Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][NH:4][C:3](=[O:12])[CH2:2]1.[CH3:13][C:14]([CH3:16])=O.[BH3-]C#N.[Na+].C(O)(=O)C.C([O-])(O)=O.[Na+]>CO>[CH:14]([N:9]1[CH2:8][CH2:7][C:6]2([O:1][CH2:2][C:3](=[O:12])[NH:4][CH2:5]2)[CH2:11][CH2:10]1)([CH3:16])[CH3:13]
Reactant: CC(C)=O
Reactant: O=C1COC2(CCNCC2)CN1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N1CCC2(CC1)CNC(=O)CO2
Temperature: 50 °C

Procedure:
1-Oxa-4,9-diaza-spiro[5.5]undecan-3-one was dissolved in MeOH and treated with acetone (6 equivalents) and NaCNBH3 (4 equivalents). To the reaction mixture was added acetic acid (3 equivalents). The reaction was heated at 50° C. for 6 hours and then cooled to room temperature. The reaction was then poured into an aqueous NaHCO3 solution and extracted with EtOAc (3×). The combined fractions were dried over MgSO4 and concentrated to provide the title compound as a yellow oil that was purified by chromatography (10% MeOH/CH2Cl2). LC/MS (m/z) 213.1 (MH+), Rt=1.38 minutes.
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=O)=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(O)[O-].[Na+].[NH2:17][CH:18]([C:22]([NH2:24])=[O:23])[C:19]([NH2:21])=[O:20]>O>[OH:20][C:19]1[C:18]([C:22]([NH2:24])=[O:23])=[N:17][CH:10]=[C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:21]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: NC(=O)C(N)C(N)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: NC(=O)c1ncc(-c2ccccc2)nc1O
Temperature: 100 °C

Procedure:
A solution of 5.4 g. of phenylglyoxal hydrate in 25 ml. water is treated with 50 ml. of aqueous sodium bisulfite (density 1.34) at 25° C. for 45 min. A solution of 3.9 g. of aminomalonamide in 39 ml. of water is added and the reaction mixture is heated at 100° C. for 2.5 hr. The resultant yellow precipitate which forms is isolated by filtration, washed with water, dried and recrystallized from ethanol to afford 3-hydroxy-5-phenylpyrazine-2-carboxamide. This product is hydrolyzed with saturated ethanolic sodium hydroxide for 16 hrs. at 150° C. to afford 3-hydroxy-5-phenylpyrazine-2-carboxylic acid. This product is refluxed with 30 ml. of carbitolacetate for 15 min. then cooled to 250° C. and petroleum ether (bp 68° C.) added to precipitate the title compound.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17]([CH:24]=[CH:25][C:26](=[O:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:16][C:15]=3[C:35]([F:38])([F:37])[F:36])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2]>CO.[Pd]>[CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17]([CH2:24][CH2:25][C:26](=[O:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:16][C:15]=3[C:35]([F:38])([F:36])[F:37])[CH:11]=2)[NH:6][CH:5]=1)([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCC(=O)C=Cc1cc(C(F)(F)F)c(Oc2ccc3[nH]cc(C(C)C)c3c2)c(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCC(=O)CCc1cc(C(F)(F)F)c(Oc2ccc3[nH]cc(C(C)C)c3c2)c(C(F)(F)F)c1

Procedure:
Analogously to the procedure of Example 25, 0.2 g (0.38 mmol) of 3-oxopentene-4-Carboxylic acid derivative from Example 26 is hydrogenated overnight in methanol with palladium on active carbon under a hydrogen atmosphere. The crude product is chromatographed on silica gel using toluene/ethyl acetate (10:1) in the isocratic mode.
Reaction SMILES: O[CH:2]([C:7]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][O:21][CH:22]3CCCC[O:23]3)[C:13](=[O:28])[N:12]([CH3:29])[C:11]=2[N:10]=[CH:9][C:8]=1[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]([F:41])([F:40])[F:39])[CH:32]=1)[CH2:3][CH:4]([CH3:6])[CH3:5]>C(O)=O.[Zn]>[CH:22]([O:21][CH2:20][CH2:19][CH2:18][N:14]1[C:15](=[O:17])[C:16]2[C:7]([CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5])=[C:8]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]([F:39])([F:40])[F:41])[CH:32]=3)[CH:9]=[N:10][C:11]=2[N:12]([CH3:29])[C:13]1=[O:28])=[O:23]
Reactant: CC(C)CC(O)c1c(Oc2cccc(OC(F)(F)F)c2)cnc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Agent: [Zn]
Solvent: O=CO
Product: CC(C)CCc1c(Oc2cccc(OC(F)(F)F)c2)cnc2c1c(=O)n(CCCOC=O)c(=O)n2C
Temperature: 100 °C
Yield: 95.3 %

