Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:36])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:36][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: Cc1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)nc1
Agent: Cl
Solvent: CO
Product: Cc1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO)C5)CC3)cc2)nc1
Yield: 80.8 %

Procedure:
A solution of the compound (107 mg, 0.21 mmol) obtained in Example 22-1) and 4 M hydrochloric acid (1,4-dioxane solution, 2 mL) in methanol (2 mL) was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (69 mg, 83%) as a colorless solid.
Reaction SMILES: C1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C=CC=1.[NH2:17][C:18]1[C:31]2[C:30](=[O:32])[C:29]3[C:24](=[C:25]([OH:41])[C:26]([O:34][C:35]4C=C[CH:38]=[CH:37][CH:36]=4)=[CH:27][C:28]=3[NH2:33])[C:23](=[O:42])[C:22]=2[C:21]([OH:43])=[C:20]([O:44][C:45]2C=C[CH:48]=[CH:47][CH:46]=2)[CH:19]=1>>[NH2:33][C:28]1[C:29]2[C:30](=[O:32])[C:31]3[C:22](=[C:21]([OH:43])[C:20]([O:44][CH2:45][CH2:46][CH2:47][CH3:48])=[CH:19][C:18]=3[NH2:17])[C:23](=[O:42])[C:24]=2[C:25]([OH:41])=[C:26]([O:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:27]=1
Reactant: Nc1cc(Oc2ccccc2)c(O)c2c1C(=O)c1c(N)cc(Oc3ccccc3)c(O)c1C2=O
Agent: O=C1c2ccccc2C(=O)c2ccccc21
Product: CCCCOc1cc(N)c2c(c1O)C(=O)c1c(O)c(OCCCC)cc(N)c1C2=O

Procedure:
When the process described in Example 165a is carried out and, instead of the anthraquinone derivative mentioned there, 5.7 g of 1,8-diamino-4,5-dihydroxy-3,6-diphenoxyanthraquinone (preparation see Example 351a) are used, then 4.2 g, corresponding to 80% of theory, of 1,8-diamino-4,5-dihydroxy-3,6-di-n-butoxyanthraquinone are obtained, the colour shade of which on silica gel is a blue with the Indicator Number 14.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([C:10]1[C:15]([C:16](OCC)=[O:17])=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]([C:27](OCC)=[O:28])=[C:12]([CH:32]([CH3:34])[CH3:33])[N:11]=1)([CH3:9])[CH3:8].O>CCOCC.O1CCCC1>[OH:17][CH2:16][C:15]1[C:10]([CH:7]([CH3:9])[CH3:8])=[N:11][C:12]([CH:32]([CH3:33])[CH3:34])=[C:13]([CH2:27][OH:28])[C:14]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1nc(C(C)C)c(CO)c(-c2ccccc2)c1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40.5 ml (40.5 mmol) of a 1 molar solution of lithium aluminum hydride in ether are added dropwise under nitrogen to a solution of 6.4 g (16.2 mmol) of the compound from Example 11 in 100 ml of dry tetrahydrofuran at 0° C. The mixture is stirred overnight at room temperature, warmed to 50° C. for 3 h and cooled again to 0° C. 200 ml of water are cautiously added dropwise to the mixture, and it is filtered over kieselgur with suction and washed with 250 ml of ether. The organic phase is separated, washed once with saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The residue is stirred with petroleum ether, and the precipitate is filtered off with suction and dried in a desiccator.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C@:13]2([C:25]#[N:26])[CH2:15][C@H:14]2[CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)C>[C:7]1([C@:13]2([CH2:25][NH2:26])[CH2:15][C@H:14]2[CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: N#C[C@@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NC[C@@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To 16.2 mL 1M lithium aluminum hydride (16.2 mmol) in diethyl ether at 0° C. (1S,2R)-1-phenyl-2-{[(phenylmethyl)oxy]methyl}cyclopropanecarbonitrile (4.25 g, 16.2 mmol), accessed via the method of Preparation 3A, dissolved in 17 mL diethyl ether. After complete addition, the reaction mixture was stirred at 0° C. for 2 h followed by 4 h at ambient temperature. The reaction mixture was diluted with 360 mL diethyl ether and quenched with successive addition of 0.6 mL water, 0.6 mL 15% NaOH, and 3.0 mL water. The reaction mixture was filtered and the filtrate was concentrated to a clear oil. The oil was purified by flash chromatography (SiO2, 3→5% CH3OH/EtOAc with 1% NH4OH) to give the title product (3.08 g, 11.5 mmol, 71%) as a single diastereomer. 1H NMR (300 MHz, CDCl3) δ 7.37-7.19 (m, 10H), 4.62-4.54 (m, 2H), 3.88 (m, 1H), 3.34 (m, 1H), 2.96 (d, J=14.1 Hz, 1H), 2.70 (d, J=14.1 Hz, 1H), 1.58 (m, 1H), 1.00 (m, 1H), 0.62 (m, 1H). ES-LCMS m/z 268.4 (M+H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:16])=[C:12]([CH:15]=1)[C:13]#[N:14].O.[OH-].[Na+]>CCOCC>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:16])=[C:12]([CH:15]=1)[CH2:13][NH2:14]
Reactant: Cc1ccc(Cl)cc1C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(Cl)cc1CN
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A solution of LAH (1 M in ether, 40 mL) was added to a stirred solution of 5-chloro-2-methylbenzonitrile (3.03 g, 20.0 mmol) in Et2O (10 mL) at 0° C. and the resulting solution was warmed to ambient temperature. After 30 min the solution was cooled to 0° C. and water (1.52 mL), 15% NaOH (1.52 mL) and water (4.56 mL) were added successively. The solids were removed by filtration and the filtrate was evaporated in vacuo to give 5-chloro-2-methylbenzylamine (3.11 g) as an oil.
Reaction SMILES: [CH2:1]([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[N:38]1([C:46](=O)[CH2:47]Cl)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[N:38]1([CH2:46][CH2:47][O:10][C:8]2[CH:9]=[CH:4][C:5]([CH2:12][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[C@H:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:6][CH:7]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCCCCCC1
Product: COc1ccc([C@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3CCCCCCC3)cc2)c1
Yield: 83.2 %

