Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:5]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3Cl)[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:17][NH:18][C:19]([C:21]1[C:29]2[C:24](=[CH:25][C:26]([OH:30])=[CH:27][CH:28]=2)[N:23]([CH3:31])[C:22]=1[CH3:32])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:17][NH:18][C:19]([CH:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][C:13]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:8]=[C:7]([C:5]([N:1]5[CH2:4][CH2:3][CH2:2]5)=[O:6])[S:15][C:14]=34)=[CH:27][CH:28]=2)[N:23]([CH3:31])[CH:22]1[CH3:32])=[O:20]
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCC1
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)C1c2ccc(Oc3ccnc4cc(C(=O)N5CCC5)sc34)cc2N(C)C1C

Procedure:
This material was prepared by the reaction of 2-(azetidin-1-ylcarbonyl)-7-chlorothieno[3,2-b]pyridine 25a with 6-hydroxy-1,2-dimethyl-1H-indole-3-carbyxylic acid methylamide 16e and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CD3OD) δ 8.41 (1H, d, J=5.5 Hz), 7.80 (1H, d, J=3.20 Hz), 7.74 (1H, d, J=11.68 Hz), 7.30 (1H, s), 6.94 (1H, d, J=8.66 Hz), 6.62 (1H, d, J=5.5 Hz), 4.64–4.59 (2H, m), 4.20–4.15 (2H, m), 3.63 (3H, s), 2.85 (3H, s), 2.57 (3H, s), 2.44–2.36 (2H, m). LCMS (ESI+) [M+H]/z Calc'd 435. found 435.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[CH:17]=[C:18](I)[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=2)[CH2:3][CH2:2]1.[CH3:25][CH:26]([N:28]1[CH:32]=[C:31]([OH:33])[CH:30]=[N:29]1)[CH3:27].CC(C)(C(=O)CC(=O)C(C)(C)C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.[Cu]I>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[CH:17]=[C:18]([O:33][C:31]3[CH:30]=[N:29][N:28]([CH:26]([CH3:27])[CH3:25])[CH:32]=3)[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=2)[CH2:3][CH2:2]1
Reactant: CC(C)n1cc(O)cn1
Reactant: Cn1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)cc(I)c1=O
Agent: [Cu]I
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: CC(C)n1cc(Oc2cc(-c3cc(S(C)(=O)=O)ccc3OCC3CC3)cn(C)c2=O)cn1
Temperature: 110 °C
Yield: 39.3 %

Procedure:
A mixture of 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-iodo-1-methylpyridin-2-one (91 mg, 0.2 mmol), 1-propan-2-ylpyrazol-4-ol (45 mg, 0.36 mmol), CuI (4 mg, 10%), 2,2,6,6-tetramethyl-3,5-heptanedione (8 uL, 0.04 mmol) and K3PO4 (85 mg, 0.4 mmol) in DMSO (1 mL) was purged with nitrogen for 10 min, capped, and heated to 110° C. for 13 h. After the mixture was filtered through a short bed of celite, the filtrate was concentrated in vacuo and purified by prep-HPLC to afford the title compound (36 mg, 40%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.18-0.26 (m, 2H) 0.44-0.53 (m, 2H) 1.03-1.10 (m, 1H) 1.37-1.43 (m, 6H) 3.17-3.21 (m, 3H) 3.54-3.61 (m, 3H) 3.87-3.93 (m, 2H) 4.33-4.46 (m, 1H) 7.20-7.25 (m, 1H) 7.25-7.28 (m, 1H) 7.33-7.36 (m, 1H) 7.70-7.74 (m, 1H) 7.76-7.85 (m, 4H). LCMS (M+H)+=458.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].Br[CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1.C(N(C(C)C)CC)(C)C>CC#N.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:34][C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3ccc4ccccc4c3)C2)c1
Yield: 87 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (44.4 mg, 0.10 mmol) in CH3CN (5 ml) was added 2-Bromomethyl napthalene) (33 mg, 0.15 mmol) and diisopropylethylamine (35 μl, 0.20 mmol). The reaction was microwaved at 130° C. for 10 minutes, then diluted with EtOAc and washed with brine, sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product as a clear oil, (51 mg, 87%). Calcd for C37H40F3NO2 (M+H) 587.71, Found 588.5.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](I)=[CH:4][C:3]=1[CH3:10].[Br-].[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[Zn+].O1CCCC1>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>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:13]2[S:12][CH:16]=[CH:15][N:14]=2)=[CH:4][C:3]=1[CH3:10]
Reactant: [Zn+]c1nccs1
Reactant: Cc1cc(I)cc(C)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2nccs2)cc(C)c1Br
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 2-bromo-5-iodo-1,3-dimethyl-benzene (0.28 g), 2-thiazolylzinc bromide (0.5 mol/L in tetrahydrofuran; 1.9 mL), tetrakis(triphenylphosphine)palladium(0) (52 mg), and tetrahydrofuran (5 mL) under argon atmosphere is stirred at 100° C. for 3 h. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate) to give the title compound. LC (method 9): tR=1.19 min; Mass spectrum (ESI+): m/z=268/270 (Br) [M+H]+.
Reaction SMILES: [C:1]([OH:13])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[OH-].[Na+].[CH2:16](Br)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CS(C)=O>[CH2:16]([O:12][C:1](=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Reactant: BrCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(/C=C/c1ccc(O)c(O)c1)OCCc1ccccc1
Reaction time: 1 h

