Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14].[CH:16](=O)[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[N+:13]([C:9]1[CH:10]=[N:11][N:12]2[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH:16]2[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)([O-:15])=[O:14]
Reactant: O=CC1CCCCC1
Reactant: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Product: O=[N+]([O-])c1cnn2c1-c1ccccc1NC2C1CCCCC1
Yield: 73.8 %

Procedure:
5-(o-Aminophenyl)-4-nitropyrazole is reacted with hexahydrobenzaldehyde as described in Example 11 to give 1-nitro-5-cyclohexyl-5,6-dihydropyrazolo[1,5-c]quinazoline. M.p.: 150°-152° C. Yield: 73.8%.
Reaction SMILES: C(Cl)Cl.[N+:4]([C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1)([O-:6])=[O:5].[CH3:14][C:15]([CH3:20])([CH3:19])[C:16](Cl)=[O:17].[NH4+].[Cl-]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:16]([O:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([N+:4]([O-:6])=[O:5])[CH:8]=1)(=[O:17])[C:15]([CH3:20])([CH3:19])[CH3:14]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To 300 mL of CH2Cl2 was added 3-nitrophenol (structure 64 of Scheme XVII, where R1 =H, Y=O) (15 g, 0.11 mol), pyridine (20 mL) and DMAP (10 mg). To this cooled solution (0° C.) was slowly added trimethylacetyl chloride (18 mL, 146 mmol, 1.4 equivuiv). The solution was allowed to warm to rt and stirred for 3 h. To the amber colored solution was added sat'd NH4Cl (300 mL). The organic layer was washed with 1 N HCl (2×150 mL), 10% CuSO4. 5 H2O (2×100 mL), and brine (2×100 mL). The extract was dried (Na2SO4) and concentrated in vacuo to give 22.5 g (94%) of O-pivaloyl-3-nitrophenol as a white solid. Data for O-pivaloyl-3-nitrophenol: Rf 0.55 (silica gel, hexanes/EtOAc, 3:1); 1H NMR (400 MHz, CDCl3) 8.11 (dd, J=4.2, 1.3, 1 H), 7.96 (t, J=2.2, 1 H), 7.56 (dd, J=8.4, 8.2, 1 H), 7.42 (dd, J=6.5, 1.3, 1 H), 1.35 (s, 9 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C2C=CC=CC=2)=[C:4]([C:17](=[O:27])[C:18]2[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:19]=2[F:26])[CH:3]=1.[OH-].[K+]>CO.O>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:17]([C:18]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:19]=1[F:26])=[O:27]
Reactant: COc1cccc(F)c1C(=O)c1cc(Cl)ccc1NC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc(F)c1C(=O)c1cc(Cl)ccc1N
Temperature: 25 °C

Procedure:
To a solution of 1-fluoro-3-methoxy-benzene (19.6 g, 155 mmol) in THF (180 mL), at −78° C., was added dropwise 2.5 M n-butyllithium in hexanes (62 mL, 155 mmol). The solution was stirred at −78° C. for 3 h and then added to a suspension of 6-chloro-2-phenyl-benzo[d][1,3]oxazin-4-one (38.8 g, 150 mmol) in THF (280 mL) at −20° C. The mixture was allowed to gradually warm until the solution became homogenous. 1N HCl (150 mL) followed by EtOAc (250 mL) were then added and the solution allowed to warm to room temperature. The organic portion was collected and washed with H2O (250 mL), saturated NaHCO3 (2×250 mL) and H2O (250 mL). The organic portion was then dried over Na2SO4 and evaporated to dryness, in vacuo, to provide the N-[4-Chloro-2-(2-fluoro-6-methoxy-benzoyl)-phenyl]-benzamide as an orange solid (42.7 g). To a solution of N-[4-Chloro-2-(2-fluoro-6-methoxy-benzoyl)-phenyl]-benzamide (42.7 g, 110 mmol) in MeOH (540 mL) was added KOH (56.4 g, 1 mole) in H2O (100 mL). The solution was allowed to reflux for 16 h. The solution was then allowed to cool to room temperature and the resulting precipitate removed by filtration. The filtrate was concentrated in vacuo, diluted with EtOAc (250 mL) and washed with H2O (3×100 mL). The organic portion was then dried over Na2SO4, concentrated in vacuo and then purified by column chromatography (silica gel, 0 to 15% EtOAc/hexanes) to provide 1ac (19.6 g, 47%) MS m/z=280 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][C:3]=1[N:9]=O.[Na].C([O:14][C:15](=[O:20])[CH2:16][C:17]([CH3:19])=O)C>C(O)C>[CH2:7]([N:6]1[C:2]2=[N:1][C:17]([CH3:19])=[C:16]([C:15]([OH:20])=[O:14])[N:9]=[C:3]2[CH:4]=[N:5]1)[CH3:8]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCn1ncc(N=O)c1N
Agent: [Na]
Solvent: CCO
Product: CCn1ncc2nc(C(=O)O)c(C)nc21

