Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:26]2[CH2:28][CH2:27]2)[N:5]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1.[Cl:29][C:30]1[CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[C:33]([F:37])=[C:34]([CH:36]=1)[NH2:35].C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[NH2:35][C:34]1[C:33]([F:37])=[C:32]([C:2]2[N:3]=[C:4]([CH:26]3[CH2:28][CH2:27]3)[N:5]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=2[C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=2)[CH:31]=[C:30]([Cl:29])[CH:36]=1
Reactant: CC1(C)OB(c2cc(Cl)cc(N)c2F)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(NCCC#N)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: C[Si](C)(C)CCOCn1c(C2CC2)nc(-c2cc(Cl)cc(N)c2F)c1-c1ccnc(NCCC#N)n1
Temperature: 25 °C

Procedure:
Two separate reaction vials were each charged with 3-(4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propanenitrile (I-1c, ˜200 mg, 0.43 mmol), a solution of 5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.2 M in dioxane, 8 mL, 1.6 mmol), DME (8 mL) and aqueous 2.0 M Na2CO3 solution (2.3 mL, 4.6 mmol). The resulting mixture was sparged with Argon and Pd(PPh3)4 was added. The reaction vials were sealed and irradiated at 120° C. for 20 minutes in a microwave reactor. LCMS indicated near complete conversion. Additional 5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.2 M in dioxane, 8 mL, 1.6 mmol) was added and the reaction was irradiated at 120° C. for 7 minutes. The reactions were allowed to cool to room temperature which partitioned upon standing. The layers were separated and the organic portions of the two reactions were combined and concentrated. The resulting residue was partitioned between EtOAc (200 mL) and water (20 mL). The layers were separated and the organic portion was washed with aqueous 0.1 N HCl solution (40 mL), brine, dried (Na2SO4), and concentrated to give 3-(4-(4-(3-amino-5-chloro-2-fluorophenyl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propanenitrile as a crude residue which was carried forward without further purification: LCMS (m/z) 528.2 (MH+), tR=0.90 minute.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[C:9]([O-])([O-])=O.[K+].[K+].CI.O>C1COCC1>[CH3:9][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1cccc(N)n1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CNc1cccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 9.7 %

Procedure:
To a solution of 2,6-diaminopyridine (10 g, 91.63 mmol) in dry THF (100 mL) was added K2CO3 (18.8 g, 136.23 mmol) and CH3I (13 g, 91.63 mmol) and the reaction mixture was stirred at room temperature for 16 h. Water was added (10 mL) and the mixture was extracted with EtOAc (100 mL). The EtOAc layer was dried and was concentrated under reduced pressure. The residue was further purified by column chromatography (SiO2, 60-120, chloroform) to give 2-methylamino-6-aminopyridine (1.1 g, 10%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[OH:15].[CH3:16][C:17]([CH3:22])=[CH:18][CH:19](O)[CH3:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:4][C:3]=1[O:15][CH:19]([CH:18]=[C:17]([CH3:22])[CH3:16])[CH3:20]
Reactant: CC(C)=CC(C)O
Reactant: Oc1cc(Nc2ncccn2)ccc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)=CC(C)Oc1cc(Nc2ncccn2)ccc1Cl
Reaction time: 1 h
Yield: 17 %

Procedure:
To a flask was added 2-chloro-5-(pyrimidin-2-ylamino)phenol (50 mg, 0.23 mmol), 4-methylpent-3-en-2-ol (23 mg, 0.23 mmol), Ph3P (59 mg, 0.23 mmol) and THF (0.08 mL). The reaction vessel was lowered into a sonication bath and sonicated for several minutes giving a clear and highly viscous solution. While sonication, DEAD (0.044 mL, 0.23 mmol) was added. After 1 h, the reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel (hexane:EtOAc 7/3) to give the product in 17% yield (12 mg).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:19]([CH:28]([NH2:30])[CH3:29])=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)[CH:15]=[N:16][CH:17]=1.C(N(CC)C(C)C)(C)C>C(O)C>[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:19]([CH:28]([NH:30][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[CH:5][NH:6]4)[CH3:29])=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)[CH:15]=[N:16][CH:17]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CC(N)c1ccc2cccnc2c1-c1cncc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(Nc1ncnc2[nH]cnc12)c1ccc2cccnc2c1-c1cncc(F)c1

