Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:6][CH2:7][CH2:8][OH:9])[CH2:2][CH:3]([CH3:5])[CH3:4].[C:10]([N:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]1[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)(=[O:13])[CH:11]=[CH2:12]>CC(O)C>[CH:24]1([CH:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22][CH2:23][N:14]2[C:10](=[O:13])[CH2:11][CH2:12][N:6]([CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])[CH2:7][CH2:8][OH:9])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CC(C)CCNCCO
Reactant: C=CC(=O)N1CCc2ccccc2C1C1CCCCC1
Solvent: CC(C)O
Product: CC(C)CCN(CCO)CCC(=O)N1CCc2ccccc2C1C1CCCCC1
Temperature: 90 °C
Reaction time: 10 h
Yield: 28.8 %

Procedure:
2-(isopentylamino)-ethanol (26 mg) was added to a solution of 2-acryloyl-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (7 mg) in iPrOH (0.1 mL), followed by stirring at 90° C. for 10 hours. Thereafter, the reaction liquid was purified by preparative HPLC to obtain 2-[[3-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-3-oxopropyl](3-methylbutyl)amino]ethanol (3 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:28][C:29]1[CH:38]=[C:37]2[C:32]([CH:33]=[CH:34][CH:35]=[N:36]2)=[CH:31][CH:30]=1>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[N:5]=[CH:4][N:3]=[C:2]2[O:28][C:29]1[CH:38]=[C:37]2[C:32]([CH:33]=[CH:34][CH:35]=[N:36]2)=[CH:31][CH:30]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCS(C)(=O)=O
Reactant: Oc1ccc2cccnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4cccnc4c3)ncnc2cc1OCCCS(C)(=O)=O
Temperature: 90 °C
Yield: 81.4 %

Procedure:
4-Chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (0.15 g, 0.45 mmol), (prepared as described for the starting material in Example 50), potassium carbonate (94 mg, 0.68 mmol) and 7-hydroxyquinoline (79 mg, 0.54 mmol) were suspended in anhydrous DMF (1.5 ml) and heated to 90° C. overnight. The compound was precipitated upon addition of water. The precipitate was collected by filtration, washed with water and dried under vacuum over phosphorus pentoxide to give 6-methoxy-7-(3-methylsulphonylpropoxy)-4-(quinolin-7-yloxy)quinazoline (161 mg, 81%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[NH:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1.N#N>C(Cl)Cl>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1
Reactant: C1=CCNC1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: N#N
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1N1CC=CC1
Temperature: 25 °C
Yield: 83.8 %

Procedure:
A mixture of 1-chloro-2-methoxy-4-nitrobenzene (2.71 g, 14.47 mmol) and 2,5-dihydro-1H-pyrrole (2.0 g, 28.9 mmol) was stirred at 100° C. under a stream of N2 for 10 h. The reaction was cooled to RT to give a brown solid which was dissolved in CH2Cl2 (200 mL), washed with 100 mL of 1 N NaOH solution and brine, dried over MgSO4, and concentrated. The resulting brown oil was purified by flash chromatography (silica gel, Hexanes:EtOAc, 100:0 to 80:20) to afford the title compound (2.67 g, 84% yield) as a orange solid: 1H NMR (500 MHz, CDCl3) δ 7.84 (dd, J=8.80, 2.50 Hz, 1H), 7.65 (d, J=2.50 Hz, 1H), 6.39 (d, J=8.80 Hz, 1H), 5.89 (s, 2H), 4.46 (s, 4H), 3.83 (s, 3H). HPLC retention time: 3.315 min; LCMS (ES): m/z 221 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:16][C@H:15]3[N:12]([C:13](=[O:20])[C@@H:14]3[C@H:17]([OH:19])[CH3:18])[C:11]=2[C:21]([O-:23])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Na+].[C:25]([O:31][CH2:32]I)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27].C(OCC)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:16][C@H:15]3[N:12]([C:13](=[O:20])[C@@H:14]3[C@H:17]([OH:19])[CH3:18])[C:11]=2[C:21]([O:23][CH2:32][O:31][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CC(C)(C)C(=O)OCI
Reactant: COc1ccc(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1F
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(C(=O)OCOC(=O)C(C)(C)C)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1F
Reaction time: 0.25 h
Yield: 55.2 %

