Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cr:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Na+:6].[Na+].S(=O)(=O)(O)O.S(=O)(=O)(O)[O-].[Na+]>>[O-:2][Cr:1]([O:5][Cr:1]([O-:4])(=[O:3])=[O:2])(=[O:4])=[O:3].[Na+:6].[Na+:6].[O-:2][Cr:1]([O:5][Cr:1]([O-:4])(=[O:3])=[O:2])(=[O:4])=[O:3]
Reactant: O=[Cr](=O)([O-])[O-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]

Procedure:
Chromic acid and sodium bichromate or sodium chromate are made by roasting chromium-containing ore with soda ash (sodium carbonate) or sodium hydroxide to form sodium chromate. The roasted ore is quenched in water and the soluble sodium chromate dissolves in the water to form "yellow liquor." The sodium chromate is reacted with sulfuric acid or sodium bisulfate to produce sodium bichromate (the "bichromate process"). Upon evaporation, by-product sodium sulfate crystallizes and is filtered off. Because it is contaminated with about 200 to about 1600 ppm of hexavalent chromium, it can be sold only to low value markets such as the pulp and paper industry, and the chromium values in it are lost. Increasingly, environmental considerations limit the sale of sodium sulfate to a maximum chromium contamination of 1000 ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([NH2:16])[N:13]=[CH:12][N:11]=1.[CH3:17][O:18][CH2:19][C:20](O)=O.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:20]([CH2:19][O:18][CH3:17])[N:9]([C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:16])[N:15]=3)[C:3]=2[CH:4]=1
Reactant: Nc1ncnc(Nc2cc(Br)ccc2N)n1
Reactant: COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCc1nc2ccc(Br)cc2n1-c1ncnc(N)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-N-(2-amino-5-bromophenyl)-1,3,5-triazine-2,4-diamine (1.00 g, 3.56 mmol) in DMF (5 mL) was introduced methoxyacetic acid (320 mg, 3.56 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (750 mg, 3.91 mmol), 1-hydroxy-7-azabenzotriazole (533 mg, 3.91 mmol) and triethylamine (720 mg, 7.11 mmol). The reaction mixture was stirred for 18 hr at RT and concentrated in vacuo. The residue was suspended in water (100 mL) and the resulting precipitate collected by filtration. After washing the filter cake with EtOAc (10 mL) and methanol (10 mL), the crude amide was dried on the filter. The intermediate amide was dissolved in glacial acetic acid (20 mL) and warmed to 140° C. for 15 minutes (microwave heating in 4 batches of equal volume). Following concentration of the reaction mixture in vacuo, toluene (20 mL) was introduced and the suspension concentrated in vacuo (repeated twice) to furnish the crude title compound as a brown oil: LC-MS: m/z=+334.90/336.75 (M+H)+. This compound, with LC-MS purity=86% UV, was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[N:22]1[CH2:23][CH2:24][N:25]([C:4]([C:3]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=2[CH3:1])=[O:6])[CH2:26][CH2:27]1
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(N2CCN(C(=O)c3ccc([N+](=O)[O-])cc3C)CC2)c(C)c1
Temperature: 25 °C
Yield: 79.4 %

Procedure:
2-Methyl-4-nitrobenzoic acid (500 mg), 1-(2,4-dimethylphenyl)piperazine (523 mg) and 1-hydroxybenzotriazole 1 hydrate (373 mg) were dissolved in N,N-dimethylformamide (13 mL), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (531 mg) was added, and the mixture was stirred at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give [4-(2,4-dimethylphenyl)piperazin-1-yl](2-methyl-4-nitrophenyl)methanone (771 mg). Then, to a mixed solution of ethanol (11 mL) and water (3 mL) were added ammonium chloride (660 mg) and iron (480 mg), and the obtained [4-(2,4-dimethylphenyl)piperazin-1-yl](2-methyl-4-nitrophenyl)methanone (771 mg) was added while stirring at 60° C.-70° C. After completion of the reaction, the insoluble material was collected by filtration, and the filtrate was concentrated. To the obtained residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer to give the title compound (833 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:23][C:24]1[C:32]([OH:33])=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[CH:27][NH:28]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:23][C:24]1[C:32]([O:33][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[CH:27][NH:28]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: Oc1ccc2[nH]ccc2c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3F)ncnc2cc1OCC1CCN(C)CC1
Temperature: 95 °C
Reaction time: 3 h
Yield: 26.6 %