Procedure:
1 g of caffeic acid was dissolved in 25 mL of dimethylsulfoxide. 0.77 mL of 25% aqueous sodium hydroxide solution was added while stirring. Stirring continued for 1 hr. At the end of this period a solution of 1.10 mL of phenethyl bromide was added slowly in 30 minutes. The resulting reaction mixture was stirred at room temperature for 50 hrs. Next, the reaction mixture was poured into 75 mL of cold water and extracted with ethyl acetate (3×60 mL). The combined organic extract was washed with 50 mL of 5% HCl and water (60 mL). After drying over sodium sulfate, the solvent was distilled off under vacuum. The residue was crystallized from toluene by treatment with activated carbon to obtain caffeic acid phenethyl ester. The yield was 760 mg and the purity was greater than 90%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[CH:20]12[NH:27][CH:24]([CH2:25][CH2:26]1)[CH2:23][CH2:22][CH2:21]2>ClCCl.Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:24]23[NH:27][CH:20]([CH2:26][CH2:25]2)[CH2:21][CH2:22][CH2:23]3)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C1CC2CCC(C1)N2
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)C23CCCC(CC2)N3)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A mixture of 4-nitrobenzenesulfonyl chloride (1.78 g, 8.0 mmol), pyridine (0.78 mL, 9.6 mmol), and 8-azabicyclo[3.2.1]octane (0.796 g, 8.02 mmol) in dichloromethane (22 mL) was stirred for 5 hrs at 0° C., diluted with 1N HCl, and extracted with dichloromethane. The isolated organic layer was dried (Na2SO4), filtered, concentrated, and triturated with diethyl ether to give 1-(4-nitro-benzenesulfonyl)-8-azabicyclo[3.2.1]octane as a brown solid. The solid was added to a mixture of HCO2NH4 (1.91 g, 30.3 mmol) and 10% Pd/C (catalytic amount) in methanol (20 mL) and ethyl acetate (4 mL), stirred overnight at about 25° C., filtered, concentrated, diluted with water, and extracted with dichloromethane. The isolated organic layer was dried (Na2SO4), filtered and concentrated to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.74 (d, 2H), 7.02 (d, 2H), 4.17 (brs, 2H), 1.42-1.86 (m, 10H).
Reaction SMILES: C([O:9][C@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[N:34]1[CH:44]=[CH:43][C:38]([NH:39]C(=O)C)=[N:37][C:35]1=[O:36])(=O)C1C=CC=CC=1>N.CO>[C@H:11]1([N:34]2[CH:44]=[CH:43][C:38]([NH2:39])=[N:37][C:35]2=[O:36])[O:12][C@@H:13]([CH2:24][OH:25])[C@H:14]([OH:15])[C@@H:10]1[OH:9]
Reactant: CC(=O)Nc1ccn([C@H]2O[C@@H](COC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)c(=O)n1
Agent: N
Solvent: CO
Product: Nc1ccn([C@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)c(=O)n1
Yield: 52.1 %

Procedure:
Compound 7 (0.85 g, 1.42 mmol) in NH3 /MeOH (100 ml) was stirred at room temperature overnight and worked up as in Example 1, Step C to give pure 8 (0.18 g, 52%) as white crystals: m.p. 210° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:13]=[CH:12][C:6]([NH:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:5][CH:4]=1)[CH3:2].[CH3:14][C:15]1[C:19]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[C:18]([CH3:32])[O:17][N:16]=1>N1C=CC=CC=1>[CH3:14][C:15]1[C:19]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([S:28]([N:7]([C:6]3[CH:12]=[CH:13][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)[CH2:8][CH:9]([CH3:10])[CH3:11])(=[O:30])=[O:29])=[CH:26][CH:27]=2)=[C:18]([CH3:32])[O:17][N:16]=1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1ccc(NCC(C)C)cc1
Solvent: c1ccncc1
Product: CCc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)cc1
Reaction time: 16 h
Yield: 83 %