Procedure:
To sodium (5R,6S)-3-(3-fluoro-4-methoxyphenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (100 mg) in DMF (3 mL) was added at 0° C. pivaloyloxymethyl iodide (77 mg), and the mixture was stirred for 15 minutes. To the reaction mixture was added diethyl ether (50 mL), and the mixture was washed with saturated brine (50 mL×3times), dried over magnesium sulfate, filtered, and the solvent was removed in vacuo. The residue was purified under silica gel column chromatography (chloroform:methanol=100:0˜100:3) to give [(2,2-dimethylpropanoyl)oxy]methyl (5R,6S)-3-(3-fluoro-4-methoxyphenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (70 mg, 55%).
Reaction SMILES: [CH:1]([C:4]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([C:19]4([O:25][CH3:26])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)[N:15]3[CH3:18])=[C:11]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:10]=2)[C:7]2[CH:33]=[CH:34][CH:35]=[CH:36][C:6]=2[N:5]=1)([CH3:3])[CH3:2].[CH3:37][S:38]([CH:41]=[CH2:42])(=[O:40])=[O:39]>O>[CH:1]([C:4]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([C:19]4([O:25][CH3:26])[CH2:24][CH2:23][CH2:22][N:21]([CH2:42][CH2:41][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:20]4)[N:15]3[CH3:18])=[C:11]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[N:10]=2)[C:7]2[CH:33]=[CH:34][CH:35]=[CH:36][C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: COC1(c2nc3c(N4CCOCC4)nc(-n4c(C(C)C)nc5ccccc54)nc3n2C)CCCNC1
Reactant: C=CS(C)(=O)=O
Solvent: O
Product: COC1(c2nc3c(N4CCOCC4)nc(-n4c(C(C)C)nc5ccccc54)nc3n2C)CCCN(CCS(C)(=O)=O)C1
Reaction time: 4 h
Yield: 76.2 %

Procedure:
A mixture of 2-(2-isopropylbenzoimidazol-1-yl)-8-(3-methoxypiperidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine (150 mg, 0.31 mmol) and methanesulfonylethene (32 μL, 0.37 mmol) in IMS (5 mL) was allowed to stir for 4 h at room temp. before pouring the reaction mixture into H2O. The resulting precipitate was collected by filtration and dried under vacuum affording 713 (141 mg, 77%). LCMS (method I): RT 2.82 min, [M+H]+ 597.2. 1H NMR (DMSO, 400 MHz): δ 7.92-7.91 (1 H, m), 7.65-7.64 (1 H, m), 7.24-7.23 (2 H, m), 4.25 (4 H, brd s), 4.00-3.85 (4 H, m), 3.8-3.75 (4 H, m), 3.40-3.20 (2 H, m), 3.15-3.00 (4 H, m), 2.95 (3 H, s), 2.81-2.76 (4 H, m), 2.30-2.20 (1 H, m), 2.10-2.95 (2 H, m), 1.84-1.74 (2 H, m), 1.36 (6 H, dd, J=6.77, 2.96 Hz)
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][N:5]([C:12](=[O:27])[CH2:13][CH2:14][C:15]1[S:16][C:17]2[C:23]([F:24])=[CH:22][C:21]([F:25])=[C:20]([F:26])[C:18]=2[N:19]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+]>O.O1CCOCC1>[F:26][C:20]1[C:18]2[N:19]=[C:15]([CH2:14][CH2:13][C:12]([N:5]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:4][C:3]([OH:28])=[O:2])=[O:27])[S:16][C:17]=2[C:23]([F:24])=[CH:22][C:21]=1[F:25]
Reactant: COC(=O)CN(C(=O)CCc1nc2c(F)c(F)cc(F)c2s1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CN(C(=O)CCc1nc2c(F)c(F)cc(F)c2s1)c1ccccc1
Yield: 53.2 %

