Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][C@@H:10]([C:34]([O:36]CC)=[O:35])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([C:29]([O:31]CC)=[O:30])[NH:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[O:22])=[CH:14][CH:13]=1)=[O:8].[OH-].[Na+].O>O1CCOCC1.CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][C@@H:10]([C:34]([OH:36])=[O:35])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C@H:19]([C:29]([OH:31])=[O:30])[NH:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[O:22])=[CH:16][CH:17]=1)=[O:8]
Reactant: CCOC(=O)[C@@H](Cc1ccc(C[C@@H](NC(=O)c2ccccn2)C(=O)OCC)cc1)NC(=O)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(N[C@H](Cc1ccc(C[C@@H](NC(=O)c2ccccn2)C(=O)O)cc1)C(=O)O)c1ccccn1
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a cooled (0° C.) solution of 1,4-bis-(2-(2-pyridylcarbonylamino)-2-ethyloxycarbonyl-(2R)-ethyl)-benzene (1.40 g; 2.70 mmol) in dioxane (4 ml) and EtOH (4 ml) an aqueous 2N NaOH solution (4 ml, 8.0 mmol) and water (2 ml) was added. The mixture was allowed to come to r.t. overnight. The solution was concentrated to approximately 5 ml under reduced pressure and the pH of the residual solution was adjusted to pH 3 by addition of aqueous 4N HCl, whereupon an oil separated. The mixture was extracted with ethyl acetate (3×15 ml). The combined organic layer was dried (MgSO4), concentrated and the residue purified by: flash chromatography (chloroform/MeOH/HOAc 8/2/1) to yield 1,4-Bis-(2-(2-pyridylcarbonylamino)-2-carboxy-(2R)-ethyl)-benzene (1.1 g, 70%).
Reaction SMILES: [H-].[Na+].C1COCC1.C(OCC)(=O)CC(OCC)=O.[CH3:19][C:20]1[C:21](/[CH:34]=[CH:35]/[C:36]([O:38][C:39]2[CH:50]=[CH:49][CH:48]=[CH:47][C:40]=2[C:41]([O:43]CC=C)=[O:42])=[O:37])=[CH:22][C:23]2[C:24]([CH3:33])([CH3:32])[CH2:25][CH2:26][C:27]([CH3:31])([CH3:30])[C:28]=2[CH:29]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:19][C:20]1[C:21](/[CH:34]=[CH:35]/[C:36]([O:38][C:39]2[CH:50]=[CH:49][CH:48]=[CH:47][C:40]=2[C:41]([OH:43])=[O:42])=[O:37])=[CH:22][C:23]2[C:24]([CH3:33])([CH3:32])[CH2:25][CH2:26][C:27]([CH3:30])([CH3:31])[C:28]=2[CH:29]=1
Reactant: C=CCOC(=O)c1ccccc1OC(=O)/C=C/c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2c(cc1/C=C/C(=O)Oc1ccccc1C(=O)O)C(C)(C)CCC2(C)C

Procedure:
117 mg (4.9 mmol) of sodium hydride (80% in oil) and 15 ml of THF are introduced into a round-bottomed flask under a stream of nitrogen. 540 μl (3.6 mmol) of diethyl malonate are then added dropwise and the mixture is stirred until the evolution of gas has ceased. This solution is introduced dropwise into a mixture of 1.4 g (3.24 mmol) of allyl (E)-2-[3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)acryloyloxy]benzoate, 20 ml of THF and 187 mg of tetrakis(triphenylphosphine)palladium(0) and stirred at room temperature for three hours. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (95/5). After evaporating the solvents, 800 mg (63%) of (E)-2-[3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)acryloyloxy]benzoic acid, with a melting point of 137-8° C., are collected.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][CH2:17][O:18][CH3:19])[C:5]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[C:6]([CH2:8]O)[CH:7]=1.N1C=CC=CC=1.S(Cl)([Cl:28])=O.O>O1CCCC1>[Cl:28][CH2:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([O:15][CH2:16][CH2:17][O:18][CH3:19])[C:5]=1[O:10][CH2:11][CH2:12][O:13][CH3:14]
Reactant: O=S(Cl)Cl
Reactant: COCCOc1cc(F)cc(CO)c1OCCOC
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: COCCOc1cc(F)cc(CCl)c1OCCOC
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of (5-fluoro-2,3-bis{[2-(methyloxy)ethyl]oxy}phenyl)methanol (0.31 g, 1.1 mmol) and pyridine (0.15 mL 1.9 mmol) in tetrahydrofuran (10 mL) at 0° C. was added thionyl chloride (0.093 mL, 1.3 mmol) and the reaction mixture warmed to room temperature and stirred for one hour. Then it was poured into water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined extract was washed with water and brine (20 mL each), dried over sodium sulfate, filtered and concentrated to give 1-(chloromethyl)-5-fluoro-2,3-bis{[2-(methyloxy)ethyl]oxy}benzene (0.33 g, 1.1 mmol, 100% yield), 1H NMR (400 MHz, CDCl3): 6.76-6.26 (m, 2H), 4.69 (s, 2H), 4.22-4.13 (m, 4H), 3.86-3.78 (m, 4H), 3.46 (s, 6H).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:13])=[N:9][NH:10]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[C:19](=O)([O-])O.[Na+]>CO>[CH3:19][O:2][C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:13])=[N:9][NH:10]2)=[CH:6][CH:5]=1)=[O:3]
Reactant: Cc1n[nH]c2cc(C(=O)O)ccc12
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2c(C)n[nH]c2c1
Yield: 87 %