Procedure:
To a solution of 5-(1-hydroxy-3-methylbutyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy) propyl)-6-(3-(trifluoromethoxy)phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 46, step 2, 60 mg, 0.103 mmol) in HCOOH (4 mL) was added Zn dust (34 mg, 0.515 mmol). The reaction was heated at 100° C. for 3 h, cooled to RT and filtered. The filtrate was concentrated and dried to give 3-(5-isopentyl-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenoxy)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (50 mg, 96.1% yield) as a solid. LCMS: MH+ 510 and TR=2.446 min. Used without further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[CH2:12]1[O:15][CH:13]1[CH3:14].[CH2:16]1OC1.C1OC1C.C1OC1>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[CH3:14][CH2:13][O:15][CH2:12][CH3:16]
Reactant: C1CO1
Reactant: CC1CO1
Agent: Oc1ccc2ccccc2c1
Solvent: Cc1ccccc1
Product: CCOCC
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a clean, dry stirred tank pressure vessel with nitrogen inlet is charged 952.71 g (6.61 moles) of 2-Naphthol and 1445 mLs of Toluene. The vessel is purged with nitrogen and a catalytic amount (4.96 g) of BF3/Etherate Solution is charged. The temperature is raised to 110° C. and a mixture of 1919.03 g (33.04 moles) of Propylene Oxide and 873.28 g (19.82 moles) of Ethylene Oxide is added at a constant rate to keep the pressure inside the vessel below 50 psig. After all Propylene Oxide/Ethylene Oxide is added, the reaction mixture is allowed to react for an additional 3 hours after which the temperature is raised to 150° C. and the toluene is distilled off under nitrogen sparge. After the distillation of Toluene, the temperature is cooled to 110° C. and vacuum is applied for 1 hour.
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[CH:8]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(O)C>[CH:8]1([NH:14][C:2]2[CH2:6][S:5][C:4](=[O:7])[N:3]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C1NC(=S)CS1
Reactant: NC1CCCCC1
Solvent: CCO
Product: O=C1N=C(NC2CCCCC2)CS1

Procedure:
To a solution of 4-thioxo-1,3-thiazolidin-2-one (1.00 g) in ethanol (30 mL) was added cyclohexylamine (0.88 mL), and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained powder was washed with ethyl acetate to give the title compound (599 mg).
Reaction SMILES: [K].[Cl:2][C:3]1[C:13]([Cl:14])=[C:12]([Cl:15])[C:11]([Cl:16])=[C:5]2[C:6]([NH:8][C:9](=[O:10])[C:4]=12)=[O:7].[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>O1CCOCC1>[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20]([N:8]1[C:9](=[O:10])[C:4]2=[C:3]([Cl:2])[C:13]([Cl:14])=[C:12]([Cl:15])[C:11]([Cl:16])=[C:5]2[C:6]1=[O:7])=[O:21]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: O=C1NC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: [K]
Solvent: C1COCCO1
Product: O=C(c1ccc(Cl)cc1Cl)N1C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C

Procedure:
The potassium salt of 3,4,5,6-tetrachlorophthalimide (0.10 mole) and dioxane (1200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,4-Dichlorobenzoyl chloride (0.10 mole) is then added dropwise, with stirring, to the reaction mixture at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is stripped of solvent to yield the desired product N-(2,4-dichlorobenzoyl)-3,4,5,6-tetrachlorophthalimide.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[C:9]([C:15]#[N:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.[H-].[Na+].[CH2:24](Br)[CH2:25][CH2:26][CH3:27]>O>[C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH2:24][CH2:25][CH2:26][CH3:27])[C:10](=[O:14])[C:9]([C:15]#[N:16])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1nn(-c2ccccc2)c(=O)[nH]c1=O
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c(C#N)nn(-c2ccccc2)c1=O
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
Intermediate c (9 g, 0.042 mol) was added to DMF (100 mL). To the mixture was added NaH (1.3 g, 0.054 mol) in batch under an ice bath. After stirring for 30 min, n-butyl bromide (3.4 mL, 0.042 mol) was added dropwise. Ater the dropwise addition, the reaction was conducted at 70° C. for 6 h. After completion of the reaction, the reaction solution was poured into water (600 mL). A great deal of solid separated out and was filtered by suction. The filtered cake was washed with water and dried to produce Intermediate f (8.2 g) in a yield of 81.4%.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[NH2:4].[Cl:11][CH2:12][C:13](Cl)=O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:11][CH2:12][C:13]1[O:1][N:2]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)[N:4]=1
Reactant: O=C(Cl)CCl
Reactant: NC(=NO)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: ClCc1nc(-c2ccccn2)no1
Reaction time: 24 h