Procedure:
To a solution of N-[3-(4,5,7-trifluorobenzothiazol-2-yl)propionyl]-N-phenylglycine methyl ester (420 mg, 1 mmol) in a mixture of water (3 ml) and dioxane (6 ml) was added dropwise 2N sodium hydroxide (1.2 ml) with stirring under ice cooling and the mixture was stirred for 1 hour at room temperature. The reaction mixture was then diluted with water and washed with ether. The aqueous layer was acidified with 7% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, then dried and evaporated to yield a residue, which was recrystallized from ethyl acetate-isopropyl ether to give N-[3-(4,5,7-trifluorobenzothiazol-2-yl)propionyl]-N-phenylglycine 210 mg, 52%) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]2)=[CH:4][CH:3]=1.Cl[C:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][N:23]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1.O>[O:24]1[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:12]([C:13]([F:14])([F:15])[F:16])=[CH:11][C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]3)=[CH:6][CH:7]=2)=[N:23]1
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Reactant: Clc1noc2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)c1cc(C(F)(F)F)n(-c2ccc(Nc3noc4ccccc34)cc2)n1
Reaction time: 168 h
Yield: 18.7 %

Procedure:
To a stirred solution of 1-(4′-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole (0.20 g, 0.68 mmol) and 3-chlorobenzisoxazole (0.10 g, 0.65 mmol) in tetrahydrofuran (2.5 mL) under argon was added sodium bis-trimethylsilyl amide (1.0 M in tetrahydrofuran, 0.68 mL, 0.68 mmol). After seven days, the mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried (magnesium sulfate) and concentrated. The residue was purified by flash chromatography (elution with ethyl acetate/hexanes) to give the above-named compound (0.050 g). m.p. 209-210° C. NMR (CDCl3, 400 MHz): δ 7.77 (d, 1H), 7.64 (m, 3H), 7.53 (d, 2H), 7.37 (m, 1H), 7.09 (s, 1H), 6.68 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH:11][C:12]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:13]=1[C:14](O)=[O:15].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:22][O:21][C:19]1[CH:18]=[CH:17][C:13]([C:14]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][NH:6]3)=[O:15])=[C:12]([OH:11])[CH:20]=1
Reactant: COc1ccc(C(=O)O)c(O)c1
Reactant: Nc1cccc2[nH]ccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2cccc3[nH]ccc23)c(O)c1
Yield: 84.6 %

Procedure:
A mixture of 3.96 g of 4-amino-1H-indol, 70 ml of tetrahydrofuran. 5 g of 2-hydroxy-4-methoxy-benzoic acid and 6.2 g of dicyclohexylcarbodiimide was refluxed for 24 hours and was evaporated to dryness under reduced pressure at 50° C. The residue was taken up in ethyl acetate and excess 4-amino-1H-indole was removed by washing with 2N hydrochloric acid. The mixture was evaporated to dryness under reduced pressure and the residue was taken up in ether and dried at 50° C. to obtain 7.1 g of 4-methoxy-2-hydroxy-N-(1H-indol-4-yl)-benzamide melting at 190° C.
Reaction SMILES: [CH:1]([C:3]1[C:20]([O:21]C)=[CH:19][CH:18]=[CH:17][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12]CC)=[O:11])=[O:2].[I-].[Mg+2].[I-].Cl>O1CCCC1.CCOCC>[CH:1]([C:3]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:15])([CH3:16])[C:10]([OH:12])=[O:11])=[O:2]
Reactant: CCOC(=O)C(C)(C)CCCOc1cccc(OC)c1C=O
Agent: Cl
Agent: [I-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(CCCOc1cccc(O)c1C=O)C(=O)O

Procedure:
To a stirred solution of ethyl 5-(2-formyl-3-methoxyphenoxy)-2,2-dimethylpentanoate (6.46 g, 0.021 M) in dry tetrahydrofuran (60 ml) was added dropwise a solution of magnesium iodide (8.67 g, 0.031 M) in dry ether (130 ml). The mixture was then stirred under reflux (51/2 hr). The cooled mixture, containing ethyl 5-(2-formyl-3-hydroxyphenoxy)-2,2-dimethylpentanonate, was poured into 10% hydrochloric acid (110 ml). The organic layer was separated and the aqueous phase extracted with ethyl acetate. The combined organic solutions were washed with water, dried (sodium sulphate) and evaporated. The residue was dissolved in 95% ethanol (50 ml) and 2 N sodium hydroxide solution (100 ml) and stirred at room temperature (20 hr). The solution was then evaporated and the residue diluted with water and extracted with ether. The aqueous phase was acidified with concentrated hydrochloric acid with cooling and the solid produced filtered off and washed with water to give 5-(2-formyl-3-hydroxyphenoxy)-2,2-dimethylpentanoic acid, m.p. 76°-77° C. from benzene/petrol.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][O:11][C:12](=[O:30])[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:15])[CH3:14].C(OCC)(=O)C>C(O)(=O)C>[CH3:10][O:11][C:12](=[O:30])[C:13]([C:16]1[CH:21]=[C:20]([N+:6]([O-:9])=[O:7])[CH:19]=[CH:18][C:17]=1[O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([CH3:15])[CH3:14]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)C(C)(C)c1ccccc1OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)C(C)(C)c1cc([N+](=O)[O-])ccc1OCc1ccccc1
Temperature: 45 °C
Reaction time: 4 h
Yield: 46 %