Procedure:
6-Carboxy-3-methyl-1H-indazole (359 mg, 2.11 mmol) was dissolved in methanol (50 ml), and concentrated sulfuric acid (0.1 ml) was added. The mixture was heated under reflux for 22 hr. After cooling, a saturated aqueous sodium hydrogencarbonate solution was added and the methanol was distilled away under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure to give the objective compound (340 mg, 87%) as brown crystals.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[C:10]([CH:11]=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1>CCO>[CH3:3][O:4][C:5]1[C:10]([CH2:11][OH:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: COc1ncccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ncccc1CO
Temperature: -40 °C
Reaction time: 0.75 h

Procedure:
To a solution of NaBH4 (0.075 g, 2.04 mmol) in absolute EtOH (10 mL) was dropwise added a solution of 2-methoxy-pyridine-3-carbaldehyde (0.98 g, 7.15 mmol) in EtOH (2 mL) at −40° C. under N2. The reaction mixture was stirred at −40° C. for 45 min and then carefully quenched with brine. After warmed up to room temperature, the reaction solvent was removed and then diluted with EtOAc and water. The aqueous layer was extracted with EtOAc (×2) and the combined organics were washed with water, brine and dried over anhydrous Na2SO4. The mixture was filtered through Celite-silica gel. The concentration under the reduced pressure provided the product, which was carried to the next step without further purification. 1H NMR (300 MHz, CDCl3) 8.13 (m, 1H), 7.63 (m, 1H), 6.90 (m, 1H), 4.67 (s, 2H), 4.02 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][OH:11])[CH:4]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH:10]=[O:11])[CH:4]=1
Reactant: COc1cc(CO)ncc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(C=O)ncc1C
Reaction time: 6 h
Yield: 60 %

Procedure:
To a solution of 0.13 g of (4-methoxy-5-methylpyridin-2-yl)methanol in 2 mL of dichloromethane, 0.14 g of manganese dioxide was added. The mixture was stirred for 6 hours while dividedly further adding 0.36 g of manganese dioxide at room temperature. The insoluble substance was filtered off, the solvent was distilled off under reduced pressure, and the resultant residue was purified by flash column chromatography using gradient elution of hexane:ethyl acetate=9:1 to 4:1 to obtain 77 mg of 4-methoxy-5-methylpyridine-2-carbaldehyde as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][C:16]1[N:17]=[CH:18][NH:19][CH:20]=1.O>CN(C=O)C>[Br:15][C:16]1[N:17]=[CH:18][N:19]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:20]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Brc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nccc(-n2cnc(Br)c2)n1
Temperature: 0 °C
Yield: 23.1 %