Procedure:
49 g. of 5-amino-1-ethyl-4-nitrosopyrazole (0.35 mol.) are added to a solution of 8.05 g. of sodium (0.35 mol.) in 350 ml. of absolute ethanol and this is stirred at room temperature for 30 minutes. After the addition of 50 g. of acetoacetic acid ethyl ester (0.385 mol.) the reaction mixture is heated at reflux temperature for 31/2 hours. The precipitated sodium salt is filtered off, washed with ether and dried at 50°, yield 47.1 g. (59%). By dissolving the sodium salt in water, treatment with charcoal and acidification with concentrated hydrochloric acid, 1-ethyl-6-methyl-1H-pyrazolo-[3,4-b]pyrazine-5-carboxylic acid, m.p. 148°-149° (ethanol) is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([F:24])[C:10]([NH2:23])=[C:11]3[C:16]=2[O:15][CH2:14][C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[N:12]3)=[C:5]([CH3:25])[O:4][N:3]=1.[BH4-].[Na+]>C(O)C.O>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([F:24])[C:10]([NH2:23])=[C:11]3[C:16]=2[O:15][CH2:14][CH:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[NH:12]3)=[C:5]([CH3:25])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1cc(F)c(N)c2c1OCC(c1cccnc1)=N2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1noc(C)c1-c1cc(F)c(N)c2c1OCC(c1cccnc1)N2
Temperature: 90 °C
Yield: 32.3 %

