Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]([NH:18][C:19]([N:21]([CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])[CH2:9][O:10]CC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.O.[Pd]>[CH2:1]([C@H:8]([NH:18][C:19]([N:21]([CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:20])[CH2:9][OH:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCN(CCc1ccccc1)C(=O)N[C@H](COCc1ccccc1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CN(C)CCN(CCc1ccccc1)C(=O)N[C@H](CO)Cc1ccccc1
Yield: 89.8 %

Procedure:
To a solution of 1-[(1S)-1-benzyl-2-(benzyloxy)ethyl]-3-[2-(dimethylamino)ethyl]-3-phenethyl urea (Compound 2-1, 414 mg) in ethanol (4.5 ml), there was added 20% palladium hydroxide-on-carbon (100 mg) in the nitrogen gas atmosphere. This mixture was stirred for 3 days in the hydrogen gas atmosphere. The palladium-on-carbon was removed by the filtration through celite and the resulting filtrate was concentrated under reduced pressure to thus give the title compound (Compound 3-1, 299 mg).
Reaction SMILES: [I:1][C:2](=[CH:4][CH2:5][C@@H:6]([O:16][Si](CC)(CC)CC)[C:7]([CH3:15])=[CH:8][C:9]1[N:10]=[C:11]([CH3:14])[S:12][CH:13]=1)[CH3:3]>C(O)(=O)C.C1COCC1.O>[OH:16][C@@H:6]([C:7]([CH3:15])=[CH:8][C:9]1[N:10]=[C:11]([CH3:14])[S:12][CH:13]=1)[CH2:5][CH:4]=[C:2]([I:1])[CH3:3]
Reactant: CC[Si](CC)(CC)O[C@H](CC=C(C)I)C(C)=Cc1csc(C)n1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC(I)=CC[C@@H](O)C(C)=Cc1csc(C)n1

Procedure:
A solution of (5R)-2-iodo-6-methyl-7-(2-methylthiazol-4-yl)-5-(triethylsilyloxy)-2,6-heptadiene (2.28 g) in 50 mL of 3:1:1 acetic acid/THF/water is stirred at ambient temperature for 8 hoursours, then concentrated. The residue is dissolved in ethyl acetate, washed sequentially with sat. NaHCO3 and brine, then dried over MgSO4, filtered, and evaporated. The product is purified by SiO2 chromatography (30% ethyl acetate/hexanes).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.C([Li])CCC.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=2)[N:18]=[CH:17][CH:16]=1.II.[OH-].[Na+]>CCOCC.CCCCCC.O1CCCC1.O>[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=2)[N:18]=[C:17]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=2)[CH:16]=1
Reactant: Fc1ccc(Br)cc1
Reactant: Fc1ccc2nccc(Cl)c2c1
Agent: II
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1ccc(-c2cc(Cl)c3cc(F)ccc3n2)cc1
Reaction time: 0.25 h
Yield: 50.8 %

Procedure:
To a solution of 4.37 g (25 mmol) of 1-bromo-4-fluorobenzene in 35 ml of ether cooled to -10° was added 15 ml of a 1.6M solution of butyl lithium in hexane in portions while maintaining the temperature below 0°. This mixture was stirred below 0° for 15 min. A solution of 3.63 g (20 mmol) of 4-chloro-6-fluoroquinoline in 20 ml of tetrahydrofuran was added while maintaining the temperature below 0°. The dark solution was stirred at room temperature for 20 min. To the reaction mixture was then added 5 ml of water and 5 g of iodine, and 10 ml of 3N sodium hydroxide. After 10 min of stirring the solid was collected to give 2.8 g of product, mp 130°-133°.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([OH:14])[C:7]([CH3:13])([CH3:12])[CH2:8][O:9]2)=[CH:4][CH:3]=1.N1C=CN=C1.[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([O:14][Si:24]([C:21]([CH3:23])([CH3:22])[CH3:20])([CH3:26])[CH3:25])[C:7]([CH3:12])([CH3:13])[CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)COc2cc(Br)ccc2C1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)COc2cc(Br)ccc2C1O[Si](C)(C)C(C)(C)C
Yield: 54226.5 %