Procedure:
A solution of 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (213 mg, 0.662 mmol), (prepared as described for the starting material in Example 10), and 4-fluoro-5-hydroxyindole (120 mg, 0.794 mmol), (prepared as described for the starting material in Example 242), in DMF (3 ml) containing potassium carbonate (137 mg, 0.994 mmol) was stirred at 95° C. for 3 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. The residue was triturated in cold ether. The solid was filtered and dried under vacuum to give 4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (77 mg, 26%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([O:41]C2CCCCO2)[C:20]2[CH:40]=[CH:39][C:23]([CH2:24][O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[C:28]([OH:35])[C:27]=3[CH2:36][CH2:37][CH3:38])=[CH:22][CH:21]=2)=[CH:15][C:14]=1[C:48]1[N:49]=[N:50][NH:51][N:52]=1>CO>[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:41])[C:20]2[CH:40]=[CH:39][C:23]([CH2:24][O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[C:28]([OH:35])[C:27]=3[CH2:36][CH2:37][CH3:38])=[CH:22][CH:21]=2)=[CH:15][C:14]=1[C:48]1[N:49]=[N:50][NH:51][N:52]=1
Reactant: CCCc1c(OCc2ccc(C(OC3CCCCO3)c3ccc(F)c(-c4nn[nH]n4)c3)cc2)ccc(C(C)=O)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CCCc1c(OCc2ccc(C(O)c3ccc(F)c(-c4nn[nH]n4)c3)cc2)ccc(C(C)=O)c1O
Reaction time: 24 h
Yield: 94.8 %

Procedure:
Add p-toluenesulfonic acid (2.00 mg, 0.012 mmol) to a solution of 1-(4-{4-[[4-fluoro-3-(2H-tetrazol-5-yl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzyloxy}-2-hydroxy-3-propyl-phenyl)-ethanone (0.130 g, 0.232 mmol) in methanol (0.2 M) and stir for 24 h. Evaporate solvent and filter through a pad of silica gel to afford the title compound (0.100 g, 0.220 mmol, 91%): MS (m/z): 475 (M−1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[C:17](Cl)(=[O:19])[CH3:18]>[Ti](Cl)(Cl)(Cl)Cl.ClC1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([C:17](=[O:19])[CH3:18])=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Reactant: CC(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: CCOC(=O)c1oc2ccc(C(C)=O)c(O)c2c1C
Yield: 55.4 %

Procedure:
To 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester 0.5 g (2.27 mmol) was added 15 mL of chlorobenzene, 0.27 g (3.4 mmol) of acetyl chloride and 0.63 mL (5.7 mmol) of titanium tetrachloride. The mixture was sealed in a pressure tube and the tube was placed in 95° C. oil bath for 5 h with stirring. The reaction mixture was washed with 0.5N HCl and was extracted with ethyl acetate. Removal of the solvents gave the crude product, which was purified by column chromatography to give 0.33 g (59% yield) of 5-acetyl-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1>C(Cl)Cl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(NC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Tert-butyl 4-(4-chlorophenylamino)piperidine-1-carboxylate (2.67 g, 8.59 mmol) prepared in Reference Example 131 was dissolved in methylene chloride (20 ml), to which trifluoroacetic acid (15 ml) was added dropwise, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was then dissolved in methylene chloride. This solution was neutralized with sodium hydroxide aqueous solution, and the mixture was extracted with methylene chloride. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to afford 4-(4-chlorophenylamino)piperidine as a pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][CH:5]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=2)[N:6]1[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[O:33][CH3:34].[F:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:1][O:2][C:3](=[O:35])[CH2:4][CH:5]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:41]3[CH:40]=[CH:39][CH:38]=[C:37]([F:36])[CH:42]=3)=[CH:18][CH:17]=2)[N:6]1[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[O:33][CH3:34]
Reactant: COC(=O)CC1c2cccc(F)c2N=C(c2ccc(Br)cc2)N1c1cc(C(F)(F)F)ccc1OC
Reactant: OB(O)c1cccc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)CC1c2cccc(F)c2N=C(c2ccc(-c3cccc(F)c3)cc2)N1c1cc(C(F)(F)F)ccc1OC