Procedure:
To a mixture of sulfuric acid (0.27 ml) and nitric acid (0.34 ml), a solution of the compound (1.0 g) obtained in Example 561 in acetic acid (30 ml) was added dropwise at 5° C. The reaction mixture was stirred at 45° C. for 4 h, poured into ice cold water and ethyl acetate was added to the mixture. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=9:1) to give 530 mg of the titled compound (yield, 46%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][C:20]([CH3:25])([CH3:24])[CH2:21][CH2:22][NH2:23]>C1(C)C=CC=CC=1>[CH3:19][C:20]([CH3:25])([CH3:24])[CH2:21][CH2:22]/[N:23]=[CH:12]/[C:11]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:10]=1[NH:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cccc(F)c1NCCN1CCCCC1
Reactant: CC(C)(C)CCN
Solvent: Cc1ccccc1
Product: CC(C)(C)CC/N=C/c1cccc(F)c1NCCN1CCCCC1
Yield: 95.9 %

Procedure:
Crude 2-(2-(piperidin-1-yl)ethylamino)-3-fluorobenzaldehyde (372 mg, 1.486 mmol) and 3,3-dimethylbutan-1-amine (225.6 mg, 300.0 μL, 2.229 mmol) were stirred in toluene (7 mL) with 4A MS at RT overnight. The mixture was filtered and the volatiles were removed on rotary evaporator at 40° C. to give 475 mg of crude 2-((E)-(3,3-dimethylbutylimino)methyl)-6-fluoro-N-(2-(piperidin-1-yl)ethyl)benzenamine which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[F:18][CH:19]([F:29])[C:20]1[N:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[CH:22]=[N:21][C:20]([CH:19]([F:29])[F:18])=[CH:25][N:24]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: O=C(O)c1cnc(C(F)F)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: C[C@]1(c2cc(NC(=O)c3cnc(C(F)F)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-difluoromethyl-pyrazine-2-carboxylic acid (CAS 1174321-06-2, US2009209757) following procedure I yielded the title compound as a light yellow solid. MS (ISP): m/z=398.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][N:3]=1.[CH3:14][N:15]1[CH:19]=[CH:18][C:17]([NH2:20])=[N:16]1>O1CCOCC1.Cl[Pd-](P(C1CC2CC1CC2)C1CC2CC1CC2)[C-]1C=CC=C1N(C)C.[CH-]1C=CC=C1.[Fe+2]>[CH:9]1([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH:20][C:17]3[CH:18]=[CH:19][N:15]([CH3:14])[N:16]=3)=[N:3][CH:4]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Brc1ccc(OC2CCCC2)cn1
Reactant: Cn1ccc(N)n1
Agent: CN(C)c1ccc[c-]1[Pd-](Cl)P(C1CC2CCC1C2)C1CC2CCC1C2
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: C1COCCO1
Product: Cn1ccc(Nc2ccc(OC3CCCC3)cn2)n1
Temperature: 80 °C
Yield: 29 %