Procedure:
To a solution of 7-bromo-3,3-dimethyl-chroman-4-ol (300 mg, 1.44 mmol) in DMF (3.33 mL) was added imidazole (119 mg, 1.75 mmol) followed by TBDMS-Cl (263 mg, 1.75 mmol). The next day, the reaction was diluted with ethyl acetate and washed with water (3×) and saturated sodium bicarbonate (1×). The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude material was purified using silica gel chromatography (100% pentane to 50% pentane in ethyl acetate) to yield the desired product (290 g, 65% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]#[N:12])[CH:10]=1)[C:5]([O-])=[O:6].C(O)C.[BH4-].[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[C:4]([CH2:5][OH:6])[CH:3]=1)[C:11]#[N:12]
Reactant: N#Cc1cc(Cl)cc(C(=O)[O-])c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1cc(Cl)cc(CO)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 57.2 %

Procedure:
(Step 2) To a mixed solution of 3-chloro-5-cyanobenzoate (1.13 g) obtained in Step 1 in tetrahydrofuran:ethanol=10:1 (33 ml) was added lithium tetrahydroborate (0.19 g) at 0° C. After stirring at 60° C. for 2 hr, the reaction solution was quenched with ice and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was treated by silica gel chromatography (ethyl acetate:hexane=1:1) to give 3-chloro-5-(hydroxymethyl)benzonitrile (0.60 g) as a white solid.
Reaction SMILES: [C:1]([N:4]1[CH:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[C:13](Br)[C:14]([O:16][CH3:17])=[CH:15][C:7]=2[C:6]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[C:21]([Cl:28])[CH:20]=2)=[N:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O.NN>COCCO.[Pd]>[C:1]([N:4]1[CH:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:7]=2[C:6]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([Cl:28])[CH:20]=2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1Br)CC(C)N(C(C)=O)N=C2c1ccc([N+](=O)[O-])c(Cl)c1
Agent: [Pd]
Agent: NN
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCO
Product: COc1ccc2c(c1)C(c1ccc(N)c(Cl)c1)=NN(C(C)=O)C(C)C2
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 30.7 %

Procedure:
4.66 g (10 mmoles) of (±)-3-acetyl-7-bromo-4,5-dihydro-1-(3-chloro-4-nitrophenyl)-4-methyl-8-methoxy-3H-2,3-benzo-diazepine are dissolved in 190 cm3 of methyl cellosolve, then 2.1 g (15 mmoles) of potassium carbonate and 1.8 g of 10% palladium/charcoal catalyst and, under vigorous stirring, 1.95 cm3 (40 mmoles) of 98% hydrazine hydrate are added. The reaction mixture is stirred at 90° C. for 0.5 hours, the catalyst is filtered, the filtrate is evaporated, and the residue is rubbed with 50 cm3 of water to obtain solid matter. The crude product is purified by chromatography over a column containing silica gel and using a mixture of ethyl acetate and hexane, then the product is recrystallized from ethanol. Thus, 1.1 g (30%) of the title compound are obtained in the form of white solids melting at 152–155° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:19]([CH3:20])[C:18]3[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:17]=3[N:16]=2)=[CH:9][CH:8]=1)[NH2:5].[C:28]([CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][C:37]1=O)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(OC)C=CC=CC=1>[Pd]>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]2[N:19]([CH3:20])[C:18]3[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:17]=3[N:16]=2)=[CH:11][CH:12]=1)[NH:5][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:28](=[O:35])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2nc3ccc(OC)cc3n2C)cc1
Reactant: O=C1CCCCC1C(=O)c1ccccc1
Agent: [Pd]
Solvent: COc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(OCc2nc3ccc(OC)cc3n2C)cc1)Nc1ccccc1C(=O)c1ccccc1

Procedure:
A mixture of 4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine methyl ester (1.1 g), 2-benzoylcyclohexanone (0.7 g), palladium on carbon (10%, 0.2 g) and anisole (15 ml) was heated at reflux for 21 hours. Insoluble material of the reaction mixture was removed by filtration and the anisole of the filtrate was evaporated under reduced pressure. The residue was chromatographed on a silica gel column using hexane:ethyl acetate=1:2 as the eluant to afford the title compound (0.95 g, Rf=0.51 (thin layer chromatography on silica gel using hexane:ethyl acetate=1:3 as the eluant)).
Reaction SMILES: C(O[C:4]([CH:6]1[C:10]2([CH2:12][CH2:11]2)[CH2:9][N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)=[O:5])C.[CH3:20][Li]>C(OCC)C>[CH2:13]([N:8]1[CH2:7][CH:6]([C:4](=[O:5])[CH3:20])[C:10]2([CH2:11][CH2:12]2)[CH2:9]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: [Li]C
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC12CC2
Solvent: CCOCC
Product: CC(=O)C1CN(Cc2ccccc2)CC12CC2
Temperature: -10 °C
Reaction time: 1 h
Yield: 54.6 %

