Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH:42]=[CH:41][N:40]=[CH:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:38]3[CH:42]=[CH:41][N:40]=[CH:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(-n3ccnc3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and imidazole according to conditions described in general procedure C. Mp: 153-154° C.; 1H NMR (400 MHz, CDCl3) δ 3.29 (s, 4 H), 3.89 (s, 4 H), 6.79-6.85 (m, 2 H), 7.01 (d, J=1.5 Hz, 1 H), 7.12 (d, J=8.2 Hz, 1 H), 7.35 (d, J=2.7 Hz, 1 H), 7.38 (d, J=2.3 Hz, 1 H), 7.53-7.64 (m, 3 H), 7.91-7.93 (m, 1 H), 7.97 (d, J=7.4 Hz, 1 H), 8.05 (d, J=8.2 Hz, 1 H), 8.25-8.27 (m, 2 H), 8.53-8.56 (m, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N:11]=[C:12]=[O:13].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>C(Cl)Cl>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH:11][C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])[CH:4]=1
Reactant: O=C=Nc1cc([N+](=O)[O-])ccc1F
Reactant: C1CCNC1
Solvent: ClCCl
Product: Nc1ccc(F)c(NC(=O)N2CCCC2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 1-fluoro-2-isocyanato-4-nitrobenzene (1.125 g, 6.18 mmoles) and pyrrolidine (485 mg, 6.8 mmoles) in DCM (20 mL) was stirred at r.t. for 14 hrs. After concentrated, the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous citric acid solution and dried over MgSO4, followed by hydrogenation with Pd/C (wet, 10%, 0.15 g) under a hydrogen balloon overnight. After filtration and concentration, the reasonable pure N-(5-amino-2-fluorophenyl)pyrrolidine-1-carboxamide (3, 1.44 g) was used for the next reactions. MS+: 224.2, UV: λ=271.6 nm. 1H NMR: (DMSO) δ7.44 (s, 1H), δ6.78 (m, 1H), δ6.20 (m, 1H), δ3.32 (m, 4H), 1.83 (m, 4H).
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.C=[CH:15][CH2:16][CH3:17].[CH3:18]C=CC.[OH-].[Na+]>>[C:16]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([OH:7])[C:1]=1[CH3:8])([CH3:15])([CH3:17])[CH3:18]
Reactant: CC=CC
Reactant: C=CCC
Reactant: Cc1ccccc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(O)cccc1C(C)(C)C
Reaction time: 8 h

Procedure:
Into a reaction vessel equipped with a stirrer, gas blowing tube, thermometer and condenser is fed cresol into which sulfuric acid has been dissolved (sulfuric acid is dissolved in 1.2% by weight based on 100% by weight of cresol) at 795 g/hr, further, butylation reaction is conducted for 8 hours at 65° C. under normal pressure with blowing in an isobutyrene mixed gas containing 1-butene, 2-butene and the like, and the resulted butylated reaction mixture is neutralized with an aqueous NaOH solution. For the neutralization, 1.5 equivalent NaOH is added per charged sulfuric acid and the treatment is conducted for 3 hours at 110° C., then an aqueous layer is separated, and the resulted oil layer is washed with water to obtain 11.79 kg of t-butylcresol mixture (cresolcontent6.4%, 4M2B contentl6.3%, 3M6B content 13.3%, dibutylated isomer content 58.6%, content of other components 5.4%).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Br:9][C:10]1[CH:11]=[CH:12][C:13](F)=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1.C(N(CC)CC)C>C(OCC)(=O)C>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([NH:1][N:2]2[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1
Reactant: CN1CCN(N)CC1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(Nc2ccc(Br)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Yield: 63.2 %

Procedure:
Heat a mixture of 1-amino-4-methyl piperazine (0.217 mol, 25.0 g), 5-bromo-2-fluoronitrobenzene (0.239 mol, 52.6 g) and triethylamine (0.46 mol, 46 g) in ethyl acetate (900 mL) to reflux for 16 h. Cool the reaction mixture to room temperature, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate. Purify on a silica gel column using 5% methanol in dichloromethane as eluent to give the title compound (43.2 g, 63%). ES-MS m/z 315 [M+1]+.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:18](Br)[C:19]#[CH:20]>CN(C=O)C>[CH2:20]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])[C:19]#[CH:18]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of isatin (200 mg, 1.36 mmol) in DMF (5 mL) was added cesium carbonate (487 mg, 1.5 mmol). The reaction was stirred at room temperature for 90 minutes. Propargyl bromide (243 uL, 1.63 mmol) was then added. The reaction was stirred overnight at room temperature, concentrated in vacuo, dissolved in EtOAc and washed with saturated NaHCO3(aq) (1×). The layers were separated and the aqueous layer was extracted with additional EtOAc (2×). The combined organic phases was dried over Na2SO4, filtered and concentrated in vacuo. Further purification of the residue was not necessary. The title compound was obtained as an orange solid (255 mg, quantitative yield). 1H NMR (400 MHz, CDCl3) δ 2.31 (t, J=2.54 Hz, 1H), 4.55 (d, J=2.54 Hz, 2H), 7.12-7.15 (m, 1H), 7.19 (dt, J=7.52, 0.78 Hz, 1H), 7.63-7.68 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH:14]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)#[N:2].Cl.[CH2:32]([O:34][C:35](=[O:39])[CH2:36][CH2:37][NH2:38])[CH3:33].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[C:1]([C:3]1[C:7]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH:14]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:38][CH2:37][CH2:36][C:35]([O:34][CH2:32][CH3:33])=[O:39])=[O:27])=[CH:24][CH:23]=1)[CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)#[N:2]
Reactant: COc1ccc2oc(C(Nc3ccc(C(=O)O)cc3)C3CCCCC3)c(C#N)c2c1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(OC)cc3c2C#N)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a mixture of 4-{[(3-cyano-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}benzoic acid (240 mg) synthesized above, β-alanine ethyl ester hydrochloride (137 mg), 1-hydroxybenzotriazole monohydrate (136 mg), triethylamine (248 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (171 mg), and the mixture was stirred overnight at room temperature. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60% ethyl acetate/hexane) to give the title object compound (285 mg, 95%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:9]1=[O:20])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:26][C:25]3[CH:28]=[CH:29][C:30]([F:31])=[C:23]([F:22])[CH:24]=3)=[CH:17][CH:18]=2)[C:9]1=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(O)cc2)C1=O
Reactant: Fc1ccc(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(OCc3ccc(F)c(F)c3)cc2)C1=O