Procedure:
A mixture of 6-bromo-9H-purine (0.1072 g, 0.54 mmol), 1-[8-(5-fluoropyridin-3-yl)quinolin-7-yl]ethanamine (0.072 g, 0.27 mmol), and N,N-diisopropylethylamine (0.05630 mL, 0.32) in ethanol (0.9 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/minute) to give the desired product as a tris-TFA salt. LCMS calculated for C21H17FN7(M+H)+: m/z=386.2; found: 386.1. 1H NMR (DMSO-d6, 400 MHz) δ 9.40 (1H, s), 8.81 (1H, m), 8.65 (1H, s), 8.62 (1H, s), 8.50 (1H, s), 8.41 (2H, m), 8.11 (1H, d, J=8.8 Hz). 7.97˜7.84 (2H, m), 7.55 (1H, dd, J=8.4 and 4.4 Hz), 5.25 (1H, m), 1.58 (3H, d, J=6.8 Hz) ppm. 19F NMR (DMSO-d6, 376.28 MHz) δ −75.0 ppm.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[CH:17]=2)=[C:12]([OH:23])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:24](O)[CH2:25][OH:26].C1(C=CC(O)=CC=1)O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH2:25]1[O:26][C:18]2([CH2:19][CH2:20][CH:21]=[C:16]([C:13]3[CH:14]=[CH:15][C:10]([C:2]([CH3:1])([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][C:12]=3[OH:23])[CH2:17]2)[O:22][CH2:24]1
Reactant: CCCCCCC(C)(C)c1ccc(C2=CC(=O)CCC2)c(O)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: Oc1ccc(O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCC(C)(C)c1ccc(C2=CCCC3(C2)OCCO3)c(O)c1

Procedure:
A solution of 500 mg. (1.59 mmole) of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-2-cyclohexenone, 7.8 g. (127 mmole) of ethylene glycol, 375 mg. (3.18 mmole) of hydroquinone and 50 mg. (0.263 mmole) of p-toluenesulfonic acid monohydrate in 50 ml. of benzene was heated at reflux for 12 hours using a Dean-Stark condensor filled with 3 A molecular sieves. The reaction was cooled and added to 500 ml. saturated sodium bicarbonate. The quenched mixture was extracted with three 150 ml. portions of ether, dried over magnesium sulfate and evaporated to a solid. This solid was purified via column chromatography on 50 g. of silica gel eluted with 50% ether-petroleum ether to yield (after crystallization from pentane) 393 mg. (69%) of the title product.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[N:8][C:9]([NH2:12])=[N:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[CH:14]([C:17]1([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[CH:25][CH:24]=[CH:23]3)[CH2:19][CH2:18]1)[CH:15]=O>C(O)(C)C>[N:1]1([C:6]2[CH:7]=[N:8][C:9]3[N:10]([C:14]([C:17]4([C:20]5[CH:21]=[C:22]6[C:27](=[CH:28][CH:29]=5)[N:26]=[CH:25][CH:24]=[CH:23]6)[CH2:19][CH2:18]4)=[CH:15][N:12]=3)[CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Reactant: Nc1ncc(-n2cccn2)cn1
Solvent: CC(C)O
Product: c1cnc2ccc(C3(c4cnc5ncc(-n6cccn6)cn45)CC3)cc2c1
Temperature: 90 °C

