Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:21][CH:20]2[CH2:44][OH:45])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:46](Cl)([CH3:49])(=[O:48])=[O:47]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:21][CH:20]2[CH2:44][O:45][S:46]([CH3:49])(=[O:48])=[O:47])=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: CS(=O)(=O)Cl
Product: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
By reacting tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 148(h)] with mesyl chloride according to a method known from the literature there was obtained tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-methanesulphonyloxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [MS: 707 (M+NH4)+ ] as a colourless solid. Further reaction with diethylamine in acetonitrile at 50° C. analogously to Example 34 gave tert-butyl (3RS,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-diethylaminomethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a brown foam; MS: 667 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([SH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:16]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[O:19]>CN(C)C=O>[Cl:24][C:23]1[C:16]([S:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19]
Reactant: SCc1ccccc1
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(Cl)c1SCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
To a suspension of 112.1 g of potassium-t-butoxide in 1000 mL of dimethylformamide under a nitrogen atmosphere, 124.3 g of benzylmercaptan was added dropwise while maintaining the reaction temperature at 20°-25° C. with an ice-water bath. After stirring at 25° C. for 1.5 hours, a solution of 175 g of 2,3-dichlorobenzaldehyde dissolved in 750 mL of N,N-dimethylformamide was added dropwise, while maintaining the reaction temperature at 25°-40° with a water bath. After stirring at 25° C. for 12 hours, the reaction mixture was poured onto excess ice water to yield a precipitate. The suspension was filtered, and the isolated solid was washed with water, suction-dried and finally dried in vacuo at 40° C. overnight to afford 201 g of the title compound as a light yellow solid; m.p. 65°-68° C.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:12][C:13](=[O:24])[C:14]2[N:19]([CH3:20])[N:18]=[C:17]([CH2:21][CH2:22][CH3:23])[C:15]=2[N:16]=1)C=C.C1(O)C=CC=CC=1.N1CCCCC1>C(O)C>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:12][C:13](=[O:24])[C:14]2[N:19]([CH3:20])[N:18]=[C:17]([CH2:21][CH2:22][CH3:23])[C:15]=2[N:16]=1
Reactant: C=CCOc1ccccc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Solvent: C1CCNCC1
Solvent: Oc1ccccc1
Solvent: CCO
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3ccccc3O)nc12

Procedure:
A mixture of 5-(2-allyloxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (0.25 g, 0.0008 mol), phenol (0.145 g, 0.0015 mol), piperidine (0.131 g, 0.0015 mol) and tetrakis-(triphenylphosphine)palladium(0) (0.046 g, 0.00004 mol) in absolute ethanol (5 ml) was refluxed overnight under nitrogen. The mixture was allowed to cool, the solvent evaporated under vacuum and the residue dissolved in ethyl acetate (40 ml). This solution was washed with water (3×10 ml), 1M HCl (3×10 ml) and brine (1×10 ml). After drying (Na2SO4) and filtration, the filtrate was evaporated under vacuum to give the crystallisation from ethyl acetate/pentane, m.p 233-238° C. Found: C, 63.17; H, 5.65; N, 19.52. C15H16N4O2 requires C, 63.36; H, 5.67; N, 19.71%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)[CH2:7][CH2:6]1.C(N(CC)CC)C.Cl>CS(C)=O>[O:17]=[C:16]1[C:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]2[N:36]=[CH:37][N:38]=[C:12]2[N:11]1[C@H:8]1[CH2:7][CH2:6][C@H:5]([O:4][CH2:3][CH:2]=[O:1])[CH2:10][CH2:9]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCO)CC2)c2ncnn12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC=O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 4′-({4-[trans-4-(2-hydroxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (1.3 g), triethylamine (1.8 mL) and dimethyl sulfoxide (8 mL) was added dropwise a solution of sulfur trioxide-pyridine complex (1.2 g) in dimethyl sulfoxide (7 mL), and the mixture was stirred at room temperature for 1.5 hr. A solution of triethylamine (1.8 mL) and sulfur trioxide-pyridine complex (1.2 g) in dimethyl sulfoxide (5 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.31 g, 23%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][N:4]=1.B1([O-])O[O:19]1.O.O.O.O.[Na+].CCOC(C)=O>C1COCC1.O>[CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([OH:19])=[CH:5][N:4]=1
Reactant: [O-]B1OO1
Reactant: CSc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1ncc(O)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 2-(methylthio)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (from step A) (1.167 g, 4.63 mmol) in THF/H2O (20 mL 1:1) at room temperature under argon was added sodium perborate tetrahydrate (2.137 g, 13.9 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was cooled to room temperature. EtOAc (10 mL) was added to the reaction mixture, which was washed with brine (15 mL×3). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was very insoluble, therefore it was used directly to next step. MS (ESI) 143 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20](=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(OC[CH:37]([O:39][CH2:40][CH3:41])[CH3:38])(=O)=O)=CC=1>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:20][CH2:41][CH2:40][O:39][CH2:37][CH3:38])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: CCOC(C)COS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCCCSc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.5 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (80 mg, 0.65 mmol) was suspended in dimethylformamide (60 ml). To the suspension were added potassium carbonate (150 mg, 1.1 mmol) and 2-ethoxypropyl p-toluenesulfonate (280 mg, 1.1 mmol) in order. The mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (5% methanol/chloroform) to give the subject compound (69 mg, yield 30%).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:16]([OH:19])([CH3:18])[CH3:17]>C(OCC)(=O)C>[CH:16]([O:19][C:8](=[N:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:18])[CH3:17]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)O
Solvent: CCOC(C)=O
Product: CC(C)OC(=NC1CCCCC1)NC1CCCCC1
Temperature: 55 °C
Reaction time: 6 h
Yield: 80.2 %