Procedure:
The title compound was prepared by a modification of a reported method: a) Mylari, B. L.; Beyer, T. A.; Scott, P. J.; Aldinger, C. E.; Dee, M. F.; Siegel, T. W.; Zembrowski, W. J. J. Med. Chem. 1992, 35, 457, and b) Palazzo, G.; Tavella, M.; Strani, G.; Silvestrini, B.; J. Med. Pharm. Chem. 1961, 4, 351. To a suspension of N′-hydroxypyridine-2-carboximidamide (25.0 g, 0.182 mol) in chloroform (350 mL) was added chloroacetyl chloride (20.5 g, 0.182 mol, 1 equiv) and triethylamine (20.23 g, 0.2 mol, 1.1 equiv). When most of the triethylamine had been added, the suspension turned to a clear light-yellow solution. The solution was allowed to stand at room temperature for 1 d. The mixture was extracted with water (3×75 mL), resulting in the precipitation of a crystalline solid. The resulting slurry was filtered, and filter cake triturated with ethanol, re-filtered, and dried, affording 29.62 g (73%) of the O-chloracetyl amidoxime intermediate. This intermediate was refluxed in xylenes (300 mL) for 3 h, and the volatiles removed completely in vacuo, affording 25.55 g (72% overall) of the pure 1,2,4-oxadiazole. 1H NMR (DMSO-d6) □5.20 (s, 2H), 7.62 (m, 1H), 8.06 (m, 2H), 8.76 (m, 1H). LC-MS (APCI) calcd for C8H6ClN3O: 195.02; found (M+H+): 196.0 m/z.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:7][C:6]=1[CH3:17])=O.[NH2:18][C:19]([NH2:21])=[S:20]>CCO>[CH3:16][O:15][CH2:14][CH2:13][O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([C:3]2[N:18]=[C:19]([NH2:21])[S:20][CH:2]=2)=[C:6]([CH3:17])[CH:7]=1
Reactant: COCCOc1cc(C)c(C(=O)CBr)c(C)c1
Reactant: NC(N)=S
Solvent: CCO
Product: COCCOc1cc(C)c(-c2csc(N)n2)c(C)c1
Yield: 90.9 %

Procedure:
A reaction mixture containing 2-bromo-1-(4-(2-methoxyethoxy)-2,6-dimethylphenyl)ethanone (322.9 mg, 1.1 mmol, 1.0 equiv) and thiourea (81.61 mg, 1.1 mmol, 1.0 equiv) in EtOH (3.0 mL) was heated at reflux for 16 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (20 mL). The solution was washed with saturated aqueous NaHCO3 (30 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30% EtOAc in hexanes as eluant) to provide 4-(4-(2-methoxyethoxy)-2,6-dimethylphenyl)thiazol-2-amine (281.0 mg, 1.0 mmol) as yellow solids in 94% yield: 1H NMR (DMSO-d6, 500 MHz) δ 6.76 (s, 2H), 5.31-5.33 (m, 1H), 4.09-4.11 (m, 2H), 3.64-3.65 (m, 2H), 3.30 (s, 3H), 2.12 (s, 6H); ESI-MS: m/z 279.7 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]([CH3:9])=[CH:7][CH:8]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:2][C:1]([C:4]1[O:5][C:6]([CH3:9])=[CH:7][CH:8]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(C)o1
Product: Cc1ccc(C(=O)C=CN(C)C)o1

