Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]([F:29])([F:28])[O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>CC(C)=O>[F:17][C:18]([F:28])([F:29])[O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=2)=[CH:22][CH:21]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Yield: 80.8 %

Procedure:
To a mixture of 300.0 mg (2.203 mmol) 4-hydroxyacetophenone and 305 mg (2.207 mmol) potassium carbonate in 15 ml acetone was added 868.7 mg (3.304 mmol) 4-(trifluoromethoxy)benzylbromide dropwise and heated under reflux for 1 d. The solvent was evaporated and to the residue was added ethyl acetate. The organic phase was washed with 1M aqueous HCl solution and water, dried over magnesium sulfate. The solvent was evaporated and the residue was subjected to silica gel chromatography (ethyl acetate/n-heptane 1:2) to yield 552 mg (1.779 mmol) 1-[4-(4-trifluoromethoxy-benzyloxy)-phenyl]-ethanone.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Br[CH2:11][C:12]1[N:13]([CH3:28])[C:14]2[C:19]([N:20]=1)=[C:18]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[N:17]=[C:16]([Cl:27])[N:15]=2>>[Cl:27][C:16]1[N:15]=[C:14]2[C:19]([N:20]=[C:12]([CH2:11][N:6]3[CH2:7][CH2:8][CH:3]([N:2]([CH3:9])[CH3:1])[CH2:4][CH2:5]3)[N:13]2[CH3:28])=[C:18]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[N:17]=1
Reactant: CN(C)C1CCNCC1
Reactant: Cn1c(CBr)nc2c(N3CCOCC3)nc(Cl)nc21
Product: CN(C)C1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)CC1
Yield: 45.8 %

Procedure:
N,N-dimethylpiperidin-4-amine (0.41 g) was reacted with 4-(8-(bromomethyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine (1.0 g) via General Procedure C to yield 1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)-N,N-dimethylpiperidin-4-amine (0.52 g) as a white solid. This intermediate was reacted with 1-(phenylsulfonyl)-1H-indol-3-ylboronic acid via General Procedure B to give intermediate N,N-dimethyl-1-((9-methyl-6-morpholino-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-9H-purin-8-yl)methyl)piperidin-4-amine. The intermediate was suspended in MeOH (3 mL) whereupon 3N KOH (0.3 mL) was added and the reaction mixture was heated at 50° C. for several hours until the protecting group was removed. Reverse phase purification gave 110. MS (Q1) 475.3 (M)+. 1H NMR (400 MHz, DMSO) δ 11.46 (s, 1H), 8.66-8.51 (m, 1H), 8.13 (d, 1H), 7.48-7.36 (m, 1H), 7.19-7.08 (m, 2H), 4.26 (s, 4H), 3.93 (d, 3H), 3.83-3.75 (m, 4H), 3.70 (s, 2H), 2.84 (d, 2H), 2.15 (s, 6H), 2.11-1.94 (m, 3H), 1.72 (d, 2H), 1.36 (q, 2H)
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:5]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:4]=[N:3]1.Cl.Cl[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)=[CH:11][CH:12]=2)=[C:5]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:4]=[N:3]1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Cn1nnc(-c2ccncc2)c1-c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccncc2)c1-c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 65 °C
Reaction time: 20 h

