:25][NH:26][O:27][CH3:28].CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[CH3:28][O:27][N:26]([CH3:25])[C:13]([C:11]1[CH:10]=[N:9][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=2)[CH:12]=1)=[O:15]
Reactant: CNOC
Reactant: COc1ccc(Cn2cc(C(=O)O)cn2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2cc(C(=O)N(C)OC)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
According to Scheme 3 Step 1: A solution of 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylic acid (34.4 mmol, 8.00 g), oxalyl chloride (68.9 mmol, 5.92 mL) and a drop of DMF in DCM (80 mL) was stirred for 1 hour at room temperature. After evaporation, the crude product was dissolved in DCM (30 mL) and was added at 0° C. to a solution of N,O-dimethylhydroxylamine hydrochloride (103 mmol, 6.31 g) in DCM (100 mL) followed by Et3N (138 mmol, 19.2 mL). The reaction mixture was stirred for 1 hour at room temperature. The reaction was quenched with a saturated solution of Na2CO3 (300 mL) and the aqueous phase was extracted with DCM. The organic phase was dried over MgSO4, was filtered and was concentrated to yield N-methoxy-1-(4-methoxybenzyl)-N-methyl-1H-pyrazole-4-carboxamide (33.8 mmol, 9.30 g, 98%) as a beige solid.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:10])=[O:9])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=[O:21])[C:19](=[O:22])[C:18]=2[O:23][CH2:24][CH3:25])=[CH:4][CH:3]=1.N[C:27]1C(O)=C(S(N(CC)OC)(=O)=O)C=CC=1>>[CH2:24]([O:23][C:18]1[C:19](=[O:22])[C:20](=[O:21])[C:17]=1[NH:16][C:5]1[C:6]([OH:15])=[C:7]([S:8]([N:11]([CH2:12][CH3:27])[O:13][CH3:14])(=[O:10])=[O:9])[CH:2]=[CH:3][CH:4]=1)[CH3:25]
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O
Reactant: CCN(OC)S(=O)(=O)c1cccc(N)c1O
Product: CCOc1c(Nc2cccc(S(=O)(=O)N(CC)OC)c2O)c(=O)c1=O

Procedure:
This compound was prepared analogously to 6-Chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide (Intermediate A step 3) by replacing 3-amino-6-chloro-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide with 3-amino-N-ethyl-2-hydroxy-N-methoxybenzenesulfonamide (step 1). [M+H]+ 371
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](O)=[O:18])=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:29][NH2:30].Cl>ClCCl.CN(C)C=O>[OH:29][NH:30][C:17](=[O:18])/[CH:16]=[CH:15]/[C:12]1[CH:13]=[CH:14][N:10]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:20])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH:11]=1
Reactant: C[Si](C)(C)ON
Reactant: Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)O)c2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NO)c2)cc1
Reaction time: 1.5 h
Yield: 20.6 %

Procedure:
0.231 g of (E)-3-[1-(toluene-4-sulfonyl)-1H-pyrrol-3-yl]-acrylic acid (compound A1) are dissolved in 8 ml of dichloromethane at room temperature. Then 50 μl of N,N-dimethylformamide (DMF) are added, 0.275 g of oxalic acid chloride dissolved in 2 ml of dichoromethane are added dropwise and stirred for 1.5 hour. To the solution are added 0.439 g of O-(trimethylsilyl)hydroxylamine and stirred for 15 minutes. Then 20 ml of aqueous hydrochloric acid (1 M strength) are added and extracted with ethyl acetate. The combined organic phase is dried over sodium sulfate. Afterwards it is filtered and evaporated under vacuo. The crude product is purified by silica gel flash chromatography using a gradient of dichloromethane and methanol from 98:2 to 6:4 to yield 0.050 g of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:22][CH2:21]O[CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:29](OC(N1CCC(=C(Br)C2C=CC(C(N3CCCCC3)=O)=CC=2)CC1)=O)(C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([CH:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]2)[C:9]2[CH:10]=[CH:11][C:12]([C:15]([N:17]3[CH2:22][CH2:21][CH2:29][CH2:19][CH2:18]3)=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(C(c2cccc(F)c2)C2CCNCC2)cc1)N1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)c2ccc(C(=O)N3CCCCC3)cc2)CC1
Product: O=C(c1ccc(C(c2cccc(F)c2)C2CCNCC2)cc1)N1CCCCC1

Procedure:
Same procedure as described for the preparation of compound 85, but using compound 83 as starting material.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[CH:5]=[C:6]([CH3:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[Br:21]N1C(=O)CCC1=O.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[Br:21][C:13]1[CH:14]=[C:9]([CH:10]=[CH:11][C:12]=1[O:15][CH3:16])[O:8][C:7]1[C:6]([CH3:17])=[CH:5][C:4]([N+:18]([O-:20])=[O:19])=[CH:3][C:2]=1[CH3:1]
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1Br
Yield: 97.2 %

Procedure:
To a solution of 3,5-dimethyl-4-(4′-methoxyphenoxy)nitrobenzene (4.0 g) (J. Med. Chem., 38: 703 (1995)) in chloroform (150 ml) were added N-bromosuccinimide (2.6 g) and trifluoroacetic acid (1.1 ml), and the resulting mixture was heated under reflux for 90 min. Additional portions of N-bromosuccinimide (2.6 g) and trifluoroacetic acid (1.1 ml) were added, followed by further heating for 18 h. The reaction was washed with sodium bicarbonate, dried (Na2SO4) and concentrated to afford the title compound of Step A as an orange solid (5.0 g). MS (APCI+) Calc: 351; Found: 352 (M+1).