Procedure:
A mixture of 5-(1H-pyrazol-1-yl)pyrimidin-2-amine (0.08 g, 0.5 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.1 g, 0.5 mmol) in isopropanol (15 mL) was heated at 90° C. overnight. After cooling, the mixture was purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=353.1.
Reaction SMILES: [CH2:1]([N:4]([C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([C:25](=[O:37])[NH:26][CH2:27][C:28]2[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=2[CH3:34])[C:19]=1[CH3:38])[CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[CH2:1]([N:4]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[C:18]1[C:19]([CH3:38])=[C:20]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[C:25]([NH:26][CH2:27][C:28]1[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=1[CH3:34])=[O:37])[CH:2]=[CH2:3].[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]
Reactant: C=CCN(c1cc(Cl)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCN(c1cc(Cl)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of compound tert-butyl 4-(allyl (5-chloro-3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenyl)amino)piperidine-1-carboxylate (0.2 g, 0.36 mmol) in DCM (5 mL) was cooled to 0° C. and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 18 h. and concentrated to dryness. The residue was washed with diethyl ether and then purified by preparative HPLC to afford the title compound as TFA salt (0.06 g, 37%). LCMS: 443.25 (M+1)+; HPLC: 97.14% (@ 254 nm) (Rt; 5.074; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.38 (bs, 1H), 8.21 (t, 1H), 8.05 (d, 1H), 7.21 (d, 1H, J=4.4 Hz), 6.97 (d, 1H, J=1.6 Hz), 5.86 (s, 1H), 5.56-5.64 (m, 1H), 4.97-5.09 (m, 2H), 4.24 (d, 2H, J=4.4 Hz), 3.62 (d, 2H, J=5.2 Hz), 3.23 (m, 2H), 3.10-3.16 (m, 1H), 2.85-2.88 (m, 2H), 2.19 (s, 3H), 2.18 (s, 3H), 2.10 (s, 3H), 1.83-1.86 (m, 2H), 1.68-1.73 (m, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:20]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[N:14]=[C:13]2[CH3:21])=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[CH3:21][C:13]1[N:12]([C:9]2[N:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=2)[C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[N:14]=1
Reactant: CCOC(=O)c1ccc(-n2c(C)nc3cnccc32)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2cnccc2n1-c1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-(5-Ethoxycarbonylpyrid-2-yl)-2-methylimidazo[4,5-c]pyridine (2.75 g, 9.75 mmol) was dissolved in ethanol (15 ml) and 2N aqueous sodium hydroxide (5.8 ml) was added. The mixture was stirred for 3 days at room temperature and then the solvent was removed under reduced pressure. The residue was neutralised (pH6) with dilute hydrochloric acid, and the resulting precipitate was filtered off and dried in vacuo. The title compound was obtained as a white solid (1.70 g, 69%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:14])([C:10]([F:13])([F:12])[F:11])[C:5]([O:7]CC)=O.[C:15](#[N:17])[CH3:16]>C1COCC1>[F:14][C:4]([F:3])([C:10]([F:11])([F:12])[F:13])[C:5](=[O:7])[CH2:16][C:15]#[N:17]
Reactant: CCOC(=O)C(F)(F)C(F)(F)F
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)C(F)(F)C(F)(F)F
Temperature: 50 °C

Procedure:
A stirred suspension of sodium hydride (15.6 g of a 60% dispersion in mineral oil, 0.39 mol) in THF (100 mL) was heated to 50° C. To this was added a mixture of ethyl 2,2,3,3,3-pentafluoropropanoate (25 g, 0.13 mol) and dry acetonitrile (5.3 g, 0.13 mol), dropwise, and the resulting colorless suspension was heated at 50° C. for 4 h. After cooling to rt the reaction mixture was concentrated under reduced pressure and the residue poured into water (100 mL) and extracted with diethyl ether (100 mL). The aqueous layer was separated, acidified to pH 2 with aqueous 2 M HCl and extracted with diethyl ether (2×200 mL). The combined diethyl ether layers were dried over magnesium sulfate then concentrated under reduced pressure to afford 4,4,5,5,5-pentafluoro-3-oxopentanenitrile an orange oil (17 g) which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.O.C(OCC)(=O)C.[C:17]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:20])[CH:18]=[CH2:19]>CN(C)C=O.C(N(CC)CC)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH2:8][C:7]1[C:2](/[CH:19]=[CH:18]/[C:17]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])=[N:3][CH:4]=[C:5]([F:9])[CH:6]=1
Reactant: Nc1cc(F)cnc1Cl
Reactant: C=CC(=O)OCCCC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCOC(=O)/C=C/c1ncc(F)cc1N
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a solution of 150 g of 2-chloro-5-fluoropyridin-3-amine in 600 mL of N,N-dimethylformamide, 190 mL of butyl acrylate and 287 mL of triethylamine were added under a nitrogen flow, and the mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to 58° C., thereto were added 13.1 g of bis(tri-tert-butylphosphine)palladium(0), and the mixture was stirred at 110 to 120° C. for 40 minutes. The reaction mixture was cooled to 57° C., 13.1 g of bis(tri-tert-butylphosphine)palladium(0) was added thereto, and the mixture was stirred at 110 to 120° C. for 3 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The insoluble substance was filtered off, the organic layer of the filtrate was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Cyclohexane and ethyl acetate were added to the resultant residue, and the solid was filtered off to obtain 200 g of butyl (2E)-3-(3-amino-5-fluoropyridin-2-yl)acrylate as a light brown solid.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([C:14]([NH:16][O:17]C3CCCCO3)=[O:15])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].O>CO>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([C:14]([NH:16][OH:17])=[O:15])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc(C(=O)NOC3CCCCO3)cc2C1
Solvent: CO
Solvent: O
Product: CC(=O)N1CCc2ccc(C(=O)NO)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To 6.29 g of 2-acetyl-N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide are added 57 ml water, 88 ml methanol and 1.4 g DowexWX2-100. The mixture is stirred overnight at ambient temperature and filtered. The filtrate is evaporated and 4.17 g of the title compound as a yellow solid are obtained. MP 177-181° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([OH:10])=O)[S:4][N:3]=1.S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([Cl:13])=[O:10])[S:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1snc(Cl)c1Cl
Product: O=C(Cl)c1snc(Cl)c1Cl