Procedure:
Synthesized from pivalic acid (S)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 1-azocan-1-yl-2-chloroethanone (15 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (9.0 mg) was obtained.
Reaction SMILES: O[CH:2]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C(N(S(F)(F)[F:26])CC)C.OP([O-])(O)=O.[Na+]>ClCCl>[F:26][CH:2]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CCOP(=O)(OCC)C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(F)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43 %

Procedure:
The title compound was prepared as described in Taylor, W P, et. Al, Bioorg. Med. Chem. 4:1515-1520 (1996). The product from Example 30, Part A (500 mg, 1.729 mmol) was dissolved in dichloromethane (10 mL) and treated by drop wise addition of (diethylamino)sulfur trifluoride (DAST) (2.5 mL, 18.9 mmol). The mixture was stirred at room temperature for 18 h. A solution of half saturated sodium phosphate monobasic (20 mL) was added followed by dichloromethane (20 mL) addition and separation of the resulting organic phase. The organic solution was dried and concentrated under vacuum, and then subjected to column chromatography using silica gel eluting with a 1/1 mixture of hexanes/ethyl acetate to provide the title compound as an oil (215 mg, 43%).
Reaction SMILES: [BH4-].[Na+].C(O)(=O)C.[CH3:7][N:8]1[C@@H:13]2[CH2:14][CH:15]=[C:16]([O:18]C)[CH2:17][C@H:12]2[O:11][CH2:10][CH2:9]1>CO.C(O)C>[CH3:7][N:8]1[C@@H:13]2[CH2:14][CH2:15][C:16](=[O:18])[CH2:17][C@H:12]2[O:11][CH2:10][CH2:9]1
Reactant: COC1=CC[C@@H]2[C@@H](C1)OCCN2C
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CO
Product: CN1CCO[C@@H]2CC(=O)CC[C@H]21