Procedure:
A mixture of 3.09 g of dicyclohexylcarbodiimide, 30 mg of cuprous chloride and 994 mg of isopropanol was stirred under an inert atmosphere at 55° C. for 6 hours and was then diluted with ethyl acetate. The organic phase was washed with water, then with N ammonium hydroxide solution, was dried and filtered. The filtrate was evaporated to dryness under reduced pressure to obtain 3.2 g of O-isopropyl-N,N'-dicyclohexyl-isourea which was used as is for the next step.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[H-].[Na+].[C:18]1(=[O:34])[N:22]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)[C:21](=[O:29])[C:20]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:19]12.Cl.O1CCOCC1>C1(C)C=CC=CC=1.CN(C=O)C>[C:1]([NH:4][C:5]([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][N:22]1[C:21](=[O:29])[C:20]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:19]2[C:18]1=[O:34])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCCCCN1C(=O)c2ccccc2C1=O)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Yield: 163.1 %

Procedure:
Diethyl acetamidomalonate (2.80 g, 12.9 mmole) in 10 ml dimethylformamide (dried over 4A sieves, degassed) was added dropwise over 15 minutes to a suspension of sodium hydride (515 mg of 60% NaH/oil washed free of oil with hexane, 12.9 mmole) in 10 ml DMF with external cooling to maintain reaction temperature <10° C. The reaction mixture was warmed slowly to room temperature over 45 minutes. A solution of 5-phthalimidopentyl bromide (4.24 g, 14.3 mmole) in 10 ml DMF was added in four portions at room temperature while maintaining the internal temperature <40° C. The mixture was stirred for 24 hours until complete by TLC (product Rf =0.43, starting material Rf =0.32 (B)). Upon completion, the reaction mixture pH was adjusted to "pH 6" (pH 0-14, ColorpHast indicator strips, E. Merck, moistened) with 4N HCl/dioxane. The solvent was removed by rotary evaporation to give 9.10 g of an oil, which was purified by Still column chromatography (230-400 mesh Whatman G-60 silica gel, 320 g, CHCl3 eluant). The purified adduct 5 was crystallized from ethyl acetate/cyclohexane, 1:3. Yield: 4.35 g (78%). Mp 70°-72° C. TLC: Rf =0.43 (B). MW calc 432.19, found 432. Anal. calc for C22H28N2O7 : C, 61.10; H, 6.53; `N, 6.48. Found: C, 60.72; H, 6.61: n, 6.12. HPLC 97.4%. 1H NMR (CDCl3) 1.15 (2H, m), 1.25 (6H, t, 7 Hz), 1.33 (2H, br m), 1.56 (3H, s), 1.66 (4H, m), 2.05 (1H, s), 2.32 (2H, m), 3.65 (2H, t, 7 Hz), 4.25 (4H, q, 7 Hz), 7.72 (2H, m) and 7.90 (2H, m) for AA'BB"system.
Reaction SMILES: [NH:1]([CH3:3])[CH3:2].[O-:4][N+:5]1[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][C:9]=2[N:8]=[C:7]([CH2:18][CH2:19][CH:20]=O)[N:6]=1)[CH2:15][CH2:14][CH2:13]3.[BH3-]C#N.[Na+].CC(O)=O>CO>[CH3:2][N:1]([CH3:3])[CH2:20][CH2:19][CH2:18][C:7]1[N:6]=[N+:5]([O-:4])[C:10]2[CH:11]=[C:12]3[C:16]([CH2:15][CH2:14][CH2:13]3)=[CH:17][C:9]=2[N:8]=1
Reactant: O=CCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)CCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Reaction time: 0.33 h
Yield: 55.1 %