Procedure:
After thionyl chloride (10 ml) had been added to 3,4-dichloro-5-isothiazole-carboxylic acid (0.99 g), the mixture was refluxed by heating for 2 hours. The excess of thionylchloride was then distilled off under reduced pressure, and 3,4-dichloro-5-isothiazolecarboxylic acid chloride was obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:25]2CCOCC2)=[O:24])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9](N)[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[NH4+].C(=O)(O)[O-].[Na+]>>[CH2:1]([C:5]1[N:6]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH2:25])=[O:24])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCC(=O)N1CCOCC1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [NH4+]
Product: CCCCc1nc2cnc3ccccc3c2n1CCCCC(N)=O
Temperature: 130 °C
Yield: 94 %

Procedure:
Ethyl 5-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)pentanoate (10.0 g, 28.2 mmol, prepared in Example 46) and ammonium acetate (10 g) were sealed in a high-pressure vessel, heated for two days at 130° C., and then allowed to cool to ambient temperature. Saturated aqueous sodium bicarbonate was added, and the mixture was then extracted with dichloromethane. The combined organic fractions were washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 8.6 g of 5-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)pentanamide.
Reaction SMILES: C([Mg]Cl)(C)C.[Cl-].[Li+].Br[C:9]1[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]=[O:22]>C1COCC1>[CH3:14][N:13]1[C:9]([CH:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=2)[OH:22])=[CH:10][N:11]=[CH:12]1
Reactant: Cn1cncc1Br
Reactant: O=Cc1ccccn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1cncc1C(O)c1ccccn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of isopropylmagnesium chloride/lithium chloride complex (1.3 M in THF, 19.5 mL, 25.35 mmol) was added dropwise by syringe to a solution of 5-bromo-1-methyl-1H-imidazole (4.12 g, 25.58 mmol) in dry THF (130 mL) at 0° C. After 15 minutes, the Grignard solution was added via cannulation to a solution of picolinaldehyde (2.0 ml, 20.93 mmol) in dry THF (55 mL) at 0° C. The reaction mixture was stirred for 5 minutes at 0° C., then warmed to room temperature for 1 hour. The reaction mixture was then cooled in an ice bath and quenched with saturated aqueous ammonium chloride. The mixture was partitioned between brine and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-5% MeOH-DCM) to provide the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH2:14].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18](B(O)O)[CH:17]=1>COCCOC.C(=O)([O-])O.[Na+]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:18]2[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=2)[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH2:14]
Reactant: OB(O)c1cccnc1
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cc(-c2cccnc2)cc([N+](=O)[O-])c1N
Temperature: 25 °C

Procedure:
A stirred solution of 2-Amino-5-bromo-3-nitro-benzoic acid methyl ester (2 g, 7.27 mmol) in 1,2-dimethoxyethane (53 ml) was purged with nitrogen for 15 min and treated with aqueous sodium hydrogen carbonate solution (1M, 14.5 ml) followed by pyridine 3-boronic acid (1.33 g, 10.9 mmol) and 1,1-bis-(diphenylphosphino)ferrocene palladium (II) chloride complex (0.6 g, 0.733 mmol). The resultant mixture was boiled under reflux in a nitrogen atmosphere for 18 h. After cooling to ambient temperature, the dark mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (300 ml) and extracted with ethyl acetate (3×250 ml). This was washed with brine (200 ml), dried (MgSO4) and the solvent removed in vacuo to give a residue which was purified by flash chromatography (silica) eluting with 30% to 100% ethyl acetate in 40-60 petroleum ether. The 2-Amino-3-nitro-5-pyridin-3-yl-benzoic acid methyl ester was obtained as a yellow solid (1.1 g, 56%).
Reaction SMILES: [F:1][CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:21]([O-])=O)[CH:9]=2)[N:4]=1.C(O)(=O)C>[H][H].C(Cl)(Cl)Cl.[C].[Pd]>[F:1][CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:21])[CH:9]=2)[N:4]=1
Reactant: [H][H]
Reactant: Cc1ccccc1-n1c(CF)nc2ccc([N+](=O)[O-])cc2c1=O
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1ccccc1-n1c(CF)nc2ccc(N)cc2c1=O
Yield: 5.2 %