Procedure:
A solution (−78° C.) of 5-benzyl-5-azaspiro[2.4]heptane-7-carboxylic acid ethyl ester (Example A1a, 8.15 g, 31.4 mmol) in diethyl ether (200 mL) under a nitrogen atmosphere is treated with methyllithium (1.4 M in diethyl ether, 22.4 mL, 31.4 mmol) over a period of 10 minutes. After 1 hour, reaction mixture is warmed to −10° C. and quenched with saturated aqueous ammonium chloride. The mixture is poured into a separatory funnel and the organic layer is washed with saturated aqueous ammonium chloride, water, and brine. The organic layer is then dried with MgSO4, filtered, and the filtrate concentrated. The resulting residue is purified via flash column chromatography (1% triethylamine/7% isopropanol/92% CH2Cl2) to afford the title compound (3.93 g). MS CI: m/z 230 (MH+).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:20][NH2:21]>>[CH3:20][N:21]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CN
Reactant: CCCCCCCCCCCCCCCCCCO
Product: CCCCCCCCCCCCCCCCCCN(C)CCCCCCCCCCCCCCCCCC

Procedure:
In a manner analogous to that of Example 10 stearyl alcohol was reacted with monomethylamine to yield methyl-distearylamine. In addition the reaction gas consisting of 100 l of hydrogen and 5 l of monomethylamine was circulated via a gas pump, and the amine while had been used up in the reaction was continuously added in doses via a mercury dipping pipe. The pressure in the apparatus was kept constant. After a continuous addition of 2 moles of stearyl alcohol (90 g/h) within 6 hours, the amine addition was stopped. 33.8 milliliters of water had separated. The reaction was completed by adding the calculated amount of stearyl alcohol. After distillation of the crude product, 4.1% of higher condensed by-products were left. The yield of methyldistearylamine was 92.4% with a degree of purity of the product of 98.5%. cl EXAMPLE 12
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]2[CH2:39][C@@:37]3([CH3:38])[C@@H:33]([CH2:34][CH2:35][C:36]3=[O:40])[C@H:32]3[C:23]2=[C:24]2[C:29]([CH2:30][CH2:31]3)=[CH:28][C:27](=[O:41])[CH2:26][CH2:25]2)=[CH:18][CH:17]=1.[H-].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH3:12][C:11]([Si:8]([CH3:10])([CH3:9])[O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:15][C:16]1[CH:17]=[CH:18][C:19]([C@H:22]2[CH2:39][C@@:37]3([CH3:38])[C@@H:33]([CH2:34][CH2:35][C:36]3=[O:40])[C@H:32]3[C:23]2=[C:24]2[C:29]([CH2:30][CH2:31]3)=[CH:28][C:27](=[O:41])[CH2:26][CH2:25]2)=[CH:20][CH:21]=1)([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCCOCCBr
Reactant: C[C@]12C[C@H](c3ccc(O)cc3)C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CCC2=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOCCOc1ccc([C@H]2C[C@]3(C)C(=O)CC[C@H]3[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Reaction time: 3 h
Yield: 70.9 %

Procedure:
412 mg of the product obtained in Stage B in solution in 2 cm3 of dimethylformamide is added to 362 mg of a mixture containing 362 mg of 11beta-(4-hydroxyphenyl)4,9-estra-diene-3,17-dione, 4 cm3 of dimethylformamide and 55 mg of sodium hydride. Agitation is carried out for 3 hours at ambient temperature, an aqueous solution of ammonium chloride is added, followed by extraction with ethyl acetate, washing with salt water, drying and evaporating the solvent. After chromatography on silica (eluant: ethyl acetate-essence G 6-4), 400 mg of expected product is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:15]2[CH2:19][CH:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9]1.[NH2:25][OH:26].[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:15]2[CH2:19][CH:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][C:10]([CH:13]=[N:25][OH:26])=[CH:9]1
Reactant: NO
Reactant: CC(=O)NCC1CC(c2ccc(-n3ccc(C=O)c3)c(F)c2)=NO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)NCC1CC(c2ccc(-n3ccc(C=NO)c3)c(F)c2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
(-)-5-Acetamidomethyl-3-(3-fluoro-4-(3-formylpyrrol-1-yl)phenyl)isoxazoline (Example 15) (329 mg) is suspended in 4 ml 95% ethanol in a 50 ml one neck round bottom flask under nitrogen. The suspension is treated with hydroxylamine (80 mg) followed by sodium hydroxide (60 mg) and 0.4 ml water. The reaction is stirred 1 hour at room temperature, the pH is adjusted to 7 with 5% hydrochloric acid, and the white solid is collected. The solid is collected, washed with water, and is dried to give 300 mg (87%) of the title compound as a white solid. The title compound is obtained via chromatography over silica gel (230-400 mesh), eluting with 5% methanol/dichloromethane, mp 216-217° C., [α]25D -67° (c 0.67, DMSO).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:30]1[N:31]=[C:32]([NH:35]C=O)[S:33][CH:34]=1)[C:5]([NH:7][CH:8]1[C:28](=[O:29])[N:10]2[C:11]([C:25]([OH:27])=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH2:22][CH:23]=[CH2:24])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6].Cl>CO>[CH3:1][O:2][N:3]=[C:4]([C:30]1[N:31]=[C:32]([NH2:35])[S:33][CH:34]=1)[C:5]([NH:7][CH:8]1[C:28](=[O:29])[N:10]2[C:11]([C:25]([OH:27])=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH2:22][CH:23]=[CH2:24])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Yield: 76.9 %