Procedure:
To 4-ethyl-N-isobutylaniline (50 mg, 0.282 mmol) in pyridine (1 mL) was added 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (94 mg, 0.310 mmol) and the reaction stood at room temperature, in air, for 16 hours. The crude was then purified by MDAP (Method F), to provide 103.6 mg of desired product. LCMS (M+1) 443, RT 1.39 mins.
Reaction SMILES: O1CCCOB1[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[O:22][CH3:23].N1C=CC(B(O)O)=CC=1>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:16]([O:22][CH3:23])[CH:17]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: COc1cc(Cl)ccc1CBr
Agent: OB(O)c1ccncc1
Product: COc1cc(Cl)ccc1Cc1cccnc1

Procedure:
The title compound was prepared by substituting 1-bromomethyl-4-chloro-2-methoxy-benzene and 3-[1,3,2]dioxaborinan-2-yl-pyridine for 1-bromomethyl-4-chloro-2-methoxy-benzene and 4-pyridyl boronic acid, respectively, in Example 700A. MS (ESI) m/e 234 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:44][CH2:45][O:46]C(=O)C(C)(C)C.C1C=CC=CC=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCOCC)C>[CH2:1]([O:8][C@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:12][CH:10]1[O:11][CH2:44][CH2:45][OH:46])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: CC(C)(C)C(=O)OCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: c1ccccc1
Solvent: CCOCOCC
Product: OCCOC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 0 °C

Procedure:
A mixture that consists of 54.1 g (100 mmol) of 2,3,4,6-tetra-O-benzyl-mannopyranose, 1.7 g (5 mmol) of tetrabutylammonium hydrogen sulfate and 33.7 g (600 mmol) of fine-powder potassium hydroxide in 350 ml of diethoxymethane is cooled to 0° C. At 0° C., 31.4 g (150 mmol) of 2,2-dimethyl-propionic acid-2-bromoethyl ester is added in drops over 30 minutes while being stirred vigorously. It is stirred for two hours at 0° C. 300 ml of benzene is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of ethanol/100 ml of water. 100 ml of 50% aqueous potassium hydroxide solution is added, and it is refluxed for eight hours. It is cooled to 0° C., set at pH 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water and 400 ml of ethyl acetate, and the pH of the aqueous phase is set at 5 while being stirred (10% aqueous hydrochloric acid). The organic phase is separated, and the aqueous phase is extracted once more with 200 ml of ethyl acetate. The combined organic phases are dried on magnesium sulfate, the solvent is distilled off in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/nhexane/ethanol=20:8:2). The product-containing fractions are concentrated by evaporation.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.CS(O[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)(=O)=O.C1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[N:3]=[CH:4][C:5]([O:8][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[N:6][CH:7]=1
Reactant: Oc1cnc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cnc(Br)cn2)CC1

Procedure:
A mixture of 5-bromopyrazin-2-ol B4a (525 mg, 3 mmol), tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (1.117 g, 4 mmol), 18-crown-6 (79 mg, 0.3 mmol), K2CO3 (829 mg, 6 mmol) in butan-2-one (19 mL) is subjected to microwave irradiation at 130° C. for 15 min. The solids are filtered off, washed with ethyl acetate and purified by flash chromatography (hexanes/ethyl acetate gradient) to afford tert-butyl 4-(5-bromopyrazin-2-yloxy)piperidine-1-carboxylate B4b as a white solid: MS calcd. For C14H21BrN3O3 ([M+H]+): 358.1, found: 358.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH2:14][CH2:13]1.Cl.[F:28][C:29]1([F:34])[CH2:32][CH:31]([NH2:33])[CH2:30]1.[F-].[K+].CCN(C(C)C)C(C)C>CS(C)=O.O>[F:28][C:29]1([F:34])[CH2:32][CH:31]([NH:33][C:2]2[N:7]=[C:6]3[CH:8]=[N:9][CH:10]=[CH:11][C:5]3=[N:4][C:3]=2[N:12]2[CH2:17][CH2:16][CH:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[CH2:14][CH2:13]2)[CH2:30]1
Reactant: Fc1ccc(OC2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Reactant: NC1CC(F)(F)C1
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: Fc1ccc(OC2CCN(c3nc4ccncc4nc3NC3CC(F)(F)C3)CC2)c(F)c1
Temperature: 23 °C
Reaction time: 120 h
Yield: 94.5 %