Procedure:
A solution of anhydrous Me2NH (2.4 g, 52 mmol) in MeOH (50 mL) was added to a solution of propanal 75 (1.5 g, 6.2 mmol) in MeOH (50 ml) at 0° C. and the solution stirred for 20 min. NaCNBH3 (1.5 g, 24 mmol) was added and the solution stirred for 30 min, then HOAc (2 ml) was added and the mixture was stirred at 20° C. for 16 h. The solvent was evaporated and the residue was partitioned between DCM (200 mL) and water (200 mL). The aqueous phase was extracted with DCM (2×200 ml), the combined organic phase was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10% MeOH/EtOAc, to give 1-oxide 78 (930 mg, 55%) as a yellow oil: 1H NMR [(CD3)2SO] δ 8.17 (s, 1H, H-9), 7.81 (s, 1H, H-5), 3.06-3.12 (m, 4H, H-6, H-8), 2.94-3.03 (m, 4H, 2×CH2), 2.66 [s, 6H, N(CH3)2], 2.07-2.18 (m, 4H, H-7, CH2); 13C NMR δ 164.1, 155.0, 149.2, 146.8, 131.9, 122.4, 113.7, 56.6, 43.0 (2), 33.3, 32.7, 32.4, 25.4, 22.7; HRMS (FAB+) calcd for C15H21N4O (MH+) m/z 273.1715, found 273.1714.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([NH:15][C:16]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][N:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:9]=1)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>CCOC(C)=O>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([NH2:7])=[CH:9][C:10]=1[NH:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][N:23]=2)=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1Nc1ncccc1-c1ccncn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1Nc1ncccc1-c1ccncn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The title compound was prepared according to the procedure described in J. Am. Chem. Soc. 1993, 115, 905-916. To [4-methyl-3-(3-pyrimidin-4-yl-pyridin-2-ylamino)-phenyl]-carbamic acid tert-butyl ester (550 mg, 1.46 mmol) was added CH2Cl2 (15 mL) and TFA (3.0 mL). The mixture was stirred for 3 h at 0° C., diluted with EtOAc and extracted with 50% aqueous Na2CO3. The organic layer was dried over Na2SO4, filtered and concentrated to yield 4-methyl-N3-(3-pyrimidin-4-yl-pyridin-2-yl)-benzene-1,3-diamine. MS m/z=278 [M+1]+. Calc'd for C16H15FN5: 277.33.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:14])([F:13])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[CH3:15][C:16]([CH3:18])=[O:17].Cl>CCCCCCC.C(O)(C)C>[F:3][C:4]([F:14])([F:13])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:15][C:16](=[O:17])[CH:18]=[CH:9][C:8]2[CH:7]=[CH:6][C:5]([C:4]([F:3])([F:13])[F:14])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: CC(C)O
Product: O=C(C=Cc1ccc(C(F)(F)F)cc1)C=Cc1ccc(C(F)(F)F)cc1
Temperature: 20 °C
Yield: 74.6 %