Procedure:
A mixture of 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.60 g), conc.hydrochloric acid (0.70 g) and methanol (36 ml) was stirred for 2 hours at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate. The volume of the solution was increased to 50 ml. by adding water. The aqueous solution was washed with ethyl acetate (25 ml) and adjusted to pH 1.5 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.90 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:14][CH2:15][CH2:16][N:17]=[C:18]=[O:19]>C1COCC1>[Cl:14][CH2:15][CH2:16][NH:17][C:18](=[O:19])[NH:1][C:2]1[C:3]([CH3:13])=[C:4]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NCCCl
Reactant: Cc1c(N)cccc1NS(C)(=O)=O
Solvent: C1CCOC1
Product: Cc1c(NC(=O)NCCCl)cccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-(3-amino-2-methyl-phenyl)-methanesulfonamide (1.5 g, from Example 6, part 1) in THF (30 mL) was added 2-chloroethylisocyanate (0.7 mL) dropwise at 0° C. The reaction mixture was slowly warmed to room temperature and stirred overnight. The precipitate was filtered, rinsed with THF, and dried to give N-{3-[3-(2-chloro-ethyl)-ureido]-2-methyl-phenyl}-methanesulfonamide (1.8 g). To the above compound (1.7 g) in acetonitrile (100 mL) was added potassium fluoride (40 wt. % on alumina) (3.5 g). The mixture was heated at 80° C. for 8 hr and filtered, washed with methanol . The filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with methanol:dichloromethane (5:95) to afford N-[2-methyl-3-(oxazolidin-2-ylideneamino)-phenyl]-methanesulfonamide. This was converted to oxalate salt (0.5 g), mp 124-140° C. in a manner similar to that described above in Example 7, part 4.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[N:3]1[CH2:24][CH2:23][C:6]2([N:10]([CH3:11])[C:9](=[O:12])[CH:8]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:7]2=[O:22])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35].O>O1CCCC1>[CH2:37]([O:36][C:34](=[O:35])[O:22][C:7]1[C:6]2([CH2:5][CH2:4][N:3]([N:2]([CH3:1])[CH3:25])[CH2:24][CH2:23]2)[N:10]([CH3:11])[C:9](=[O:12])[C:8]=1[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21])[CH3:38]
Reactant: Cc1cc(C)c(C2C(=O)N(C)C3(CCN(N(C)C)CC3)C2=O)c(C)c1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)N(C)C12CCN(N(C)C)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
105 mg 8-Dimethylamino-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]decane-2,4-dione (from Step 4) and 62 mg triethylamine are dissolved in 5 ml tetrahydrofuran, and the mixture cooled in an ice bath. Then, 40 mg ethyl chloroformate is added at 0° C. The mixture is allowed to warm to room temperature, and stirred for 2 hours. Then water is added and the mixture extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, and the solvent evaporated. The crude product is purified by chromatography on silica gel, with acetone as a solvent, yielding 110 mg Carbonic acid 8-dimethylamino-1-methyl-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester ethyl ester as an oil. 1H-NMR (CDCl3): 6.85 ppm (s, 2H), 4.03 ppm (q, 2H), 3.00 ppm (m, 2H), 2.96 ppm (s, 3H), 2.85 ppm (m, 2H), 2.42 ppm (s, 6H), 2.27 ppm (m, 2H), 2.24 ppm (s, 3H), 2.16 ppm (s, 2H), 1.83 ppm (m, 2H), 1.09 ppm (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([CH3:13])[C:6]([OH:12])=[CH:7][CH:8]=2)[N:3]=1.I[CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH:15]([O:12][C:6]1[C:5]([CH3:13])=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([CH3:1])=[N:3]2)=[CH:8][CH:7]=1)([CH3:17])[CH3:16]
Reactant: Cc1ccc2ccc(O)c(C)c2n1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc2ccc(OC(C)C)c(C)c2n1
Yield: 24.1 %