Procedure:
A mixture of 4-(3-methyl-5-(pyridin-4-yl)-3H-1,2,3-triazol-4-yl)phenol (88 mg, 0.35 mmol), 2-(chloromethyl)quinoline hydrochloride (82 mg, 0.38 mmol), and cesium carbonate (455 mg, 1.4 mmol) in dimethylformamide was stirred at 65° C. for 20 h, filtered, and concentrated. The residue was chromatographed on silica eluting with a gradient of 50% to 100% ethyl acetate in hexanes giving a light yellow solid (100 mg, 73%). 1H NMR (CDCl3, 400 mHz) δ 8.48 (d, 2H, J=6.2 Hz), 8.24 (d, 1H, J=8.3 Hz), 8.09 (d, 1H, J=8.3 Hz), 7.85 (d, 1H, J=7.9 Hz), 7.76 (ddd, 1H, J=8.5, 7, 1 Hz), 7.70 (d, 1H, J=8.7 Hz), 7.57 (m, 1H), 7.54 (m, 2H), 7.24 (m, 2H), 7.20 (m, 2H). 5.46 (s, 2H), 3.90 (s, 3H). MS (AP+) m/e 394 (MH+).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[I:9]N1C(=O)CCC1=O>C(Cl)Cl>[I:9][CH2:1][C:2]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3]2
Reactant: C=C1CCC(O)CC1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: ICC12CCC(CC1)O2
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.6 %

Procedure:
To a solution of 4-methylenecyclohexanol (1.88 g) in CH2Cl2 (37.6 mL) was added N-iodosuccinimide (4.5 g) under nitrogen atmosphere, which was stirred at ambient temperature for 3 hours. The resultant was washed with Na2S2O3 aq., H2O, and brine. The organic phase was dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give 1-(iodomethyl)-7-oxabicyclo[2.2.1]heptane (1.5 g) as colorless oil.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:23][CH:22]4[NH2:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.CCN(CC)CC.[C:34]1([N:40]=[C:41]=[S:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[C:34]1([NH:40][C:41]([NH:24][CH:22]2[CH2:23][CH:21]2[C:18]2[CH:19]=[CH:20][C:15]([C:12]3[N:13]=[CH:14][N:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=4)[N:11]=3)=[CH:16][CH:17]=2)=[S:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: S=C=Nc1ccccc1
Reactant: NC1CC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(C4CC4NC(=S)Nc4ccccc4)cc3)n2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 33.2 %

Procedure:
The amine trifluoroacetate salt from Example 5 (0.064 g, 0.135 mmol) was dissolved in THF (0.5 mL). Et3N (0.037 mL, 0.27 mmol) was added, followed by phenyl isothiocyanate (0.020 mL, 0.15 mmol). The resulting dark yellow solution was heated to 80° C. and stirred for 4 h. The solution was cooled to 25° C., loaded directly onto a silica gel column and purified (gradient elution with 15% to 40% to 80% EtOAc in hexanes) to afford the product (0.0222 g, 33%) as a yellow oil: IR νmax 3380, 3218 (br), 1617, 1598, 1518, 1497, 1448, 1356, 1326, 1264, 1221, 1168, 1111, 1065, 986, 910, 851, 756, 732, 694 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 8.11 (d, J=8.3 Hz, 2H), 7.90 (br s, 1H), 7.78 (d, J=9.0 Hz, 2H), 7.46-7.32 (m, 5H), 7.31-7.21 (m, 5H), 3.10 (br s, 1H), 2.25 (br s, 1H), 1.51-1.30 (m, 2H); HRMS-ESI (m/z) [M]+ calcd for C25H20F3N5OS, 495.134. found, 495.1341.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([Sn](C)(C)C)=[N:14][N:13]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:10]3=[CH:11][N:12]=2)[CH:2]=1.[Cl:28][C:29]1[N:34]=[C:33](Cl)[CH:32]=[CH:31][N:30]=1>>[Cl:28][C:29]1[N:34]=[C:33]([C:15]2[C:9]3[C:10](=[CH:11][N:12]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:8]=3)[N:13]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:14]=2)[CH:32]=[CH:31][N:30]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C[Si](C)(C)CCOCn1nc([Sn](C)(C)C)c2cc(-c3cccnc3)ncc21
Product: C[Si](C)(C)CCOCn1nc(-c2ccnc(Cl)n2)c2cc(-c3cccnc3)ncc21
Yield: 50 %