Procedure:
A solution of sodium hydroxide (15 g of 10% aqueous) is added with stirring, and under a nitrogen atmosphere to a solution of 4-trifluoromethylbenzaldehyde (6.42 g; 0.369 mol) in heptane (70 ml). Next, a solution of acetone (10.7 g; 0.184 mol) in heptane (30 ml) is added to the above two phase system at a temperature range of from 25° C. to 30° C. over a period of two hours. The reaction mixture is then stirred for two hours at 25° C. to 30° C. Concentrated hydrochloric acid (9.4 ml) and isopropyl alcohol (48 ml) are then added, the mixture heated at reflux for 1.5 hours, and is then cooled to 20° C. The precipitated solid is filtered, washed with heptane (40 ml), and water and dried under vacuum to afford 50.8 g of title product, 98.8% pure, mp 154° C. to 156° C. (yield: 73.7%).
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3](O)=O.[NH2:14][C:15]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.Cl.[NH2:51]CCC(OCC)=O>N1C=CC=CC=1>[F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]1[N:51]=[C:17]([OH:18])[C:16]2[C:15](=[C:23]([C:24]([F:27])([F:26])[F:25])[CH:22]=[CH:21][CH:20]=2)[N:14]=1
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Reactant: O=C(O)C(F)(F)c1ccc(F)cn1
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: c1ccncc1
Product: Oc1nc(C(F)(F)c2ccc(F)cn2)nc2c(C(F)(F)F)cccc12
Temperature: 150 °C
Reaction time: 1 h
Yield: 43.3 %

Procedure:
To 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetic acid (172 mg, 0.9 mmol) and 2-amino-3-(trifluoromethyl)benzoic acid (185 mg, 0.9 mmol) in pyridine (3 mL) was added triphenyl phosphite (0.26 mL, 1 mmol) and the mixture was heated in a microwave synthesizer at 150° C. for 10 min. The mixture was cooled to rt and then ethyl 3-aminopropanoate hydrochloride (156 mg, 1 mmol) was added and the mixture was heated in a microwave synthesizer at 180° C. for 3 min. The crude mixture was concentrated under reduced pressure. THF (6 mL) was added followed by sodium ethoxide (21% in EtOH, 1.2 mL) and the mixture was stirred at 50° C. for 1 h. An additional amount of sodium ethoxide (21% in EtOH, 1 mL) was added and the mixture was stirred at 70° C. for 45 min. The cooled mixture was then was partitioned between EtOAc and 4 N HCl and the organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in hexanes and Et2O and concentrated under reduced pressure. The residue was then triturated with hexanes and collected by filtration to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-(trifluoromethyl)quinazolin-4-ol (140 mg, 43%) as a brown solid. LC-MS (ESI) m/z 360 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N+:12]([O-])=[C:11]([CH3:21])[C:10]=1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:26]C(=O)C)(=[O:25])[CH3:24]>>[C:23]([O:26][CH2:21][C:11]1[C:10]([CH3:22])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]=1)(=[O:25])[CH3:24]
Reactant: Cc1ccc2c(c1)c(OCc1ccccc1)c(C)c(C)[n+]2[O-]
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCc1nc2ccc(C)cc2c(OCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(Benzyloxy)-2,3,6-trimethylquinoline-1-oxide (1.18 g) was dissolved in acetic anhydride (32 mL), followed by stirring at room temperature for 2 hours. After the solvent was evaporated under reduced pressure, water (50 mL) was added to the residue, followed by extraction with ethyl acetate (100 mL). The organic layer was washed sequentially with water and saturated brine, and dried. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform) to obtain [4-(benzyloxy)-3,6-dimethylquinolin-2-yl]methyl acetate (1.25 g).
Reaction SMILES: C([O:5][C:6](=[O:34])[C@@H:7]([NH:26]C(OC(C)(C)C)=O)[CH2:8][CH2:9][CH:10]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:11]([O:13]C(C)(C)C)=[O:12])(C)(C)C>CCCCCC.CC(O)C>[NH2:26][C@@H:7]([CH2:8][CH2:9][CH:10]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)[C:11]([OH:13])=[O:12])[C:6]([OH:34])=[O:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CC(C)O
Solvent: CCCCCC
Product: N[C@@H](CCC(Cc1ccc(O)cc1)C(=O)O)C(=O)O
Yield: 4.6 %