Procedure:
A mixture of 37.24 g of 2-acetyl-5-methylfuran and 150 ml of N,N-dimethylformamide dimethylacetal was heated on a steam bath under an air condenser for 16.5 hours. The solvent was removed in vacuo and the residue taken up in dichloromethane and passed through a short column of magnesium silicate. The filtrate was evaporated on a steam bath with the addition of n-hexanes to a volume of 100-150 ml. Cooling with scratching gave 28.31 g of the desired compound, mp 123°-125° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[C:15]([CH3:20])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:11]=1>>[CH3:27][C:25]1[NH:24][N:23]=[C:22]([NH:21][C:12]2[N:11]=[C:10]([O:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:19]3[C:14]([CH:13]=2)=[C:15]([CH3:20])[CH:16]=[CH:17][CH:18]=3)[CH:26]=1
Reactant: Cc1ccc(O)cc1
Reactant: Cc1cc(Nc2cc3c(C)cccc3c(Cl)n2)n[nH]1
Product: Cc1ccc(Oc2nc(Nc3cc(C)[nH]n3)cc3c(C)cccc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-methyl-phenol and (1-chloro-5-methyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5-methyl-1H-pyrazol-3-yl)-(1-p-tolyloxy-5-methyl-isoquinolin-3-yl)-amine. LC-MS m/e 345(MH+).
Reaction SMILES: [CH3:1][N:2]([C:16]1[S:17][CH:18]=[CH:19][N:20]=1)[S:3]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)(=[O:5])=[O:4].O1CCOCC1.[OH-].[Na+].Cl>C(OCC)(=O)C>[CH3:1][N:2]([C:16]1[S:17][CH:18]=[CH:19][N:20]=1)[S:3]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1)(=[O:4])=[O:5]
Reactant: COC(=O)c1ccc(S(=O)(=O)N(C)c2nccs2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN(c1nccs1)S(=O)(=O)c1ccc(C(=O)O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To methyl 4-[methyl(thiazol-2-yl)sulfamoyl]benzoate (4.22 g, 13.5 mmol) and 1,4-dioxane (32 mL) was added aq. NaOH (62 mL of 2.5 M, 155 mmol) and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was cooled to room temperature. Ethyl acetate (135 mL) was added before acidifying it to pH 1 with HCl (37%). The organic and aqueous layers were separated. The aqueous layer was extracted with ethyl acetate (1×50 mL). The organic layers were dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield 4-[methyl(thiazol-2-yl)sulfamoyl]benzoic acid (3.63 g, 87%) as a white solid. ESI-MS m/z calc. 298.0, found 299.1 (M+1)+; Retention time: 1.31 minutes (3 minutes run). 1H NMR (400 MHz, DMSO) δ 13.56 (s, 1H), 8.14 (d, J=8.6 Hz, 2H), 7.92 (d, J=8.5 Hz, 2H), 7.46 (d, J=3.6 Hz, 1H), 7.44 (d, J=3.6 Hz, 1H), 3.39 (s, 3H).
Reaction SMILES: [N:1]([C:3]1[C:4]([NH2:15])=[N:5][C:6]([NH2:14])=[N:7][C:8]=1[O:9][CH2:10][CH:11]([CH3:13])[CH3:12])=O.[ClH:16]>C(O)C.[Pd]>[ClH:16].[ClH:16].[CH3:12][CH:11]([CH3:13])[CH2:10][O:9][C:8]1[N:7]=[C:6]([NH2:14])[N:5]=[C:4]([NH2:15])[C:3]=1[NH2:1]
Reactant: CC(C)COc1nc(N)nc(N)c1N=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)COc1nc(N)nc(N)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.6 %

Procedure:
To a solution of 16.9 g (0.08 mol) 5-nitroso-2,4-diamino-6-(2-methylpropoxy)pyrimidine from step 2.2 in 400 ml ethanol was added 1.5 g (0.04 mol %) palladium on charcoal (5%). The mixture was shaken at room temperature for 16 h under an atmosphere of hydrogen at 1 bar. The reaction mixture was then poured into 105 ml dilute hydrochloric acid (0.30 mol), the catalyst was filtered off and the filtrate was concentrated almost to dryness. The precipitated crystals were filtered off with suction and washed with tert-butyl methyl ether. 6-(2-Methylpropoxy)-2,4,5-pyrimidinetriamine dihydrochloride (14.6 g, 68%) was obtained as light yellow crystals.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH2:10][NH:11][C:12](=O)[CH2:13]2.O>C1COCC1.ClCCl>[CH3:7][N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH2:10][NH:11][CH2:12][CH2:13]2
Reactant: CN1C2CCC1CC(=O)NC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN1C2CCNCC1CC2
Temperature: 0 °C
Yield: 69 %