Procedure:
2,8-Dimethylquinolin-7-ol (1.0 g, 2.31 mmol), 2-iodopropane (0.785 g, 4.62 mmol) and potassium carbonate (0.957 g, 6.93 mmol) in acetone (15 mL) were heated to 70° C. in a sealed tube for 18 hours. After cooling, water (20 mL) was added and the aqueous phase was extracted with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 7-isopropoxy-2,8-dimethylquinoline (120 mg, 24.1% yield) as an oil
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].Br[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1.C(NC(C)C)(C)C.O>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]#[C:4][C:2]([CH3:3])([OH:6])[CH3:1])=[N:9][CH:10]=1
Reactant: C#CC(C)(C)O
Reactant: Brc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(O)C#Cc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under an argon atmosphere 38 mg (0.2 mmol) CuI and 143 mg (0.2 mmol) Pd(PPh3)2Cl2 are added to a solution of 0.99 mL (10.0 mmol) 2-methyl-but-3-yn-2-ol and 2.44 g (10.0 mmol) 2,5-dibromo-pyridine in 50 mL THF and 2.8 mL (20 mmol) diisopropylamine and the reaction mixture is stirred for 15 min at RT. The reaction mixture is combined with water, exhaustively extracted with EtOAc and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, cyc/EtOAc 2:1).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH:12]1([Mg]Cl)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Cl>O1CCCC1>[CH:12]1([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1C(=O)C1CCCCC1
Reaction time: 1 h

Procedure:
10.0 g of phthalic anhydride was dissolved in 200 ml of tetrahydrofuran, and 40 ml of cyclohexylmagnesium chloride (2.0M, ether solution) was added dropwise to the solution at -50° C. After stirring the solution at the same temperature for 1 hour, the reaction solution was poured into 0.5-N hydrochloric acid, and extracted with chloroform. After the organic layer was dried over magnesium sulfide, it was purified by silica gel chromatography (eluent: chloroform-methanol) to obtain 12.0 g of o-(cyclohexanoyl) benzoic acid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].C1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>O>[CH3:23][S:24]([O:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:26])=[O:25]
Reactant: CCOC(=O)C(C#N)=NO
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)=NOS(C)(=O)=O
Reaction time: 8 h
Yield: 86.3 %

Procedure:
Ethyl 2-hydroxyimino-2-cyanoacetate (28.4 g) and anhydrous potassium carbonate (13.8 g) are dissolved in water (100 ml) and thereto is added benzene (10 ml). To the mixture is added dropwise methanesulfonyl chloride (15.6 ml) with stirring under ice-cooling and the mixture is further stirred for 1 hour. After allowing to stand overnight, the reaction mixture is extracted with ethyl acetate (300 ml). The extract is washed with water and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off to give ethyl 2-methanesulfonyloxyimino-2-cyanoacetate (38.0 g; 86.3%), melting point: 79°-81° C.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][O:6][C:7]1[C:22]([Cl:23])=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])=[N:12][O:13][C:9]=2[C:8]=1[Cl:24])C.[OH-].[Na+]>C(O)C.O>[Cl:23][C:22]1[C:7]([O:6][CH2:5][C:4]([OH:25])=[O:3])=[C:8]([Cl:24])[C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:10]=2[CH:21]=1
Reactant: CCOC(=O)COc1c(Cl)cc2c(-c3ccccc3F)noc2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)COc1c(Cl)cc2c(-c3ccccc3F)noc2c1Cl

Procedure:
14.0 g of ethyl{[5,7-dichloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]oxy}acetate is heated in 75% ethanol/H2O (700 ml) with stirring until a solution results. 20 ml of a 50% solution of NaOH is added and a precipitate forms. With additional heating and stirring the precipitate goes into solution and is allowed to stir for 2.5 hours. The ethanol is then evaporated in vacuo and the residue is made acidic with 10% HCl. The precipitated solid is filtered and dried in vacuo to afford {[5,7-dichloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]oxy}acetic acid, mp 160°-170° C.