Procedure:
To a solution of 8-(3,5-dimethylisoxazol-4-yl)-6-fluoro-3-pyridin-3-yl-2H-1,4-benzoxazin-5-amine (40 mg, 0.1 mmol) in ethanol (0.8 mL) and water (0.2 mL), sodium tetrahydroborate (4.5 mg, 0.12 mmol) was added and the mixture was heated at 90° C. for 15 minutes. Sodium tetrahydroborate (4.5 mg, 0.12 mmol) was added and the mixture was heated to 90° C. for 15 minutes again. The mixture was evaporated and extracted with ethyl acetate. The organic extracts were evaporated. Purification by preparative LCMS (pH 10) gave the desired compound 11 mg, 30%. 1H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.50 (m, 1H), 7.80 (m, 1H), 7.40 (m, 1H), 6.35 (m, 1H), 5.61 (s, 1H), 4.78 (s, 2H), 4.60 (m, 1H), 4.20 (m, 1H), 3.98 (m, 1H), 2.20 (s, 3H), 2.01 (s, 3H). LCMS calculated for C18H18FN4O2 (M+H)+: m/z=341.1. found: 340.9.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=S)=[CH:13][CH:12]=1.O[Li].O.OO>O1CCCC1>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[O:9][C:3]3[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:13][CH:12]=1
Reactant: Cc1cccc(N)c1O
Reactant: S=C=Nc1ccc(Br)cc1
Agent: OO
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc2nc(Nc3ccc(Br)cc3)oc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
An ambient solution of 2-amino-6-methylphenol (0.74 g, 6.0 mmol) and 4-bromophenyl isothiocyanate (1.28 g, 6.0 mmol) in tetrahydrofuran (20 mL) was stirred for 16 h. The reaction was cooled (0° C.), and LiOH.H2O (0.521 g, 12.41 mmol) was added, followed by the dropwise addition of 30% H2O2 (3.41 mL, 31.0 mmol) over 15 minutes. The reaction was warmed to room temperature and stirred for 16 h. The reaction was then quenched by the addition of 20% aqueous sodium sulfite solution (50 mL) and ethyl acetate (75 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×75 mL). The combined organics were dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 gel, eluting with 25% ethyl acetate in hexane, to give the title compound. MS (ESI) m/z 303 [M+H]+.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[CH:14]=[N:15][OH:16].O>CN(C=O)C>[Cl:1][C:13]1([CH:14]=[N:15][OH:16])[CH:17]=[CH:18][CH:19]=[C:11]([O:10][CH3:9])[CH2:12]1
Reactant: COc1cccc(C=NO)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC1=CC=CC(Cl)(C=NO)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-chlorosuccinimide (32.2 g, 241 mmol) was added to a solution of 3-methoxybenzaldehyde oxime (30.4 g, 201 mmol) in DMF (200 ml) at RT, causing the temperature to rise briefly to 50° C. The reaction mixture was cooled in an ice bath, stirred overnight at RT, mixed with water (250 ml) while being cooled with ice and the precipitate formed was removed by suction-filtration. The filtrate was extracted with ether (3×400 ml) and the combined organic phases were washed with water (300 ml) and sat. aq. NaCl solution (300 ml), dried and the solvent was removed under vacuum. The desired product 1-chloro-1-hydroxyiminomethyl-3-methoxybenzene was obtained as a yellowish solid (32.86 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]#[CH:16])[CH:12]=[CH:11][C:10]=1[F:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(NC(C)C)(C)C.C(OCC)(=O)C.[Cu]I>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]#[C:16][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:11][C:10]=1[F:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Ic1ccccc1
Reactant: C#Cc1ccc(F)c(NC(=O)OC(C)(C)C)c1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(C#Cc2ccccc2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
A mixture of 1-(tert-butoxycarbonylamino)-5-ethynyl -2-fluorobenzene (0.11 g), iodobenzene (0.1 g), tetrakis -(triphenylphosphine)palladium(0) (16 mg) and copper (I) iodide (5 mg) in N,N-diisopropylamine (2 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1) to give 1-(tert -butoxycarbonylamino)-2-fluoro-5-phenylethynylbenzene (0.14 g). This material was dissolved in ethyl acetate (3 mL). To the solution was added 10% palladium-carbon powder (50 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give 1-(tert-butoxycarbonylamino)-2-fluoro -5-(2-phenylethyl)benzene (0.11 g). To this material was added hydrochloric acid (4 mol/L ethyl acetate solution, 3 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate =8/1 -5/1) to give the title compound (53 mg).
Reaction SMILES: [NH2:1][CH:2]([CH3:5])[CH2:3][OH:4].[H-].[Na+].Cl.Cl[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1>CN(C)C=O>[CH3:5][CH:2]([NH2:1])[CH2:3][O:4][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1
Reactant: CC(N)CO
Reactant: Clc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(N)COc1ccncc1
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
6.2 g of 2-amino-1-propanol was added dropwise to a stirred mixture of 4.0 g of 60% sodium hydride and 50 mL of N,N-dimethylformamide at 5° C.-10° C. After the reaction mixture was stirred for 30 minutes, 12.5 g of 4-chloropyridine hydrochloride in limited amounts was added to the reaction mixture. The mixture was stirred for 20 hours at room temperature. After completion of the reaction, the solids were filtered off. The solvent in the filtrate was removed under reduced pressure. The residue was purified by column chromatography on silica gel to obtain 3.8 g of the desired product (yield: 30%). Refractive index: 1.5469.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[S:17]([OH:20])(=[O:19])=[O:18]>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([S:17]([OH:20])(=[O:19])=[O:18])[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(-c2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(-c2ccccc2)c(S(=O)(=O)O)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 44.4 %

Procedure:
To a stirred solution of 4-nitrobiphenyl (50.00 g, 0.25 mol) in chloroform (750 mL) was added dropwise at room temperature chlorosulfonic acid (17 mL, 0.3 mol). The reaction mixture was stirred at 60° C. for 6 h. The white precipitate formed was collected by filtration and washed with cold chloroform. The product was air dried to give 31.00 g of 4-nitrobiphenylsulfonic acid (Yield 61%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:37][CH:36]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.[CH3:56][C:57]([CH3:61])([CH3:60])[CH:58]=O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][N:53]([CH2:56][C:57]([CH3:61])([CH3:60])[CH3:58])[CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:39][CH:40]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1
Reactant: Cc1cc(COc2ccc(C3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Reactant: CC(C)(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C3(N4CCN(CC(C)(C)C)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 5.5 %

Procedure:
Using a procedure analogous to Example 15, the product from example 14 (100 mg, 0.125 mmol) was treated with trimethylacetaldehyde (21.5 mg, 2.0 eq) to provide the title barbituric acid (6.0 mg, 5.5%). MS found: (M+H)+=530.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[C:18](=[O:21])([O-])[O-].[Na+].[Na+].CO>C(Cl)Cl.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:21]=[C:18]1[NH:8][CH:7]=[C:6]([C:2]2[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=2)[CH:5]=[CH:4]1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NCCc1ccc(-c2ccc(=O)[nH]c2)cc1
Temperature: 90 °C
Yield: 117.1 %