Procedure:
Combined 3-chloro-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)pyrido[3,4-b]pyrazine (0.46 g, 1.221 mmol), 3,3-difluorocyclobutanamine hydrochloride (0.526 g, 3.66 mmol), and potassium fluoride (0.092 g, 1.587 mmol) in DMSO (5 mL) and added DIPEA (1.063 mL, 6.10 mmol) at 23° C. The reaction was stirred at 23° C. for 5 days and diluted with water (20 mL) to furnish a yellow-orange suspension. The resulting solid was filtered, rinsed with water, and dried in vacuo to give the title compound (516.4 mg, 95%) as a yellow-orange solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.87-1.98 (m, 2H), 2.07-2.18 (m, 2H), 2.77-2.91 (m, 2H), 2.96-3.07 (m, 2H), 3.23-3.32 (m, 2H), 3.69-3.78 (m, 2H), 4.35-4.45 (m, 1H), 4.63 (tt, J=7.9, 3.8 Hz, 1H), 7.00-7.07 (m, 1H), 7.24-7.40 (m, 3H), 7.48 (d, J=5.4 Hz, 1H), 8.33 (d, J=5.4 Hz, 1H), 8.82 (s, 1H); ESI-MS m/z [M+H]+ 447.9.
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C:14]3=[C:15]([OH:32])[C:16]4[C:28](=[O:29])[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][C:26]=5[O:30][CH3:31])[C:20](=[O:21])[C:17]=4[C:18]([OH:19])=[C:13]3[CH2:12][C@@:11]([OH:36])([C:33]([CH3:35])=[O:34])[CH2:10]2)[CH2:5][C@H:4]([NH2:37])[C@@H:3]1[OH:38].[C:39]([CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])(=O)[CH3:40].C1(C)C=CC=CC=1.CC(C)=O>C(Cl)Cl>[CH3:47][CH2:46][O:45][C:43](/[CH:42]=[C:39](/[NH:37][C@@H:4]1[C@H:3]([OH:38])[C@H:2]([CH3:1])[O:7][C@@H:6]([O:8][C@@H:9]2[C:14]3[C:13](=[C:18]([OH:19])[C:17]4[C:20](=[O:21])[C:22]5[CH:23]=[CH:24][CH:25]=[C:26]([O:30][CH3:31])[C:27]=5[C:28](=[O:29])[C:16]=4[C:15]=3[OH:32])[CH2:12][C@@:11]([OH:36])([C:33]([CH3:35])=[O:34])[CH2:10]2)[CH2:5]1)\[CH3:40])=[O:44]
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(C)=O)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Reactant: CCOC(=O)CC(C)=O
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C(\C)N[C@H]1C[C@H](O[C@H]2C[C@](O)(C(C)=O)Cc3c(O)c4c(c(O)c32)C(=O)c2c(OC)cccc2C4=O)O[C@@H](C)[C@H]1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.53 gram of daunorubicin in a free base is dissolved in 100 ml of methylene chloride. 1 ml of ethyl acetylacetate is added to the solution by constant stirring. The entire mixture is agitated for 12 hours at room temperature in a nitrogenic atmosphere. The reaction is checked by means of thin-layer chromatography on a silica gel in a toluene-acetone system in a ratio of 8:1. The solution is then evaporated until a small volume of composition remains and, the final product is pecipitated by the addition of a mixture of ethyl ether and hexane in a ratio of 1:1. The precipitated results from the mixture of acetone and ethyl ether. 0.4 g of N-(1-carboethoxy-propen-1-yl-2)-daunorubicin is obtained which corresponds to 60 percent of the theoretical yield. The composition decomposes at 151°-154° C., M.S.F.D. m/z 639 (M+, 80 percent of relative intensity); 640 (M+ +1, 100 percent of relative intensity); IR (KBr)ν=1590, 1610, 1650, 1670, 1715, 1720, cm-1 (chelate and free carbonyl groups).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2[N:18]=[C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH:20]3[C:24]3[O:28][N:27]=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH:25]=3)[N:16]=[C:15]([NH:35][CH:36]3[CH:40]=[C:39]([CH3:41])[NH:38][N:37]3S(C3C=CC(C)=CC=3)(=O)=O)[CH:14]=2)(=O)=O)=CC=1.[CH3:52][NH2:53].C1COCC1>>[CH3:52][NH:53][CH2:12][C:13]1[N:18]=[C:17]([N:19]2[CH2:23][CH2:22][CH2:21][CH:20]2[C:24]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH:25]=2)[N:16]=[C:15]([NH:35][C:36]2[CH:40]=[C:39]([CH3:41])[NH:38][N:37]=2)[CH:14]=1
Reactant: CN
Reactant: CC1=CC(Nc2cc(COS(=O)(=O)c3ccc(C)cc3)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)N(S(=O)(=O)c2ccc(C)cc2)N1
Solvent: C1CCOC1
Product: CNCc1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Yield: 77 %