Procedure:
Starting from 100 mg (0.18 mmol) of the bromide from Example 11A, reaction by general method [D] with 30.5 mg (0.22 mmol) of 3-fluorophenylboronic acid, 6.37 mg (0.01 mmol) of bis(triphenylphosphine)palladium(II) chloride and 23.07 mg (0.22 mmol) of sodium carbonate in 10 ml of 1,2-dimethoxyethane and 0.1 ml of water results in 22.6 mg (22% of theory) of the target compound.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:10]=[CH:9]2)=[N:6][CH:7]=1.BrC1C=CC([F:24])=CN=1>>[F:24][C:4]1[C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:10]=[CH:9]2)=[N:6][CH:7]=[CH:2][CH:3]=1
Reactant: Fc1ccc(Br)nc1
Reactant: Fc1ccc(-n2cnc3cnccc32)nc1
Product: Fc1cccnc1-n1cnc2cnccc21

Procedure:
Intermediate 8 was prepared in a manner analogous to Intermediate 1, substituting 2-bromo-3-fluoropyridine for 2-bromo-5-fluoropyridine. MS (ESI): mass calculated for C11H7FN4, 214.07; m/z found 215.1 [M+H]+.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:2]=1.[OH:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:3]2[CH:2]=[CH:1][C:6]([NH:7][C:27](=[O:28])[C:26]3[CH:25]=[CH:24][C:23]([N:20]4[CH2:21][CH2:22][CH:17]([OH:16])[CH2:18][CH2:19]4)=[CH:31][CH:30]=3)=[CH:5][CH:4]=2)=[CH:10][CH:11]=1
Reactant: Nc1ccc(Nc2ccc(N)cc2)cc1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Product: Nc1ccc(Nc2ccc(NC(=O)c3ccc(N4CCC(O)CC4)cc3)cc2)cc1

Procedure:
Compound 749 was prepared according to the procedure described in Scheme IV from 4,4′-diaminodiphenylamine and 4-(4-hydroxypiperidin-1-yl)benzoic acid. [M+H]+ calcd for C25H26N4O3: 403.21; found 403.04.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[N:11]1([CH2:17][CH2:18][NH2:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[N:11]1([CH2:17][CH2:18][NH:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: NCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Product: O=[N+]([O-])c1ccc(NCCN2CCOCC2)cc1

Procedure:
Using 1-iodo-4-nitro-benzene (500 mg) instead of 1-bromo-3-nitro-benzene, and 2-morpholin-4-yl-ethylamine (316 mg) instead of morpholine, in the same manner as Step A in Example 1-D-105, the desired compound was obtained (315 mg, 62%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10](=[O:12])[CH3:11])=[CH:4][C:3]=2[O:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:28]1([CH2:34][S:35][CH:36]([C:40](O)=[O:41])[C:37](O)=[O:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[O:9]1[C:8]2[CH:7]=[CH:6][C:5]([C:10]3[O:12][C:37](=[O:38])[C:36]([S:35][CH2:34][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[C:40]([OH:41])[CH:11]=3)=[CH:4][C:3]=2[O:2][CH2:1]1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc2c(c1)OCO2
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc3c(c2)OCO3)cc(O)c1SCc1ccccc1

Procedure:
The title compound was prepared by Method A using 3',4'-(methylenedioxy)acetophenone (0.871 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio] propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 170° C.; 1H NMR (400 MHz, DMSO-d6) δ3.98 (s, 2 H), 6.13 (s, 2 H), 6.61 (s, 1 H), 7.05 (d, 2 H), 7.27 (m, 7 H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14](O)=[O:15])[CH:8]=2)[N:3]=1.[F:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14]([N:25]3[CH2:26][CH2:27][CH:22]([F:21])[CH2:23][CH2:24]3)=[O:15])[CH:8]=2)[N:3]=1
Reactant: FC1CCNCC1
Reactant: Nc1ccc2cc(-c3ccccc3C(=O)O)ccc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc2cc(-c3ccccc3C(=O)N3CCC(F)CC3)ccc2n1