Procedure:
2-Bromo-5-cyclopentyloxy-pyridine (0.97 mmol), sodium-tert.-butylate (1.4 eq.), and 1-methyl-1H-pyrazole-3-amine (1.2 eq.) are dissolved in degassed dioxane (2 ml) and heated to 80° C. Chloro-(di-2-norbornylphosphino)(2-dimethylaminoferrocene-1-yl)palladium (II) (3 mg) in degassed dioxane (1 ml) is added and the reaction mixture is heated for 1 hour at 150° C. in the microwave. The reaction is quenched with ethylacetate/methanol (30 ml, 9:1) and filtrated over celite. The solvent of the filtrate is removed in vacuo. (5-Cyclopentyloxy-pyridine-2-yl)-(1-methyl-1H-pyrazole-3-yl)-amine (“A25”) is obtained after reversed phase column chromatography (water/acetonitrile+0.1% TEA) as a colorless powder in a yield of 29%; HPLC (method C): 1.55 min; LC-MS (method A): 0.97 min, 259.15 (M+H+);
Reaction SMILES: [CH3:1]/[C:2](/[C:5]([CH3:7])=[O:6])=[N:3]\[OH:4].[CH3:8][CH:9]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)[CH3:10].Cl>C(O)(=O)C>[CH3:1][C:2]1[N+:3]([O-:4])=[C:15]([C:14]2[CH:17]=[CH:18][C:11]([CH:9]([CH3:10])[CH3:8])=[CH:12][CH:13]=2)[O:6][C:5]=1[CH3:7]
Reactant: CC(=O)/C(C)=N/O
Reactant: CC(C)c1ccc(C=O)cc1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1oc(-c2ccc(C(C)C)cc2)[n+]([O-])c1C

Procedure:
18.4 g of diacetyl monoxime and 29.6 g of 4(2-propyl)-benzaldehyde are added to 50 ml of glacial acetic acid, and HCl gas is introduced with ice-cooling for 30 minutes. The product is precipitated as the hydrochloride by addition of methyl tert-butyl ether and filtered off with suction, and the precipitate is washed with methyl tert-butyl ether. The precipitate is suspended in a mixture of dichloromethane and water, and a basic pH is established using ammonia. The mixture is extracted three times with, in each case, 500 ml of dichloromethane and ethyl acetate, the combined organic phases are dried over MgSO4 and the solvent is then removed under reduced pressure. This gives 38.2 g 4,5-dimethyl-2-(4-(2-propyl)-phenyl)-oxazole 3-oxide as a yellowish solid.
Reaction SMILES: NC1C=C(C=C(S(=O)(=O)N)C=1NC1C=CC=CC=1)C(O)=O.OS(O)(=O)=O.[NH:27]([C:34]1[C:46]([S:47](=[O:50])(=[O:49])[NH2:48])=[CH:45][C:37]([C:38]([O:40]CCCC)=[O:39])=[CH:36][C:35]=1[NH:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[OH-].[Na+]>O.C(O)CCC>[NH:27]([C:34]1[C:46]([S:47](=[O:50])(=[O:49])[NH2:48])=[CH:45][C:37]([C:38]([OH:40])=[O:39])=[CH:36][C:35]=1[NH:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCCCNc1cc(C(=O)OCCCC)cc(S(N)(=O)=O)c1Nc1ccccc1
Agent: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Nc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Product: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Nc1ccccc1

Procedure:
A mixture of 3-amino-4-anilino-5-sulphamyl-benzoic acid (4 g), n-butanol (50 ml), and conc. H2SO4 (0.4 ml) was boiled under reflux with water separator for 5 days. The resulting solution of butyl 4-anilino-3-butylamino-5-sulphamyl-benzoate was saponified by addition of 2 N sodium hydroxide and boiling under reflux for 45 minutes. After neutralization with 4N hydrochloric acid, the reaction mixture was evaporated in vacuo. The residue was dissolved in hot water (50 ml), and the 4-anilino-3-butylamino-5-sulphamyl-benzoic acid was precipitated by addition of 4N hdyrochloric acid to pH 3. The crude acid was dissolved in diethyl ether (50 ml), and undissolved impurities were filtered off. The etherial solution was evaporated to dryness, and the residue was recrystallized from acetone-water and aqueous ethanol, after which the compound was obtained with a melting point of 230°-231° C.
Reaction SMILES: [CH2:1]([C:3]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([CH3:30])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([CH2:18][CH3:19])([OH:17])[CH2:15][CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Cl.[CH3:32][O:33][C:34](=[O:37])[CH2:35][NH2:36]>>[CH3:32][O:33][C:34](=[O:37])[CH2:35][NH:36][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([C:3]([CH2:1][CH3:2])([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([CH2:18][CH3:19])([OH:17])[CH2:15][CH3:16])=[C:8]([CH3:20])[CH:7]=2)[CH2:4][CH3:5])=[CH:22][C:23]=1[CH3:30]
Reactant: CCC(O)(CC)COc1ccc(C(CC)(CC)c2ccc(C(=O)O)c(C)c2)cc1C
Reactant: COC(=O)CN
Agent: Cl
Product: CCC(O)(CC)COc1ccc(C(CC)(CC)c2ccc(C(=O)NCC(=O)OC)c(C)c2)cc1C
Yield: 96.1 %