Procedure:
A mixture of 6-[(4-methylphenylsulphonyloxy)methyl]-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-2-N-[4-methylphenylsulphonyl]-1H-pyrazol-3-ylamino)pyrimidine (Method 52) (190 mg, 0.26 mmol) and a solution of 2N methylamine in THF (5 ml, 10 mmol) were heated at 90° C. in a sealed vessel under microwave irradiation for 1 hour. The volatiles were removed by evaporation and the residue purified by reverse phase HPLC using a C18 column eluting with water/acetonitrile/TFA (95:5:0.2 decreasing in polarity to 0:100:0.2). Product containing fractions were combined and passed through a 50 g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, followed by 7M methanolic ammonia to elute the product. The solvent was removed by evaporation of give the title compound (87.1 mg, 77%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.[Br:10]N1C(C)(C)C(=O)N(Br)C1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9][Br:10])[CH:3]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(Br)cc(CBr)c1
Temperature: 25 °C
Yield: 249.8 %

Procedure:
To a solution of 1-bromo-3,5-dimethylbenzene (25.0 g, 135.0 mmol) in CCl4 (150 mL), was added 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (14.5 g, 54.0 mmol) and dibenzoyl peroxide (BPO) (0.2 g) and the mixture was refluxed for 7 h. After the reaction mixture was cooled to room temperature, the precipitate was filtered out using Celite, and then the solid was rinsed two times with pentane (50 mL). The combined filtrates were washed with water (50 mL), followed by saturated sodium bicarbonate (50 mL) and sodium thiosulfate (50 mL×2). The organic layer was dried over anhydrous sodium sulfate. Evaporation of the solvent afforded the compound 1-bromo-3-(bromomethyl)-5-methylbenzene (35.6 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[C:5]([C:6]3[CH:18]=[CH:17][O:16][C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[H][H]>O1CCOCC1.C(O)(=O)C.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[NH2:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[C:5]([C:6]3[CH2:18][CH2:17][O:16][C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(N)ccc2c1ncc1occc12
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)c1c(N)ccc2c3c(cnc12)OCC3
Reaction time: 24 h
Yield: 58.5 %

Procedure:
A solution of methyl 7-aminofuro[2,3-c]quinoline-6-carboxylate (Intermediate 24, 1.13 g) in a mixture of dioxane (5 mL) and acetic acid (5 mL) was treated under an atmosphere of nitrogen with palladium hydroxide on carbon (10%, 0.1 g). The nitrogen was replaced by hydrogen and the mixture was stirred under an atmosphere of hydrogen for 24 hours. The mixture was diluted with ethyl acetate and filtered through Celite and the filtrate was washed with 1M aqueous sodium hydroxide solution, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of methanol and ethyl acetate with a gradient of 0-10%. The isolated product was triturated with a mixture of ether and cyclohexane and the solid was collected by filtration to give methyl 7-amino-1,2-dihydrofuro[2,3-c]quinoline-6-carboxylate (0.666 g) as a yellow solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[CH2:17]([C:19]1[NH:23][C:22]([C:24](O)=[O:25])=[N:21][C:20]=1[CH3:27])[CH3:18].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C>[CH2:17]([C:19]1[NH:23][C:22]([C:24]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH3:16])=[O:25])=[N:21][C:20]=1[CH3:27])[CH3:18]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: CCc1[nH]c(C(=O)O)nc1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1C

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (0.77 g, 3.32 mmol), 5-ethyl-4-methyl-1H-imidazole-2-carboxylic acid obtained in Example (15e) (0.26 g, 1.66 mmol), WSC hydrochloride (1.85 g, 9.65 mmol) and DMAP (0.2 g, 1.64 mmol), to obtain 0.43 g of the title compound as a white foamy substance (70%).