Procedure:
Following the procedure of Example 1, 15.2 g of the above enamine in 150 ml of methanol were reduced with 3.78 g of sodium borohydride in 150 ml of ethanol in the presence of 5.14 ml of glacial acetic acid. The product of the reaction, trans-(±)-4-methyl-7-methoxy-3,4,4a,5,8,8a-hexahydro-2H-[1,4]benzoxazine, was hydrolysed by treatment with acid as in Example 1 to yield trans-(±)-4-methyl-3,4,4a,5,6,7,8,8a-octahydro-2H-[1,4]benzoxazin-7-one. The product was purified from a highly colored impurity by treatment with sodium bisulfite as in Example 1.
Reaction SMILES: [N:1](=[C:3]1[C:8]([CH3:10])([CH3:9])[NH:7][C:6](=[O:11])[CH2:5][S:4]1)[OH:2].O1CCOCC1.[OH-].[K+].[CH3:20][N:21]([S:25][N:26]([CH3:28])[CH3:27])[C:22](F)=[O:23]>C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3.O>[CH3:27][N:26]([CH3:28])[S:25][N:21]([CH3:20])[C:22]([O:2][N:1]=[C:3]1[C:8]([CH3:9])([CH3:10])[NH:7][C:6](=[O:11])[CH2:5][S:4]1)=[O:23]
Reactant: CC1(C)NC(=O)CSC1=NO
Reactant: CN(C)SN(C)C(=O)F
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CN(C)SN(C)C(=O)ON=C1SCC(=O)NC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
A mixture of 5.8 g of 2-oximino-3,3-dimethyltetrahydro-1,4-thiazin-5-one, 200 ml dioxane, 2.1 g powdered potassium hydroxide and 0.1 g dicyclohexyl-18-crown-6, was charged to a stirred flask and 5.3 g of N-methyl-N-(dimethylaminosulfenyl)carbamoyl fluoride was added at 30° C over a 1-minute period. The reaction mixture was stirred overnight at room temperature and then added to cold water and stirred for 5 minutes. The resulting mixture was extracted with methylene chloride. The methylene chloride layer was washed thoroughly with water and then dried with magnesium sulfate. The methylene chloride was stripped from the product under reduced pressure and the crystalline residue was recrystallized from ethylene acetate to provide 7.0 g of 2-[O-(N-Dimethylaminosulfenyl-N-methylcarbamoyl)oximino]-3,3-dimethyltetrahydro-1,4-thiazin-5-one, m.p. 165°-167° C. An nmr spectrum supported the proposed structure.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]2[N:23]=[C:22]([S:33]([C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)=[O:9])[NH:21][C:20]=2[C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(-c2nc(Sc3ccncc3)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccncc3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 3.90 g of 4,5-bis(4-methoxyphenyl)-2-(4-pyridylthio)imidazole in 100 ml of dichloromethane. The mixture is agitated for 3 hours at room temperature, the solution is washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is recrystallized from ethanol/ether, thus producing 3.41 g of 4,5-bis(4-methoxyphenyl)-2-(4-pyridylsulfinyl)imidazole, mp 170°-171°.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[CH:13][C:12]([O:25][CH2:26][CH3:27])=[C:11]([CH3:28])[N:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4].[BH4-].[Na+].C(O)(=O)C.CCOCC>C(O)C.Cl>[CH2:26]([O:25][C:12]1[CH:13]=[C:14]2[C:9](=[N:10][C:11]=1[CH3:28])[N:8]=[CH:7][C:6]([CH:1]([OH:5])[CH2:2][CH2:3][CH3:4])=[C:15]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH3:27]
Reactant: CCCC(=O)c1cnc2nc(C)c(OCC)cc2c1Nc1ccc(OC)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CCO
Product: CCCC(O)c1cnc2nc(C)c(OCC)cc2c1Nc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3-butyryl-6-ethoxy-4-(4-methoxyanilino)-7-methyl-1,8-naphthyridine (8.0 g) in absolute ethanol (200 ml) was added dropwise at 0° C. over 1 hour to a solution of sodium borohydride (2.4 g) in absolute ethanol (200 ml). The mixture was allowed to warm up to ambient temperature and stirred at this temperature for 18 hours. Glacial acetic acid was added carefully to destroy excess borohydride and the resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (200 ml) and extracted with dichloromethane to give a residue which was dissolved in IMS and saturated with hydrogen chloride gas. Ether was added to induce crystallisation. The mixture was filtered to give 1-[6-ethoxy-4-(4-methoxyanilino)-7-methyl-1,8-naphthyridin-3-yl]butan-1-ol, m.p. 120°-124° C.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([O:24][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: OC1CCCC1
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Product: O=C(NC(=O)C(c1ccccc1)c1ccccc1)OC1CCCC1