Procedure:
Following the Stille coupling procedure of Example 299, 5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(trimethylstannyl)-1H-pyrazolo[3,4-c]pyridine and 2,4-dichloropyrimidine were reacted. The product was purified via silica gel chromatography using a gradient of ethyl acetate in heptane to afford 60 mg (50%) of 3-(2-Chloropyrimidin-4-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine. ESI MS m/z 439.2 (M+1).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:12]=[CH:11][C:6]2[CH2:7][O:8][B:9]([OH:10])[C:5]=2[CH:4]=1.C(N(CC)CC)C.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[C:23]([C:30]([F:33])([F:32])[F:31])[CH:22]=1.Cl>ClCCl>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:2][C:3]2[CH:12]=[CH:11][C:6]3[CH2:7][O:8][B:9]([OH:10])[C:5]=3[CH:4]=2)=[O:26])=[C:23]([C:30]([F:31])([F:32])[F:33])[CH:22]=1
Reactant: Nc1ccc2c(c1)B(O)OC2
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)B(O)OC2)c1ccc(F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A 500 ml round bottom flask was charged with a mixture of 6-amino-1-hydroxy-2,1-benzoxaborolane hydrochloride (5 g, 26.9 mmol, 1 eq), triethylamine (11.2 ml, 80.7 mmol, 3 eq) and dichloromethane (200 ml). 4-Fluoro-2-(trifluoromethyl)benzoyl chloride (4.3 ml, 28.2 mmol, 1.05 eq) was then added, and the reaction mixture was allowed to stir at room temperature overnight. 1M HCl (100 ml) was added to the mixture and the reaction was stirred for an additional hour. The resulting precipitate was then collected, and the off-white powder was dried under vacuum. LCMS (m/e) 340 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.96 (s, 2 H) 7.39 (d, J=8.4 Hz, 1 H) 7.61-7.73 (m, 2 H) 7.75-7.87 (m, 2 H) 8.13 (dd, J=1.8, 0.4 Hz, 1 H) 9.25 (s, 1 H) 10.59 (s, 1 H) Amount Obtained: 5.2 g, 57% yield.
Reaction SMILES: [Si]([O:8][CH:9]1[CH:22]([O:23][Si](C(C)(C)C)(C)C)[C:21]2C=C(I)C=C[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)(C(C)(C)C)(C)C.O1[CH2:36][CH2:35][CH2:34][CH2:33]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(O)C>[C:9]1(=[O:8])[C:10]2[CH:11]=[CH:12][C:13]3[C:14](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:15]=2[CH:16]=[CH:21][C:22]1=[O:23]
Reactant: C1CCOC1
Reactant: CC(C)(C)[Si](C)(C)OC1c2ccccc2-c2ccc(I)cc2C1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCO
Product: O=C1C=Cc2c(ccc3ccccc23)C1=O
Temperature: 25 °C
Yield: 76 %