Procedure:
To a microwave reaction vessel was added ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (3.7 g, 13 mmol), 6-bromoquinolin-2-amine (2.0 g, 9.0 mmol), PdCl2(PPh(t-Bu)2)2 (0.084 g, 0.13 mmol), potassium acetate (1.8 g, 18 mmol), EtOH (9.9 ml, 170 mmol) and water (2.4 ml, 134 mmol). The reaction mixture was heated at 85° C. for 8 h, and was then partitioned between EtOAc and water. The organic layer was washed with water and brine and allowed to stand for 72 h. The supernatant was decanted from the resulting precipitate and the precipitate was dried in vacuo to give ethyl 2-(2-aminoquinolin-6-yl)benzoate. Step 2 6-(2-Ethoxyphenyl)quinolin-2-amine (1.0 g, 3.8 mmol) was taken up in THF and then 5N NaOH was added and the solution was stirred for 72 h. DCM was added and the solid was filtered to give ethyl 2-(2-aminoquinolin-6-yl)benzoate. Step 3 A solution of 2-(2-aminoquinolin-6-yl)benzoic acid (50 mg, 0.19 mmol), 4-fluoropiperidine (25 mg, 0.24 mmol), HATU (91 mg, 0.24 mmol), DIEA (100 uL, 0.57 mmol), and DMF (1 mL) was heated in a shaker oven at 60° C. for 1 h. The resulting solution was purified by HPLC (CH3CN/water modified with 0.1% TFA) to give (2-(2-aminoquinolin-6-yl)phenyl)(4-fluoropiperidin-1-yl)methanone. MS (ESI, pos. ion) m/z: 350 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([Br:11])[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:6]=2[C:5](=[O:16])[NH:4][C:3]1=[O:17].Cl[CH2:19][C:20]1[N:29]=[C:28]([CH3:30])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)C>C(O)C.O.CN1CCCC1=O>[CH3:30][C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([CH2:19][N:4]2[C:5](=[O:16])[C:6]3[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:8]([Br:11])=[N:9][C:10]=3[N:2]([CH3:1])[C:3]2=[O:17])[N:29]=1
Reactant: CC#CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Reactant: Cc1nc(CCl)nc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCO
Product: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Temperature: 140 °C
Reaction time: 2 h

Procedure:
10.00 kg (33.66 mol) of 3-methyl-7-(2-butin-1-yl)-8-bromoxanthine, 7.13 kg (37.02 mol) of 2-chloromethyl-4-methylquinazoline, 3.92 kg (37.02 mol) of anhydrous sodium carbonate and 30 liters of N-methyl-2-pyrrolidone are initially charged in the reactor. The reactor contents are heated to 140° C. and stirred at 140° C. for 2 hours. After the reaction has ended, the reaction mixture is cooled to 80° C. and diluted with 60 liters of 96% ethanol and subsequently at 70° C. with 55 liters of water. At 60° C., 4.04 kg (67.32 mol) of acetic acid are metered in and flushed in with 5 liters of water. The resulting suspension is stirred at 60° C. for 30 minutes, then cooled to 23° C. and stirred for a further 30 minutes. Subsequently, the product is centrifuged off and washed first with a mixture of 20 liters of 96% ethanol and 20 liters of water, then with 40 liters of 96% ethanol and 40 liters of water. Drying is effected at 45° C. in a drying cabinet under inertization.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([OH:17])[CH2:14][C@@H:13]2[CH2:18][C:19]([OH:21])=[O:20])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[OH-].[Na+].[CH3:31]O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]2[CH2:18][C:19]([O:21][CH3:31])=[O:20])=[O:11])=[CH:22][CH:23]=1)([O-:3])=[O:2]
Reactant: O=C(O)C[C@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)C[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
(2R,4R)-1-p-Nitrobenzyloxycarbonyl-2-carboxymethyl-4-hydroxypyrrolidine (5.39 g) was dissolved in 54 ml of dry methanol, and 0.9 ml of conc. sulfuric acid was added thereto, followed by refluxing for 4 hours. The reaction mixture was neutralized with 1N sodium hydroxide solution and distilled to remove the solvent. To the residue was added ethyl acetate, and the mixture was washed with water, dried over anhydrous sodium sulfate and distilled to obtain (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-methoxycarbonylmethyl-4-hydroxypyrrolidine.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]([CH3:15])[S:11](Cl)(=[O:13])=[O:12].[CH3:16][O:17][C:18](=[O:31])[C@H:19]([C@@H:21]([CH3:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH2:20].C(N(CC)CC)C>C(Cl)Cl>[CH3:16][O:17][C:18](=[O:31])[C@H:19]([C@@H:21]([CH3:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:20][S:11]([N:10]([CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1)[CH3:15])(=[O:13])=[O:12]
Reactant: COC(=O)[C@@H](N)[C@@H](C)OCc1ccccc1
Reactant: CN(CCc1ccccn1)S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NS(=O)(=O)N(C)CCc1ccccn1)[C@@H](C)OCc1ccccc1