Procedure:
IMS (600 mL) and water (250 mL) were degassed thoroughly. tert-Butyl 4-bromophenethylcarbamate (32.7 g, 109 mmol), sodium carbonate (46.2 g, 436 mmol), palladium tetrakis (12.6 g, 11.0 mmol) and 2-methoxypyridine boronoic acid (25.0 g, 163 mmol) were added and the reaction mixture heated to 90° C. for 18 hours. The reaction was cooled to room temperature, filtered and the residue washed with IMS (100 mL) and ethyl acetate (1 L). The filtrate was washed with water (500 mL), dried (MgSO4) and concentrated to give a brown solid. The crude residue was subject to column chromatography (0 to 1.5% MeOH in DCM) to give a white solid, tert-butyl 4-(6-oxo-1,6-dihydropyridin-3-yl)phenethylcarbamate (20.95 g, 63.8 mmol, 58% yield).
Reaction SMILES: [CH:1]1([N:4]([CH2:8][CH:9]2[CH2:14]CCCO2)[C:5]([Cl:7])=[O:6])[CH2:3][CH2:2]1.C1(NC2CC[O:22][CH2:21][CH2:20]2)CC1>C(Cl)Cl.CO>[CH:1]1([N:4]([CH:8]2[CH2:9][CH2:14][O:22][CH2:21][CH2:20]2)[C:5]([Cl:7])=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(Cl)N(CC1CCCCO1)C1CC1
Reactant: C1CC(NC2CC2)CCO1
Solvent: CO
Solvent: ClCCl
Product: O=C(Cl)N(C1CCOCC1)C1CC1

Procedure:
The title compound is prepared analogously as described for cyclopropyl-(tetrahydro-pyran-2-ylmethyl)-carbamoyl chloride starting from commercially available cyclopropyl-(tetrahydro-pyran-4-yl)-amine. TLC, Rf (CH2Cl2/MeOH 95:5)=0.9.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[NH:30][C:29]2[CH:31]=[CH:32][C:33]([C:35](O)=[O:36])=[CH:34][C:28]=2[N:27]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:35]([C:33]1[CH:32]=[CH:31][C:29]2[NH:30][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)=[N:27][C:28]=2[CH:34]=1)=[O:36]
Reactant: O=C(O)c1ccc2[nH]c(-c3ccccn3)nc2c1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc2[nH]c(-c3ccccn3)nc2c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 2-pyridin-2-yl-1H-benzoimidazole-5-carboxylic acid. MS: 481.3 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH:7]=[N:8][OH:9])[C:4]([CH3:11])([CH3:10])[O:3]1.[Cl:13]N1C(=O)CCC1=O.O>CN(C=O)C>[OH:9][N:8]=[C:7]([Cl:13])[C@H:5]1[C:4]([CH3:11])([CH3:10])[O:3][C:2]([CH3:12])([CH3:1])[O:6]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1(C)O[C@@H](C=NO)C(C)(C)O1
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)O[C@@H](C(Cl)=NO)C(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
(S)-2,2,5,5-Tetramethyl-1,3-dioxolane-4-carbaldehyde oxime (13 g, 75.1 mmol) was dissolved in DMF (200 mL) and cooled in an ice bath. 1-Chloropyrrolidine-2,5-dione (10.0 g, 75.1 mmol) was added and the reaction was stirred overnight while slowly warming to ambient temperature. The pale yellow solution was poured into water (1.5 L) and extracted with EtOAc. The organic layers were washed with water and brine, dried, filtered and concentrated. The residue was purified over silica gel (40% EtOAc in hexanes) to afford (R)—N-hydroxy-2,2,5,5-tetramethyl-1,3-dioxolane-4-carbimidoyl chloride (12.4 g, 59.7 mmol, 79.6% yield).
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19]C)=[O:18])=[CH:14][CH:15]=2)[N:10]([CH3:21])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O>C1COCC1.O>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=2)[N:10]([CH3:21])[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(Cc3ccccc3)cn(C)c2c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(Cc2ccccc2)c2ccc(C(=O)O)cc21
Yield: 108.2 %