Procedure:
Into a 20 mL volume eggplant-shaped flask, 80 mg of the above-prepared 9,10-bis(t-butyldimethylsilyloxy)-2-iodo-9,10-dihydro-phenanthrene dimer, 10 mL of tetrahydrofuran, 43 mg of ethanol, and 0.4 mL of tetrabutylammonium fluoride were added and stirred at room temperature in air. The resultant reaction mixture was allowed to stand. Thereafter, the precipitate was collected by filtration and washed, thereby to give 28 mg of a phenanthrenequinone compound represented by the following chemical structural formula (1b-1) (hereinafter referred to as a “phenanthrenequinone compound (1b-1)”) (yield 76%) as a reddish brown-colored solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:31]([OH:36])(=[O:35])[C:32]([CH3:34])=O.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:11][O:10][C:8]([C:5]1[N:6]=[C:7]2[CH:34]=[C:32]([C:31]([OH:36])=[O:35])[NH:1][C:2]2=[CH:3][CH:4]=1)=[O:9]
Reactant: COC(=O)c1ccc(N)cn1
Reactant: CC(=O)C(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2[nH]c(C(=O)O)cc2n1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Methyl 5-aminopyridine-2-carboxylate (1.2 g, 5.2 mmol) and triphenylphosphine (1.5 g, 5.7 mmol) were initially charged in 10 ml of DMF, and pyruvic acid (1.83 g, 20.8 mmol), palladium(II) acetate (279 mg, 1.2 mmol) and triethylamine (2.6 g, 26 mmol) were added. The reaction mixture was stirred at a temperature of 100° C. for four hours, then cooled, concentrated on a rotary evaporator and taken up in ethyl acetate, water was added and the mixture was shaken. The aqueous phase was concentrated on a rotary evaporator and then triturated with a little cyclohexane. This gave 0.5 g (38% of theory) of 5-(methoxycarbonyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid. HPLC-MS: log P=0.44; mass (m/z): 221.0 (M+H)+; 1HNMR (D6-DMSO): δ 3.89 (s, 3H), 7.20 (s, 1H), 7.90-7.98 (m, 2H), 10 (broad, 1H), 12.24 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1>[Pd].C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: Fc1ccc2occc2c1
Agent: [Pd]
Solvent: CC(=O)O
Product: Fc1ccc2c(c1)CCO2
Yield: 85 %

Procedure:
A solution of 5-fluorobenzofuran and 10% palladium on carbon in acetic acid (25 ml) was hydrogenated under 50 psi for 12 hours. The catalyst was filtered through celite, and the celite was washed with methylene chloride (200 ml). The organic layer was washed with 1N NaOH (3×100 ml), brine (3×100 ml) and dried over anhydrous sodium sulfate. The solvent was removed under vacuum to afforded 2.59 g (85%) of product as a clear oil.
Reaction SMILES: [H-].[Na+].OC[CH:5]1[O:9][CH2:8][N:7]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6]1.S1C=CN=[CH:15]1>O1CCCC1>[CH2:15]=[C:8]1[N:7]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][O:9]1
Reactant: CC(C)(C)N1COC(CO)C1
Reactant: c1cscn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C1OCCN1C(C)(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
This example illustrates the preparation of the compounds of formula III, via the procedure described in the Application of Berkoz, Lewis and Muchowski, Ser. No. 706,412, filed on even date herewith. In this example 0.012 mole of sodium hydride (50% mineral oil) is stirred in 50 ml. of tetrahydrofuran; under nitrogen, and 0.02 mole of 5-hydroxymethyl-N-t-butyloxazolidine is added. The mixture is then warmed to 50° C until reaction ceases (about 30 minutes) and then cooled to room temperature. 0.01 Mole of 2-ethylsulfinyl-5-[2-(endobicyclo[3.1.0]hex-6-yl)ethylaminocarbonyl]thiazole in 50 ml. of tetrahydrofuran is then added. The mixture is stirred for four hours at room temperature and then poured into 200 ml. of ethyl acetate, then washed with water; dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated under vacuum affording a crude residue of 5-(5-[2-endobicyclo[3.1.0]hex-6-yl)ethylaminocarbonyl]thiazol-2-yloxy)methylene-N-t-butyloxazolidine, which is then dissolved in diethyl ether (100 ml.) and hydrogen chloride gas passed over the surface with rapid stirring until no more precipitate is formed. The precipitate is filtered off, washed with ether, then recrystallized from propanol-diethyl ether mixture. The crystals are filtered off and dried under vacuum affording 5-(5-[2-endobicyclo[3.1.0]hex-6-yl)ethylaminocarbonyl]thiazol-2-yloxy)methylene-N-t-butyloxazolidine hydrochloride.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]O.CO.C(Cl)(Cl)[Cl:24]>O=S(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][Cl:24]
Reactant: OCc1cccc(OCc2ncc3ccccc3n2)c1
Reactant: ClC(Cl)Cl
Solvent: CO
Solvent: O=S(Cl)Cl
Product: ClCc1cccc(OCc2ncc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1.00 g (3.76 mmol) of 3-(2-quinazolinylmethoxy)benzyl alcohol in 10 ml of CHCl3, 0.5 ml of SOCl2 was added, followed by stirring at room temperature for 15 hours. A small amount of MeOH was added to the reaction mixture and the solvents were distilled off under reduced pressure, whereby 1.08 g of 3-(2-quinazolinylmethoxy)benzyl chloride were obtained as white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:9]=[N:8]1)=[O:5])[CH3:2].Cl[C:22]1[N:27]=[N:26][C:25]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[C:42]4[C:37](=[CH:38][CH:39]=[C:40]([F:43])[CH:41]=4)[CH2:36][CH2:35]3)[CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[F:43][C:40]1[CH:41]=[C:42]2[C:37]([CH2:36][CH2:35][N:34]2[CH:31]2[CH2:32][CH2:33][N:28]([C:25]3[N:26]=[N:27][C:22]([C:10]4[CH:9]=[N:8][N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=4)=[CH:23][CH:24]=3)[CH2:29][CH2:30]2)=[CH:38][CH:39]=1
Reactant: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Reactant: CCOC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CCOC(=O)Cn1cc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1