Procedure:
To a suspension of LiAlH4 (0.61 g) in anhydrous THF (30 ml), cooled at 0° C., and kept under an argon inert atmosphere, a solution in THF of 9-methyl-3,9-diazabicyclo[4.2.1]nonan-4-one obtained in example 1 is dropwise added (1.00: of compound in 10 ml of THF). The obtained mixture is heated at reflux for 48 hours and then cooled at 0° C. Then water (3 ml) is slowly added to the mixture. After water addition, the mixture is kept under stirring for 1:0 minutes. A precipitate is formed, that at the end is filtered under vacuum and washed with dichloromethane. The obtained filtrate is evaporated obtaining an oil which is dissolved in dichloromethane. The obtained solution is then anhydrified on sodium sulphate and the solvent evaporated. The residual oil is distilled (45-50° C./0.1 mmHg) to give 0.63 g of 9-methyl-3,9-diazabicyclo[4.2.1]nonane (2a) as a colourless oil.
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[Br:17]Br>ClCCl.[Fe]>[Br:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:1]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2])[CH2:9][CH2:10]2
Reactant: BrBr
Reactant: CCOC(=O)C(=O)N1CCc2ccccc21
Agent: [Fe]
Solvent: ClCCl
Product: CCOC(=O)C(=O)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
To a mixture of N-ethoxalylindoline (4 g, 18.3 mmol), and iron powder (0.40 g) in dichloromethane (40 mL) was added dropwise bromine (1.43 mL, 27.7 mmol) at 0° C. The mixture was stirred for 4 h at room temperature and filtered. The filtrate was washed with aqueous sodium thiosulfate and then brine, dried over magnesium sulfate, and concentrated to give 5.24 g of 5-bromo-N-ethoxalylindoline (95%): 1H NMR (270 MHz, CDCl3) δ8.07(d, 1H, J=8 Hz), 7.35 (dd, 2H, J=8, 1 Hz), 4.38 (q, 2H, J=7 Hz), 4.27 (t, 2H, J=8 Hz), 3.20 (t, 2H, J=8 Hz), 1.41 (t, 3H, J=7 Hz).
Reaction SMILES: S(O)(O)(=O)=O.[C:6](=[NH:10])([O:8][CH3:9])[NH2:7].C[O-].[Na+].[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([C:35](=O)[CH2:36][CH2:37][CH3:38])[C:30](OCC)=[O:31])=[CH:24][CH:23]=1)#[N:15]>CO>[CH3:9][O:8][C:6]1[NH:7][C:30](=[O:31])[C:29]([CH2:28][C:25]2[CH:26]=[CH:27][C:22]([C:17]3[C:16]([C:14]#[N:15])=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:23][CH:24]=2)=[C:35]([CH2:36][CH2:37][CH3:38])[N:10]=1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: COC(=N)N
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: CCCc1nc(OC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 16.1 %