Procedure:
Using a procedure analogous to Example 1J, 4-{1-ethyl-1-[4-(2-ethyl-2-hydroxy-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid (0.64 g, 1.55 mmol) and glycine methyl ester hydrochloride (195 mg, 1.55 mmol) gives the title compound (0.72 g, 1.49 mmol, 96%). %).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[I-:12].[Na+].O>CC(C)=O>[I:12][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1
Reactant: [I-]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(CI)cc1
Yield: 95 %

Procedure:
A suspension of 1-chloromethyl-4-nitro-benzene (10 g, 58.3 mmol) and sodium iodide in acetone (150 ml) was refluxed for 1 h. Water was added until complete dissolution and the mixture extracted with ethyl acetate (4×100 ml). The combined organic layers were extracted with brine, dried over sodium sulfate and concentrated in vacuo yielding 13.9 g (95%) 1-Iodomethyl-4-nitro-benzene as beige crystals.
Reaction SMILES: [N:1]([C:4](=[CH:10][C:11]1[S:12][C:13]([Br:16])=[CH:14][CH:15]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-]>CC1C=CC=CC=1C>[Br:16][C:13]1[S:12][C:11]2[CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH:1][C:15]=2[CH:14]=1
Reactant: CCOC(=O)C(=Cc1ccc(Br)s1)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc2sc(Br)cc2[nH]1
Yield: 81.9 %

Procedure:
Acrylate 60 (3.81 g, 12.6 mmol) in o-xylene was refluxed for 20 min. After removing the o-xylene, the crude product was purified by column chromatography (EtOAc/Hexane: 1/10) to give carboxylate 61 (2.83 g, 82%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[NH:3][C:4](=[O:9])[C:5](C)([CH3:7])[CH3:6].CN(C)N.C(N(CC)CC)C.C(Cl)(=O)C(C)C>C(OCC)C>[CH3:1][N:2]([CH3:10])[NH:3][C:4](=[O:9])[CH:5]([CH3:7])[CH3:6]
Reactant: CN(C)NC(=O)C(C)(C)C
Agent: CC(C)C(=O)Cl
Agent: CN(C)N
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)C(=O)NN(C)C

Procedure:
In a fashion similar to the preparation of LtBu,NMe2H, treatment of a diethyl ether (250 mL) solution of 1,1-dimethylhydrazine (3.88 mL, 50 mmol) and triethylamine (7.52 mL, 53 mmol) with isobutyryl chloride (5.39 mL, 50 mmol) afforded LiPr,NMe2H as colorless crystals upon crystallization from Et2O and subsequent sublimation at 60° C./0.05 Torr (6.12 g, 94%): mp 94-96° C.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([NH:10][C:11](=[O:13])[CH3:12])[CH2:4][C:3]1([CH3:15])[CH3:14].C(OO)(C)(C)C.[CH2:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.N=O>[Mo](=O)(=O)=O.O>[CH:22]1([O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([NH:10][C:11](=[O:13])[CH3:12])[CH2:4][C:3]2([CH3:15])[CH3:14])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(=O)NC1CC(C)(C)N(O)C(C)(C)C1
Reactant: C1CCCCC1
Agent: O=[Mo](=O)=O
Agent: CC(C)(C)OO
Agent: N=O
Solvent: O
Product: CC(=O)NC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of 10.0 grams (47 mmol) of N-(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl) acetamide, 15.2 grams (118 mmol) of 70% aqueous tert-butyl hydroperoxide, 0.67 gram of molybdenum trioxide, and 75 ml of cyclohexane is heated at reflux and water is,collected in a Dean-Stark trap. The reaction mixture is then transferred to a Fischer-Porter pressure bottle and heated at 140° C. (bath temperature) for four hours to discharge the red color of the nitroxyl starting material. The reaction mixture is filtered, and the filtrate is diluted with ethyl acetate (150 ml ). The organic solution is stirred with 5% aqueous sodium sulfite (150 ml) for one hour to decompose any residual hydroperoxide, then washed with brine (150 ml), dried over anhydrous magnesium sulfate, and concentrated to obtain 12.6 grams of of white solid. Recrystallization from heptane affords 10.4 grams of the title compound as a white solid melting at 139°-144° C.