Procedure:
To a solution of 2,4-dichloropyrimidine (0.447 g, 3 mmol) in anhydrous DMF (4 ml) was added potassium carbonate (0.415 g, 3 mmol). The reaction mixture was cooled (0° C.) under an inert atmosphere before the addition of 4-bromo-1-H-imidazole (0.441 g, 3 mmol) as solution in DMF (2 ml). The reaction was then allowed to stir at this temperature for a further 3 hours whereupon water (3 ml) was added. The resultant white precipitate was removed from the mixture by filtration and washed with water before being dried to give the title compound as a white solid (0.18 g, 23%) which was suitably pure to be used without further purification. m/z (LC-MSW, ESP):259.2,261.2 (bromine isotopes) [M+H]+, R/T=3.47 mins.
Reaction SMILES: Br[C:2]1[C:15]([CH3:16])=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[CH:4][C:3]=1[CH3:17].C[Li].[Li+].[Br-].[Li]C(CC)C.CN([CH:30]=[O:31])C>C1COCC1.CCOCC.C1CCCCC1>[C:10]([Si:7]([CH3:9])([CH3:8])[O:6][C:5]1[CH:14]=[C:15]([CH3:16])[C:2]([CH:30]=[O:31])=[C:3]([CH3:17])[CH:4]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CN(C)C=O
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1Br
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: C1CCCCC1
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (4-bromo-3,5-dimethylphenoxy)-tert-butyl-dimethylsilane (3.1 g, 9.8 mmol) in THF (30 mL) at −78° C. under N2 protection was added dropwise methyllithium/LiBr (9.3 ml of a 1.5 M solution in Et2O, 14 mmol). After 5 min of stirring, sec-BuLi (10 mL of a 1.4 M solution in cyclohexane, 14 mmol) was added slowly to the reaction solution at −78° C. After 5 min, anhydrous DMF (1.5 mL, 20 mmol) was added slowly then the solution was warmed to 25° C. After 30 min, the reaction mixture was quenched with water. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were washed with water, brine, dried with MgSO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (6:1) to give 4-(tert-butyldimethyl-silanyloxy)-2,6-dimethylbenzaldehyde as a yellow oil.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[Cl:18][C:19]1[C:20]([F:28])=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[C:20]([F:28])=[C:21]([N:15]2[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:17]=[CH:16]2)[CH:22]=[CH:23][CH:24]=1
Reactant: OB(O)c1cccc(Cl)c1F
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Product: Oc1ccc2ncn(-c3cccc(Cl)c3F)c2n1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 3-chloro-2-fluorophenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=263.9 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 6.73 (d, J=8.7 Hz, 1H), 7.39 (td, J1=8.2 Hz, J2=1.5 Hz, 1H), 7.68 (m, 2H), 8.00 (d, J=8.7 Hz, 1H), 8.36 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[CH:28]=[CH:29][CH:30]=[C:21]([C:22]=45)[S:20]3(=[O:32])=[O:31])[CH2:14][CH:15]=2)=[CH:2]1.[H-].[Na+].[CH3:35]I>O1CCOCC1.O>[CH3:35][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[CH:28]=[CH:29][CH:30]=[C:21]([C:22]=45)[S:20]3(=[O:32])=[O:31])[CH2:12][CH:11]=2)=[CH:2]1
Reactant: CI
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CC=C(c2c[nH]c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(C2=CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)c2ccccc21
Temperature: 20 °C
Reaction time: 2 h
Yield: 29.1 %