Procedure:
To the resulting compound from Example 87 (1 mmol) and (O-benzyl)threonine methyl ester (1 mmol) in CH2Cl2 was added triethylamine (2.0 mmol). After 1 h the product was isolated as described in Example 80.
Reaction SMILES: C1(S)C=CC=CC=1.C[O:9][C:10]1[CH:15]=[C:14]([N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)[CH:13]=[CH:12][C:11]=1[C:21]1[N:26]=[N:25][C:24]([N:27]([CH3:38])[CH:28]2[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][C:30]([CH3:37])([CH3:36])[CH2:29]2)=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH3:38][N:27]([CH:28]1[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][C:30]([CH3:37])([CH3:36])[CH2:29]1)[C:24]1[N:25]=[N:26][C:21]([C:11]2[CH:12]=[CH:13][C:14]([N:16]3[CH:20]=[CH:19][CH:18]=[N:17]3)=[CH:15][C:10]=2[OH:9])=[CH:22][CH:23]=1
Reactant: COc1cc(-n2cccn2)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN(c1ccc(-c2ccc(-n3cccn3)cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: 190 °C

Procedure:
As described in GENERAL METHOD 3-1, thiophenol (0.127 mL, 1.24 mmol) was added to a microwave vial containing 6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (520 mg, 1.24 mmol) and K2CO3 (171 mg, 1.24 mmol) in NMP (5 mL). The microwave vial was evacuated and filled with N2 (2×). The reaction mixture was heated in the microwave at 190° C. for 30 min. The reaction mixture was filtered through celite (pre-packed filter funnel) washing with MeOH. The filtrate was acidified to pH 3 using 1 M HCl aqueous solution and then adsorbed onto a methanol conditioned SCX (10 g) column. The column was washed several times with methanol then eluted with 2 N ammonia in methanol solution. The product was collected and concentrated in vacuo to afford the crude product which was purified by preparative HPLC under basic conditions to provide 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol (198 mg, MS: 407.25 [M+H+], LC/MS Rt=0.53 min (LCMS method Q); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.86 (d, J=2.02 Hz, 1H), 7.71 (d, J=10.11 Hz, 1H), 7.63 (d, J=1.52 Hz, 1H), 7.54 (d, J=8.59 Hz, 1H), 7.21-7.30 (m, 2H), 6.91 (d, J=9.60 Hz, 1H) 6.31-6.41 (m, 1H), 4.76-4.95 (m, 1H), 2.89-3.01 (m, 3H), 1.62 (dd, J=12.13, 3.54 Hz, 2H), 1.34 (br. s, 2H), 1.27 (s, 6H), 1.10 (s, 6H).
Reaction SMILES: [N+]([O-])([O-])=[O:2].[NH4+].[Ce].CO[C:9]1([CH3:29])[C:14]([CH3:15])=[C:13]([O:16]C)[C:12]([CH3:18])=[C:11]([CH2:19][CH2:20][C@@:21]2([CH3:28])[CH2:25][O:24]C(C)(C)[O:22]2)[CH2:10]1>O.C(#N)C>[OH:22][C@:21]([CH3:28])([CH2:25][OH:24])[CH2:20][CH2:19][C:11]1[C:10](=[O:2])[C:9]([CH3:29])=[C:14]([CH3:15])[C:13](=[O:16])[C:12]=1[CH3:18]
Reactant: COC1=C(C)C(C)(OC)CC(CC[C@@]2(C)COC(C)(C)O2)=C1C
Reactant: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CC1=C(C)C(=O)C(CC[C@](C)(O)CO)=C(C)C1=O
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 41.4 %

Procedure:
While stirring for 2 minutes at room temperature, 2.01 g of cerium ammonium nitrate in 7.5 ml of water were added dropwise to a solution of 550 mg of (S)-4-(3,5-dimethoxy-3,4,6-trimethyl-phenylethyl)-2,2,4-trimethyl-1,3-dioxolan in 7.5 ml of acetonitrile. After 2 minutes of additional stirring, the reaction mixture was extracted three times with 20 ml of chloroform each time. The combined organic extracts were dried over sodium sulfate, whereafter the solvent was removed. After chromatography of the obtained residue on silica gel with benzene/ethyl acetate (2:1 parts by volume) and ethyl acetate, there were obtained 266 mg of (S)-(+)-2,3,6-trimethyl-5-(2,2,4-trimethyl-1,3-dioxolan-4-ethyl)-p-benzoquinone and 177 mg of (S)-(+)-5-(3,4-dihydroxy-3-methyl-1-butyl)-2,3,6-trimethyl-p-benzoquinone in the form of yellow needles with a melting point of 111°-112°.