Procedure:
The title compound, white solid, m.p. 120-123° C. and MS: m/e=323.4 (MH+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and cyclopentanol.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([C:19]1[NH:20][C:21]([C:29]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[N:31]=[C:32]([NH:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:33]([CH3:39])=[N:34]3)=[CH:22][C:23]=1[C:24]([O:26]CC)=[O:25])[NH:11]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].O1CCOCC1.O.[ClH:54]>>[ClH:54].[NH2:11][CH:10]([C:19]1[NH:20][C:21]([C:29]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[N:31]=[C:32]([NH:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:33]([CH3:39])=[N:34]3)=[CH:22][C:23]=1[C:24]([OH:26])=[O:25])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC(C)(C)C)nc23)[nH]c1C(COCc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2cccc(-c3cc(C(=O)O)c(C(N)COCc4ccccc4)[nH]3)c2nc1NC(C)(C)C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a 50-mL round bottomed flask was added ethyl 2-(2-(benzyloxy)-1-((tert-butoxycarbonyl)amino)ethyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (468b) (0.97 g, 1.61 mmol), LiOH hydrated (0.34 g, 8.04 mmol), dioxane (10 mL), and water (10 mL). The reaction mixture was heated at 100° C. for 24 h and cooled to RT. The solvent was removed and the product used without further purification. The yellow solid obtained was suspended in HCl (10 mL, 4 N in dioxane) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated under vacuum and the orange solid obtained was dried to give 2-(1-amino-2-(benzyloxy)ethyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (468c), which was used as crude material and based on theoretical yield.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([F:18])[C:10]=1[F:19])C1C=CC=CC=1.C(OC1C(F)=C(F)C=CC=1[N+]([O-])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([F:19])[C:11]=1[F:18]
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(F)c1F
Agent: [Pd]
Agent: O=[N+]([O-])c1ccc(F)c(F)c1OCc1ccccc1
Solvent: CO
Product: Nc1ccc(O)c(F)c1F
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of a mixture of 1-(benzyloxy)-2,3-difluoro-4-nitrobenzene and 2-(benzyloxy)-3,4-difluoro-1-nitrobenzene (6.54 g) in methanol (200 ml) was added 10% palladium on carbon (654 mg), followed by stirring under a hydrogen atmosphere at room temperature for 26 hr and 50 min. The atmosphere in the reaction vessel was replaced with nitrogen to stop the reaction, and the catalyst was filtered off through Celite. The filtrate was concentrated under reduced pressure to provide the titled compound as a black solid (3.52 g) which was a mixture of 6-amino-2,3-difluorophenol.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[OH-].[Na+].[C:16](ON1C(=O)CCC1=O)([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C(OCC)(=O)C.O1CCCC1>[NH:1]([C:16]([O:18][CH2:19][CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[C:32]1=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:17])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 89.4 %

Procedure:
L-Tyrosine (9.06 g, 50 mmol) was dissolved in 100 ml of water and 150 ml of tetrahydrofuran (THF) with 50 ml of 1 N NaOH. To this solution was added Fmoc-OSu (16.87 g, 50 mmol); with rapid stirring. The suspension was adjusted to pH 7 with 1N NaOH and then stirred overnight, after which a small amount of solid tyrosine still remained. Solid citric acid (15 g) was added with stirring followed by 300 ml of ethyl acetate (EtOAc). The EtOAc layer was collected washed with 3×50 ml of 10% citric acid, 4×50 ml of saturated NaCl, and dried over MgSO4. Evaporation of the EtOAc solution gave a light tan syrup which was crystallized from 200 ml of dichloromethane (DCM) to give 18.04 g (89.4% yield) of product (mp 126°-130°).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:8]([C:9]([O:11]CC)=O)=[CH:7][N:6]=[CH:5][N:4]=1.[C:16](=[N:21]O)([NH2:20])[CH:17]([CH3:19])[CH3:18].[O-]CC.[Na+]>C(O)C>[CH:17]([C:16]1[N:21]=[C:9]([C:8]2[C:3]([C:2]([F:1])([F:14])[F:15])=[N:4][CH:5]=[N:6][CH:7]=2)[O:11][N:20]=1)([CH3:19])[CH3:18]
Reactant: CCOC(=O)c1cncnc1C(F)(F)F
Reactant: CC(C)C(N)=NO
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)c1noc(-c2cncnc2C(F)(F)F)n1
Temperature: 0 °C