Procedure:
A mixture of 2-{3-[4-(3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho [1,8-cd]isothiazole 1,1-dioxide (11 g) in dmethylformamide (150 cc) is added over 30 minutes to sodium hydride (1.3 g) in a 50% dispersion in vaseline oil, under a current of argon, maintaining the temperature at about 20° C. The reaction medium is stirred for 2 hours at a temperature of about 20° C. then a solution of methyl iodide (3.9 g) in dioxane (50 cc) is added over 15 minutes. Stirring is maintained for 15 hours at a temperature of about 20° C. The reaction mixture is redissolved in distilled water (250 cc) and the organic phase is extracted with dichloromethane (4×100 cc) and then washed with distilled water (400 cc), dried over anhydrous magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is purified by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with dichloromethane as eluant, and recrystallized from boiling methyl ethyl ketone (70 cc). 2-{3-[4-(1-Methyl-3-indolyl)1,2,3,6-tetrahydro-1-pyridyl]propyl }naphtho[1,8-cd]isothiazole 1,1-dioxide (3.3 g) is obtained, m.p. 161° C.
Reaction SMILES: [NH2:1]C(N)=S.[C:5]([NH:13][C:14](=[O:16])[O-])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(N(CC)CC)C>[C:14]([NH:13][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:16])[NH2:1]
Reactant: O=C([O-])NC(=O)c1ccccc1
Reactant: NC(N)=S
Solvent: CCN(CC)CC
Product: NC(=O)NC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
In Scheme 3, step L, substep 1, the fluorinated primary alcohol (prepared in Scheme 1, step H) is deprotected under standard conditions followed by neutralization, thiourea formation and cyclization in substeps 2a and 2b to provide the protected bicyclic aminooxazine. For example, in substep 1, the fluorinated primary alcohol is dissolved in a suitable organic solvent, such as ethyl acetate or dichloromethane and treated with an excess of a suitable acid such as hydrochloric acid (4 M in 1,4-dioxane) or trifluoroacetic acid. The reaction is stirred at room temperature for about 2 hours to overnight. The deprotected amine is then isolated with techniques well known in the art such as filtration as a salt. Alternatively for substep 1, ethanol is added drop wise to a solution of excess acetyl chloride in ethyl acetate at about 0° C. and stirring for about 30 minutes. The fluorinated primary alcohol, (Scheme 1, step H) is added and the reaction is stirred overnight at room temperature. The deprotected amine salt is then isolated with techniques well known in the art such as filtration. Then, for the neutralization and thiourea formation for substep 2a, the deprotected amine salt is dissolved in a suitable organic solvent, such as acetonitrile or tetrahydrofuran and treated with about 1.1 equivalents of a suitable organic amine, such as triethylamine to neutralize the amine, and about 1.05 equivalents of benzoyl isothiocyanate is added to form the intermediate thiourea. The reaction is then stirred at 5° C. for about 1 hour or heated to about 70° for 2 hours. To cyclize and form the protected bicyclic aminooxazine in substep 2b, about 1.1 equivalents of trimethylsilyl chloride and DMSO are added and stirring is continued for about 2 hours. The reaction is quenched with potassium phosphate dibasic (20%) to adjust the pH to 7-8 and the product is isolated using techniques well known in the art to give the protected bicyclic aminooxazine product of step L. Alternatively, the amine salt can be neutralized with triethylamine as described above for step L, step 2a, and treated with benzoylcarbamate to form an N-carbamoyl benzamide intermediated that is then cyclized with diethylaminosulfur trifluoride in an organic solvent such as dichloromethane at about −78° C. and warmed to about room temperature over 1 hour. The product is isolated using techniques well known in the art to give the protected bicyclic aminooxazine product of step L.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][NH:16][CH2:15][C:14]=2[C:13]([C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=2[F:30])=[N:12]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].C=O.[CH3:35]C(C)(C)[C@H](NC(N1C2CCN(C)CC=2C(C2C=C(F)C(F)=CC=2F)=N1)=O)C(NC)=O>>[CH3:1][C:2]([CH3:32])([CH3:31])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:35])[CH2:15][C:14]=2[C:13]([C:20]2[CH:25]=[C:24]([C:26]([F:28])([F:27])[F:29])[CH:23]=[CH:22][C:21]=2[F:30])=[N:12]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(C(F)(F)F)ccc2F)c2c1CCNC2)C(C)(C)C
Agent: C=O
Product: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(C(F)(F)F)ccc2F)c2c1CCN(C)C2)C(C)(C)C

Procedure:
Compound 59 was prepared reductive amination of compound 58 with formaldehyde following the procedure as described for the synthesis of compound 37. LCMS (+ESI) m/z=456.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=1.[NH2:17][C:18]1[NH:22][N:21]=[N:20][N:19]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([NH:17][C:18]2[NH:22][N:21]=[N:20][N:19]=2)=[O:16])[N:13]=1
Reactant: Nc1nnn[nH]1
Reactant: COc1ccccc1-c1nc(C(=O)O)cs1
Solvent: CN(C)C=O
Product: COc1ccccc1-c1nc(C(=O)Nc2nnn[nH]2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
A solution of 2-(2-methoxyphenyl)-4-thiazolecarboxylic acid (250 mg) and N,N'-carbonyldimidazole (CDI, 207 mg) in dry DMF (2.5 ml) was allowed to react with stirring at room temperature for 1 hour. Then a solution of 5-aminotetrazole (109 mg) in dry DMF (1.5 ml) was added dropwise thereto and allowed to react at 70° C. for 2 hours. The solvent was removed from the mixture, and the residue was treated with water and acidified with 2N-HCl. The produced solids were filtered, washed with water, treated with stirring with ether, filtered again and dried to give white solids of the desired 2-(2-methoxyphenyl)-N-(1H-tetrazole-5-yl)-4-thiazolecarboxamide (255 mg, 79%).
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[BH4-].[Li+].CO.C(Cl)(Cl)Cl>COCCOC>[C:12]([O:11][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@H:4]1[CH2:3][OH:2])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: COCCOC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Yield: 92 %