Procedure:
Ethyl 2-(4-(6-(4-(6-fluoroindolin-1-yl)piperidin-1-yl)pyridazin-3-yl)-1H-pyrazol-1-yl)acetate was prepared according to the procedure as described in Example 1, Method A, STEP 4, reacting 1-(ethoxycarbonylmethyl)pyrazole-4-boronic acid pinacol ester and 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[C:12]([O:13][CH2:14][O:15][CH3:16])=[CH:11][CH:10]=[CH:9][N:8]=1.[F:17][C:18]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([F:32])=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][C:19]=1[CH:20]=[O:21]>C1COCC1>[F:6][C:7]1[C:12]([O:13][CH2:14][O:15][CH3:16])=[C:11]([CH:20]([C:19]2[CH:22]=[C:23]([C:26]3[C:27]([F:32])=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:24]=[CH:25][C:18]=2[F:17])[OH:21])[CH:10]=[CH:9][N:8]=1
Reactant: O=Cc1cc(-c2cccnc2F)ccc1F
Reactant: COCOc1cccnc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1c(C(O)c2cc(-c3cccnc3F)ccc2F)ccnc1F
Reaction time: 1 h
Yield: 68.3 %

Procedure:
DIPA (3.5 mL, 24.97 mmol) was dissolved in dry THF (10 mL) under nitrogen and cooled in a dry ice bath. Butyllithium solution (2.5 m in hexanes, 10.0 mL, 25.00 mmol) was added and after stirring for a few minutes 2-fluoro-3-(methoxymethoxy)pyridine (3.71 g, 23.64 mmol) in dry THF (25 mL) was added dropwise. The reaction was stirred for 1 h. A solution of 2-fluoro-5-(2-fluoropyridin-3-yl)benzaldehyde (4.71 g, 21.49 mmol) in dry THF (40 mL) was added dropwise over 10 min. The reaction was removed from the cold bath and stirred for an additional 15 min. Saturated sodium bicarbonate (20 mL) was added followed by EtOAc (300 mL) and water (400 mL). The phases were mixed and separated and the organic dried with magnesium sulfate before evaporating to dryness under reduced pressure. Purification using silica chromatography (hexane to EtOAc gradient) gave the desired (2-fluoro-3-(methoxymethoxy)pyridin-4-yl)(2-fluoro-5-(2-fluoropyridin-3-yl)phenyl)methanol (5.52 g, 14.67 mmol). MS m/z=377.1 [M+H]+. Calculated for C19H15F3N2O3: 376.10.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][N:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:16][C:12]=3[C:11](=[O:23])[N:10]([CH:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[C:9]2=[O:37])[N:3]=1.[ClH:38]>C(Cl)Cl.O1CCOCC1>[ClH:38].[CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][N:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[S:16][C:12]=3[C:11](=[O:23])[N:10]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:9]2=[O:37])[N:3]=1
Reactant: Cc1nc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)no1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1nc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)no1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl 4-{1-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (2.86 g; compound B2) in DCM (100 ml) is added a solution of hydrogen chloride in 1,4-dioxane (10 ml, 4.0 M). The reaction mixture is stirred for 1 d at RT. The precipitate is filtered off, washed with diethyl ether and dried in vacuo to afford the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Reaction time: 0.5 h