Procedure:
A mixture of 2.0 g(0.064 mol) of 2-fluoromethyl-3-(o-tolyl)-6-nitro-4(3H)-quinazolinone, 0.2 g of 5 % palladium-carbon and 100 ml of acetic acid is shaken for 30 minutes in hydrogen gas. The initial pressure of hydrogen gas is adjusted to 46 lb and the mixture is heated with an infrared lamp during the reaction. After 30 minutes of said reaction, the pressure of hydrogen gas decreases to 6 lb. After the mixture is cooled, said mixture is filtered to remove the catalyst. The filtrate is evaporated to remove acetic acid, and the residue is dissolved in chloroform. The chloroform solution is washed with 5 % aqueous sodium hydroxide and water, successively. Then, the solution is dried and evaporated to remove solvent. The oily residue thus obtained is dissolved in 2 ml of chloroform, and the chloroform solution is passed through a column of 200 g of silica gel. The silical gel column is eluted with ethyl acetate-benzene(1 : 1). Then, the eluate is evaporated to remove solvent. The crude crystal obtained is washed with isopropylether and recrystallized from isopropanol. 0.95 g of 2-fluoromethyl-3-(o-tolyl)-6-amino-4(3H)-quinazolinone is obtained.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C@H:11]1[CH2:16][N:15]([S:17]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)(=[O:19])=[O:18])[CH2:14][CH2:13][N:12]1[C:25]1[CH:30]=[CH:29][C:28]([C@:31]([OH:37])([CH3:36])[C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C[C@@H]1CN(S(C2SC=CC=2)(=O)=O)CCN1C1C=CC([C@@](O)(C)C(F)(F)F)=CC=1)C)C1C=CC=CC=1.C(N(C[C@H]1CN(S(C2SC=CC=2)(=O)=O)CCN1C1C=CC([C@@](O)(C)C(F)(F)F)=CC=1)C)C1C=CC=CC=1.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[CH2:1]([N:8]([CH2:10][C@@H:11]1[CH2:16][N:15]([S:17]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)(=[O:19])=[O:18])[CH2:14][CH2:13][N:12]1[C:25]1[CH:26]=[CH:27][C:28]([C@:31]([OH:37])([CH3:36])[C:32]([F:34])([F:33])[F:35])=[CH:29][CH:30]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc([C@@](C)(O)C(F)(F)F)cc1
Agent: CN(Cc1ccccc1)C[C@@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc([C@](C)(O)C(F)(F)F)cc1
Agent: CN(Cc1ccccc1)C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc([C@](C)(O)C(F)(F)F)cc1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: CN(Cc1ccccc1)C[C@@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc([C@@](C)(O)C(F)(F)F)cc1

Procedure:
(2R)-2-(4-((2S)-2-((benzyl(methyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2R)-2-((benzyl(methyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2S)-2-((benzyl(methyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol. 1H NMR (400 MHz, CD3OD) δ 7.88-7.86 (m, 1H), 7.66-7.64 (m, 1H), 7.44-7.40 (m, 2H), 7.31-7.21 (m, 6H), 6.86-6.82 (m, 2H), 4.08-3.97 (m, 2H), 3.72-3.66 (m, 1H), 3.53-3.45 (m, 2H), 3.43-3.37 (m, 1H), 3.19-3.11 (m, 1H), 2.95-2.87 (m, 1H), 2.70-2.65 (m, 1H), 2.62-2.54 (m, 1H), 2.25-2.19 (m, 1H), 2.17 (s, 3H), 1.67 (s, 3H). m/z (ESI, +ve ion) 553.8 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=1.01 μM; GK-GKRP EC50 (LC MS/MS)=1.22 μM.