Procedure:
To a solution compound 56c (168 mg, 0.60 mmol), and LiOH.H2O (101 mg, 2.41 mmol) in THF/H2O (3/3 mL) was stirred at room temperature for 6 h. Concentrated the resulted mixture, extracted the residue with CH2Cl2, H2O, acidified the water layer with 1N HCl(aq) to pH˜4. The organic solution was dried over Na2SO4 and concentrated to give 56d (172.2 mg), which was used in the next reaction without further purification. MS m/z (M+H+) 266.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:12][N:11]=[C:10]([NH2:20])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)(O)[O-].[Na+].[C:26](OCC)(=[O:28])[CH3:27]>S(=O)(=O)(O)O.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:12][N:11]=[C:10]([NH:20][C:26](=[O:28])[CH3:27])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: Nc1ncc(-c2ccncc2)c(-c2cccc(F)c2)n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ncc(-c2ccncc2)c(-c2cccc(F)c2)n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
A mixture of 4-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinylamine (200 mg, 0.751 mmol) acetic anhydride (6 mL) and conc. sulfuric acid (4 drops) was stirred at 90° C. for 16 hours. After cooling as it was, the reaction solution was diluted with ethyl acetate, water and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated sodium bicarbonate (×2) and brine, and then dried over anhydrous sodium sulfate and concentrated. The residue was suspended in diethyl ether, and then the resulting solid was collected by filtration and washed with diethyl ether, to give the title compound (126 mg, 54%)
Reaction SMILES: O[C:2]1([C:23]([F:26])([F:25])[F:24])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)[C:4]([C:15]2[S:19][C:18]([CH:20]([CH3:22])[CH3:21])=[N:17][N:16]=2)=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:14][S:13][C:10]1[CH:11]=[CH:12][C:7]([N:5]2[CH:6]=[C:2]([C:23]([F:26])([F:25])[F:24])[N:3]=[C:4]2[C:15]2[S:19][C:18]([CH:20]([CH3:22])[CH3:21])=[N:17][N:16]=2)=[CH:8][CH:9]=1
Reactant: CSc1ccc(N2CC(O)(C(F)(F)F)N=C2c2nnc(C(C)C)s2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CSc1ccc(-n2cc(C(F)(F)F)nc2-c2nnc(C(C)C)s2)cc1
Yield: 75.1 %

Procedure:
A mixture of 4-hydroxy-1-[4-(methylthio)phenyl]-2-[2-(isopropyl)-1,3,4-thiadiazol-5-yl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole (0.361 g, 0.90 mmol) and p-toluenesulfonic acid monohydrate (35 mg) in toluene (50 mL) was heated to reflux for 1 hour. After aqueous work up, the product (0.26 g, 75%) was isolated as a white solid; 1H NMR δ (DMSO-d6) 8.37 (1H, s), 7.50 (2H, d, J=8.3 Hz), 7.38 (2H, d, J=8.6 Hz), 3.42 (1H, m), 2.55 (3H, s), 1.35 (6H, d, J=6.7 Hz); 13C NMR δ (DMSO-d6) 177.4, 157.6, 140.3, 138.5, 133.2, 130.9(q), 127.2, 126.4, 125.7, 122.5(q), 29.9, 22.7, 14.4.
Reaction SMILES: [Cl:1][C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C)=[O:3].[CH3:17]C(O)CCCCCCCCCC.C(Cl)(Cl)=O>>[Cl:1][C:2]([O:4][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:17])=[O:3]
Reactant: CCCCCCCCCCC(C)O
Reactant: CCCCCCCCCCCCOC(=O)Cl
Agent: O=C(Cl)Cl
Product: CCCCCCCCCCC(C)OC(=O)Cl

Procedure:
The procedure is the same as for preparing n-dodecyl chloroformate except freshly distilled 2-dodecanol (41.3 g, 0.222 moles) is added to the phosgene mixture. 99% yields of 2-dodecyl chloroformate are obtained. The product is purified via distillation (90° C. at 0.1 mm Hg). 1H MNR (60 MHz, neat) δ 4.6-4.98 (1H,m), δ 1.5-1.8 (21H,m), δ0.89 (3H, t). IR (neat) 1780 cm-1 (carbonyl).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:6]=[CH:7][CH:8]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(O)C>[N:22]1([CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[O:10][C:11]4[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: C1CNCCN1
Reactant: COC(=O)c1cccc2nc(-c3cccc(CBr)c3)oc12
Solvent: CCO
Product: COC(=O)c1cccc2nc(-c3cccc(CN4CCNCC4)c3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.4 %

Procedure:
Methyl 2-(3-(bromomethyl)phenyl)benzo[d]oxazole-7-carboxylate (70 mg, 0.2 mmol) and piperazine (68.8 mg, 0.8 mmol) were added to ethanol (30 mL) and the mixture was stirred at room temperature for 1 hr. The resulting mixture was evaporated under reduced pressure to obtain methyl 2-(3-(piperazin-1-ylmethyl)phenyl)benzo[d]oxazole-7-carboxylate (79 mg, yield 91%). LC-MS (ESI) m/z 354 [M+1]+.