Procedure:
This compound was prepared in 92% yield from the ester 4g (9.2 g, 40 mmol) by reduction with lithium borohydride in dry DME following the procedure that has been described earlier1,2. TLC Rf 0.81 (eluent MeOH/CHCl3, 7/93). 1H NMR (CDCl3) δ 1.47 (s, 9H, t-Bu), 1.58-2.18 (m, 4H, CH2CH2CH), 3.15-3.66 (m, 4H, CH2N, CH2OH), 3.73-4.07 (m, 1H, CHN), 4.40-4.80 (br s, 1H, OH).
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])=[CH:16][CH:15]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:30][N:31]=[C:32]=[O:33]>C1COCC1>[CH3:30][NH:31][C:32]([N:12]1[CH2:11][CH2:10][N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:28])([F:29])[F:27])=[CH:16][CH:15]=2)[CH2:8][CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:33]
Reactant: FC(F)(F)c1ccccc1-c1ccc(CN2CCNC(c3ccccc3)C2)cc1
Reactant: CN=C=O
Solvent: C1CCOC1
Product: CNC(=O)N1CCN(Cc2ccc(-c3ccccc3C(F)(F)F)cc2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound was made in the following manner: 55 mg of 3-phenyl-1-(2′-trifluoromethyl-biphenyl-4-ylmethyl)-piperazine was dissolved in THF, 2 equiv. methylisocyanate were added. The reaction was shaken at room temperature overnight. The solvent was removed in vacuo, the residue was dissolved in DCM, washed with 1M aqueous sodium hydroxide solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford the title compound as free base. Addition of 1 equiv. of 1M HCl in dioxane and concentratation in vacuo afforded 33 mg of the title compound as hydrochloride salt. Yield 48% ES MS m/z 454
Reaction SMILES: OC[CH:3]([NH:14][C:15](=[O:21])[O:16][C:17](C)(C)C)[CH:4]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1.O1CCCC1.CC(C)([O-])C.[K+]>C(OCC)(=O)C>[O:8]1[C:7]2([CH2:6][CH2:5][CH:4]([CH:3]3[CH2:17][O:16][C:15](=[O:21])[NH:14]3)[CH2:13][CH2:12]2)[O:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC(CO)C1CCC2(CC1)OCCO2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1NC(C2CCC3(CC2)OCCO3)CO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 250 mL round bottom flask was charged with tert-butyl (2-hydroxy-1-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl)carbamate (1.5 g, 4.98 mmol), prepared in the previous step, and tetrahydrofuran (100 mL). The mixture was cooled to 0° C. and potassium tert-butoxide (670 mg, 5.97 mmol) was added. The mixture was stirred at 0° C. for 2 h. The mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to the product as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][CH3:23])[CH2:36][CH2:35]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(C(=O)Nc2cc3ccccc3nc2OC)CC1
Yield: 88 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound.
Reaction SMILES: C(N1CC[CH2:6][CH:5](CCN2C(OC)=NC3C2=NC(O[C@@H](C)CCC)=NC=3N)[CH2:4]1)C.[CH2:29]([O:33][C:34]1[N:42]=[C:41]2[C:37]([N:38]=[C:39]([O:54][CH3:55])[N:40]2[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH:48]2[CH2:53][CH2:52][CH2:51][NH:50][CH2:49]2)=[C:36]([NH2:56])[N:35]=1)[CH2:30][CH2:31][CH3:32].IC(C)C>>[CH2:29]([O:33][C:34]1[N:42]=[C:41]2[C:37]([N:38]=[C:39]([O:54][CH3:55])[N:40]2[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH:48]2[CH2:53][CH2:52][CH2:51][N:50]([CH:5]([CH3:6])[CH3:4])[CH2:49]2)=[C:36]([NH2:56])[N:35]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCC3CCCNC3)c2n1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1
Solvent: CC(C)I
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCC3CCCN(C(C)C)C3)c2n1

Procedure:
Prepared similarly to Intermediate 46 from 2-(butyloxy)-8-(methyloxy)-9-[5-(3-piperidinyl)pentyl]-9H-purin-6-amine and 2-iodopropane.