Procedure:
A solution of methyl imidocarbamate sulfate (10 g), 28% sodium methoxide (26 mL) and ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (15.8 g) in methanol (100 mL) was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and water and acetic acid were added. The precipitated solid was collected by filtration, washed with water and diethyl ether to give the title compound (2.62 g, 16%) as a colorless solid.
Reaction SMILES: [N:1]([C:4]1[C:5](=[O:15])[O:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([OH:14])[CH:8]=2)=[N+:2]=[N-:3].[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(Cl)Cl.N1C=CC=CC=1>[N:1]([C:4]1[C:5](=[O:15])[O:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][C:16](=[O:18])[CH3:17])[CH:8]=2)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1cc2ccc(O)cc2oc1=O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2cc(N=[N+]=[N-])c(=O)oc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
To a stirred suspension of 3-azido-7-hydroxycoumarin (203 mg, 1.0 mmol) in dry CH2Cl2 (15 mL), acetic anhydride (1.5 mmol) and pyridine (one drop) were added. Upon stirring overnight at room temperature, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with H2O. The organic layer was dried over anhydrous Na2SO4 and concentrated. Purification with column chromatography over silica gel (hexane-EtOAc 4:1) afforded the final product as a yellow solid (210 mg, 86%). 1H-NMR (DMSO-d6, 300 MHz) δ 2.29 (s, 3H), 7.17 (dd, J=8.0, 2.0 Hz, 1H), 7.32 (d, J=2.1 Hz, 1H), 7.67 (s, 1H), 7.70 (d, J=7.9 Hz, 1H). 13C NMR (DMSO-d6, 75 MHz) δ 21.5, 110.6, 117.8, 119.9, 125.8, 126.8, 129.2, 151.9, 152.3, 157.5, 169.6. IR (KBr): 2133 (vs), 1749, 1730 (vs), 1622 (s), 1234 (s). EI-HRMS m/e calculated for M+ C11H7N3O4 245.0437; found 245.0432.
Reaction SMILES: [C:1]([NH:11][C@@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH:13]1[O:15][CH2:14]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:20]([OH:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:27][CH2:14][CH:13]([OH:15])[C@@H:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH2:16][CH:17]([CH3:18])[CH3:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C1CO1
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(O)COCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 100 mg of (3S)-3-carbobenzoxyamino-5-methyl-1,2-epoxyhexane, 2 g of dry silica gel and 2 ml of benzyl alcohol was heated at 100° C. for 16 hours. After filtration of the silica gel, the filtrate was evaporated under reduced pressure to obtain 105 mg of (2RS, 3S)-3-carbobenzoxyamino-2-hydroxy-5-methylhexyl benzyl ether as a colorless oil. To a solution of 86 mg of the ether obtained in 10 ml of methanol was added 0.14 ml of a 2N-hydrochloric acid, and the mixture was hydrogenated over 17 mg of palladium charcoal under hydrogen atmosphere. After filtration of the catalyst, the filtrate was evaporated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: lower layer of chloroform/methanol/water=8/3/1 by volume) to obtain 17 mg of (2RS, 3S)-3-amino-2-hydroxy-5-methylhexyl benzyl ether hydrochloride as a colorless viscous oil.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([NH2:5])=[NH:4].[Cl:8][CH:9]([C:15]([CH3:17])=O)[C:10](OCC)=[O:11]>>[Cl:8][C:9]1[C:10]([OH:11])=[N:4][C:3]([C:2]([Cl:7])([Cl:6])[Cl:1])=[N:5][C:15]=1[CH3:17]
Reactant: N=C(N)C(Cl)(Cl)Cl
Reactant: CCOC(=O)C(Cl)C(C)=O
Product: Cc1nc(C(Cl)(Cl)Cl)nc(O)c1Cl

Procedure:
The carboxylic ester compounds of the present invention may be prepared by reacting trichloroacetamidine with a selected acetoacetate to form the corresponding 4-hydroxy-2-trichloromethylpyrimidine, which is then reacted with a selected carboxylic acid chloride. These general reactions are illustrated below in equations (A) and (B). In equation (A), trichloroacetamidine is reacted with ethyl 2-chloroacetoacetate to form 5-chloro-4-hydroxy-6-methyl-2-trichloromethyl-pyrimidine. In equation (B), the 5-chloro-4-hydroxy-6-methyl-2-trichloromethylpyrimidine is reacted with trichloroacetyl chloride to form 5-chloro-6-methyl-4-trichloroacetoxy-2-trichloromethylpyrimidine. ##STR3##
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:19]=1)=[CH:15][C:14]([Cl:27])=[CH:13][CH:12]=2)=[O:7])(C)(C)C.Cl>O1CCOCC1>[Cl:27][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:8]([C:6]([OH:7])=[O:5])=[C:17]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:19]=1
Reactant: CC(C)c1cccc(-c2c(C(=O)OC(C)(C)C)c(N3CCCCC3)nc3ccc(Cl)cc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)c1cccc(-c2c(C(=O)O)c(N3CCCCC3)nc3ccc(Cl)cc23)c1

Procedure:
The title compound was prepared in analogy to example 78 step E from 6-chloro-4-(3-isopropyl-phenyl)-2-piperidin-1-yl-quinoline-3-carboxylic acid tert-butyl ester (75 mg, 0.16 mmol) and 4N HCl in dioxane. Pale yellow solid (58 mg, 88%). LC-MS (ESI): 409 (M+H)+.