Procedure:
2 g of ethyl 4-trifluoromethylpyrimidine-5-carboxylate and 1.56 g of isobutyramide oxime were initially charged in 15 ml of ethanol and cooled to 0° C. 10 ml of a 1.2 molar sodium ethoxide solution were added dropwise to this solution. The mixture was allowed to warm to room temperature over a period of one hour and then heated under reflux until the reaction, according to TLC, had ended. The reaction mixture was concentrated and the residue was taken up in saturated ammonium chloride solution and extracted with diethyl ether. Chromatographic purification of the crude product gave the desired compound as a yellowish oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:10]=1[C:11]([OH:13])=O.C(N(CC)CC)C.Cl.[CH3:28][NH:29][O:30][CH3:31]>C(Cl)Cl.CN(C=O)C>[CH3:31][O:30][N:29]([CH3:28])[C:11](=[O:13])[C:10]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:9]=1[O:8][CH3:7]
Reactant: CNOC
Reactant: COc1ccc(OC)c(C(=O)O)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(OC)c(C(=O)N(C)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
Oxalyl chloride (3.6 mL, 41.3 mmol) was added to a solution of 2,5-dimethoxybenzoic acid (6.00 g, 33.0 mmol) in DCM (100 mL). Then DMF (0.2 mL) was added to the mixture. The solution was stirred at room temperature for 2 h, and the solvent was removed under reduced pressure. The crude material was placed under vacuum for 30 min to remove the residual oxalyl chloride. Triethylamine (6.8 mL, 48.78 mmol) was added dropwise to the mixture of the residue and N,O-dimethylhydroxylamine hydrochloride (4.03 g, 41.32 mmol) in DCM (100 mL) at 0° C. The solution was stirred at 0° C. for 30 min and then at room temperature for additional 30 min. The reaction was diluted with DCM (50 mL), washed with H2O (2×100 mL), washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography to yield N,2,5-trimethoxy-N-methylbenzamide (7.32 g, 99%) as clear oil which solidified over time. 1H NMR (CDCl3): δ 7.90 (m, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.58 (br s, 3H), 3.32 (br s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]#[N:32])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH3:9].[N:35]([Si](C)(C)C)=[N+:36]=[N-:37]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([CH2:30][C:31]3[N:35]=[N:36][NH:37][N:32]=3)=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)[CH3:9]
Reactant: Cc1noc(-c2ccc(-c3ccc(CC#N)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1Cl
Reactant: C[Si](C)(C)N=[N+]=[N-]
Product: Cc1noc(-c2ccc(-c3ccc(Cc4nn[nH]n4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1Cl

Procedure:
Prepared as described in Example 45 using [5-(4′-cyanomethyl-biphenyl-4-yl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester and azidotrimethylsilane.
Reaction SMILES: [ClH:1].[CH2:2]([NH:4][C:5](=[N:12][CH2:13][CH3:14])[CH2:6][C:7]([O:9]CC)=[O:8])[CH3:3].Cl>>[ClH:1].[CH2:13]([NH:12][C:5]([CH2:6][C:7]([OH:9])=[O:8])=[N:4][CH2:2][CH3:3])[CH3:14]
Reactant: CCN=C(CC(=O)OCC)NCC
Agent: Cl
Product: CCN=C(CC(=O)O)NCC

Procedure:
A solution of 2.2 g. (0.01 mole) of N,N'-diethyl-carboethoxyacetamidine hydrochloride in 60 ml. of 12N hydrochloric acid is converted to the free acid in a manner similar to the procedure of Preparation A - 1c.