Procedure:
1.56 g (3.25 mmol) (2S)-2-tert.-Butoxycarbonylamino-5-(4-hydroxy-benzyl)-hexanedioic acid di-tert.-butyl ester (Example 41b) were purified by chiral HPLC (Chiralpak AD-H 5 μm 250×300 mm; hexan/2-propanol; 40 mL7 min). Two isomers were isolated (isomer 1: 362 mg and isomer 2: 424 mg). 0.15 g (0.31 mmol) isomer 1 and 0.15 g (0.31 mmol) isomer 2 were individually deprotected according to the procedure described in Example 41c, yielding 42 mg (51%) (2S)-2-amino-5-(4-hydroxybenzyl)hexanedioic acid—Isomers C5-1 and 40 mg (48%) (2S)-2-amino-5-(4-hydroxybenzyl)hexanedioic acid—Isomers C5-2.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Br:2].[CH2:6]([N:18]([CH3:20])[CH3:19])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>O1CCOCC1>[Br-:2].[CH2:6]([N+:18]([CH3:20])([CH3:19])[CH2:1][CH:3]1[O:5][CH2:4]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCN(C)C
Reactant: BrCC1CO1
Solvent: C1COCCO1
Product: CCCCCCCCCCCC[N+](C)(C)CC1CO1
Product: [Br-]
Temperature: 90 °C

Procedure:
In a reaction flask was placed 12.4 grams of epibromohydrin, 18.73 grams of dodecyldimethyl amine and 21.34 grams of para-dioxane solvent. This was stirred and heated under nitrogen to reflux (ca. 90° C.). After 6 hours at reflux the mixture was cooled. Solvent removed under vacuum to afford product, dodecyl dimethyl (2,3-epoxypropyl) ammonium bromide as a clear gel.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[Br:14][C:15]1[C:16]([Cl:27])=[CH:17][C:18]([O:25][CH3:26])=[C:19]([CH2:21][CH2:22][CH:23]=[O:24])[CH:20]=1>CC(C)=O>[Br:14][C:15]1[C:16]([Cl:27])=[CH:17][C:18]([O:25][CH3:26])=[C:19]([CH2:21][CH2:22][C:23]([OH:3])=[O:24])[CH:20]=1
Reactant: COc1cc(Cl)c(Br)cc1CCC=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: COc1cc(Cl)c(Br)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 39.3 %

Procedure:
To a stirred solution of Jones reagent (3 mL, 5.4 mmol, 2.8 M) in acetone (20 mL), 3-(5-bromo-4-chloro-2-methoxyphenyl)propanal (860 mg, 3.1 mmol) was added. The reaction was stirred at RT for 12 h, quenched with iso-propylalcohol and then stirred for 10 min. The resulting mixture was diluted with water, extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether=1:1) to afford the desired product (358 mg, 38% yield). ESI-MS m/z: 291.1[M+H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:16]([N:10]1[C:11]2[CH2:12][CH2:13][C:4]3[CH:3]=[C:2]([Cl:1])[CH:15]=[CH:14][C:5]=3[C:6]=2[CH2:7][CH2:8][CH2:9]1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Clc1ccc2c(c1)CCC1=C2CCCN1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)N1CCCC2=C1CCc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.00 g (0.032 mol) of 8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline were dissolved in 50 ml of pyridine and 6.75 g (0.048 mol) of benzoyl chloride were added dropwise thereto at 0°. After stirring at room temperature overnight the mixture was extracted with water and chloroform, dried with magnesium sulphate and the solvent was distilled off in vacuo. Chromatography (silica gel, chloroform-hexane, 1:1) and crystallization chloroform-hexane) gave 4-benzoyl-8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]-quinoline as white crystals of melting point 194°-196°.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:12]([N:16]=[C:17]=[S:18])[CH2:13][CH2:14][CH3:15].O>CN(C)C=O>[CH2:12]([N:16]1[C:1](=[O:10])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=[C:17]1[SH:18])[CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)c1ccccc1N
Reactant: CCCCN=C=S
Solvent: CN(C)C=O
Solvent: O
Product: CCCCn1c(S)nc2ccccc2c1=O
Reaction time: 8 h

Procedure:
A stirred mixture of 7.6 g (0.05 mole) methyl anthranilate and 5.8 g (0.05 mole) n-butyl isothiocyanate in 45 ml dimethylformamide was heated at reflux for 11/2 hours, stirred overnight, then heated for 6 hours and then stirred at ambient temperature over the weekend. The reaction mixture was poured into 200 ml water (at 20° C.) to give a precipitate. The mixture was chilled and then filtered. The precipitate was washed three times with water; the filtrate was set aside. A small amount of ethanol was drained through the filter cake once. The solid was washed twice with hexane and air-dried overnight to give the above-identified product, as a solid, melting point 167°-172° C.