Procedure:
3-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester. To a mixture of sodium bicarbonate (403.3 g, 4.8 mol) and water (1.6 L) was added (S)-3-hydroxypiperidine (R)-1-(−)-camphor-10-sulfonic acid salt (3, 400.14 g, 1.2 mol) and dichloromethane (1.6 L). The mixture was stirred for 30 minutes and cooled by ice bath. To the mixture was added di-tert-butyl dicarbonate (288.1 g, 1.32 mol) portionwise in 30 minutes. The mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (4.8 L) and H2O (4.8 L) and separated in separation funnel. The organic layer was washed with brine (2 L), dried (Na2SO4) and concentrated to give the desired product (S)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester in quantitative yield (241.5 g).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[CH3:34])=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=3[CH3:34])[C:25]2=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: Cc1ccc(C)c(N=C=O)c1
Product: COc1cccc2c1ncc1c(=O)n(-c3cc(C)ccc3C)c(=O)n(C3CCCC3)c12
Yield: 34.6 %

Procedure:
1-Cyclopentyl-3-(2,5-dimethyl-phenyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (46 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.32 mmol) and 1-isocyanato-2,5-dimethyl-benzene (0.48 mmol) following general procedure C. LCMS: m/z 416 [M+1]+.
Reaction SMILES: C([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.I[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].[BrH:37].C(O)(=O)C>C(OCC)C>[BrH:37].[CH2:25]([C:22]1[CH:23]=[N:24][C:19]([N:18]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:27])[S:12][CH:13]=2)=[N:20][CH:21]=1)[CH3:26]
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Reactant: CCCCCCCCI
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(CC)cn1

Procedure:
A compound obtained using 2-[(4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 265-1 and 1-iodooctane as starting materials and by an operation similar to that of Example 326 was dissolved in diethyl ether, and reacted with 30% hydrobromic acid-acetic acid to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:24][C:25]1[N:30]=[CH:29][C:28]([C:31]([NH:33]O)=[NH:32])=[CH:27][N:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]4[O:22][N:33]=[C:31]([C:28]5[CH:27]=[N:26][C:25]([NH2:24])=[N:30][CH:29]=5)[N:32]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: N=C(NO)c1cnc(N)nc1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Product: Nc1ncc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(Cl)cc5)nc34)n2)cn1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) (171 mg, 0.5 mmol) and 2-amino-N-hydroxy-pyrimidine-5-carboxamidine (example B.5) (115 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (165 mg, 72%). MS (EI) 458.1 [(M)+]; mp 268° C.
Reaction SMILES: [CH3:1][CH:2]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:17]([O:20][CH2:21][CH2:22][CH2:23]Br)([CH3:19])[CH3:18]>C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>[CH:17]([O:20][CH2:21][CH2:22][CH2:23][NH:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])=[CH:11][CH:12]=1)([CH3:19])[CH3:18]
Reactant: CCCCCCC(C)Nc1ccc(N)cc1
Reactant: CC(C)OCCCBr
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CCCCCCC(C)Nc1ccc(NCCCOC(C)C)cc1

Procedure:
Following the same conditions as in Example 4, but reacting N-(2-octyl)-p-phenylenediamine with 3-isopropoxypropyl bromide, there is obtained the title product in dihydrochloride salt form (m.p. 200°-202°C).