Procedure:
In an analogous manner to that described in Example 2c), the alkylation of the (S)-[1-(4-hydroxy-phenyl)-2-oxo-pyrrolidin-3-yl]-carbamic acid tert-butyl ester [Example 16 a)] with 3,4-difluorobenzylbromide in presence of potassium carbonate yields the title compound as a white solid; MS: m/e=419 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:45]=[CH:44][C:7]([CH2:8][O:9][C:10]([O:12][CH:13]([CH:15]2[C:21](=[O:22])[N:20]3[CH:16]2[CH2:17][C:18]([S:36]([C:38]2N=CC=CN=2)=O)=[C:19]3[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH2:46]>ClCCl.[Cl-].C([N+](C)(C)CCCCCCCCCCCCCCCC)C1C=CC=CC=1>[C:19]([NH:20]/[CH:16]=[CH:38]\[S:36][C:18]1[CH2:17][CH:16]2[N:20]([C:21](=[O:22])[CH:15]2[CH:13]([O:12][C:10]([O:9][CH2:8][C:7]2[CH:44]=[CH:45][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:11])[CH3:14])[C:19]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(=[O:46])[CH3:18]
Reactant: O
Reactant: CC(OC(=O)OCc1ccc([N+](=O)[O-])cc1)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S(=O)c3ncccn3)CC12
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)N/C=C\SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(C(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C2C1
Reaction time: 0.42 h
Yield: 52 %

Procedure:
p-Nitrobenzyl(5RS,6SR)-6-[(1RS)-1-p-nitrobenzyloxycarbonyloxyethyl]-3-(2-pyrimidylsulphinyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (230 mg) in dichloromethane (25 ml) was treated with benzyldimethyl-n-hexadecylammonium chloride (12 mg), cooled in an ice-bath, and treated with sodium Z-2-acetamidoethenylthiolate (contanimated by 1 molar equivalent NaCl) (77 mg) in water (25 ml). After stirring vigorously for 25 min. the layers were separated, and the dichloromethane layer was washed with dilute aqueous NaHCO3, followed by brine. After drying (MgSO4) the solution was evaporated in vacuo and the residue was chromatographed on silica gel (230-400 mesh ASTM), eluting with ethyl acetate to give the title compound (118 mg, 52% yield).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH:6]1[CH2:12][CH2:11][CH2:10][C@H:7]1[CH2:8][OH:9].C([O-])(=O)C.[Na+]>CC(C)=O.O>[Cl:1][CH2:2][C:3]([N:6]1[CH2:12][CH2:11][CH2:10][C@H:7]1[CH2:8][OH:9])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: OC[C@@H]1CCCN1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(CCl)N1CCC[C@H]1CO
Reaction time: 2 h

Procedure:
A solution of chloroacetyl chloride, 27.7 g (0.247 mol), in 66.5 ml of acetone is added dropwise with stirring to a solution of 25 g (0.247 mol) of L-prolinol and 40.4 g (0.493 mol) of sodium acetate in a mixture of 400 ml of acetone and 200 ml of water at 0°-5° C. The mixture is stirred and allowed to reach room temperature over two hours, the solvent is evaporated in vacuo and the residue is suspended in 300 ml chloroform and washed with water, 2×300 ml. The chloroform layer is separated, dried over sodium sulfate, evaporated in vacuo and the residue is purified by chromatography using silica gel and eluting with dichloromethane-methanol (98:2) to give (S)-1-(chloroacetyl)-2-pyrrolidinemethanol, 34.1 g; [α]D25 -62.2° (c 1.00, methanol).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH2:13](I)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:12])[N:9]2[CH2:15][CH:14]=[CH2:13])=[CH:4][CH:3]=1
Reactant: C=CCI
Reactant: O=c1cnc2ccc(F)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1c(=O)cnc2ccc(F)cc21
Reaction time: 3 h

Procedure:
A mixture of 7-fluoro-2(1H)-quinoxalinone (3.84 g, 23 mmol), allyl iodide (2.39 mL, 25.5 mmol) and potassium carbonate (9.56 g, 69.3 mmol) in dimethylformamide (60 mL) was stirred at room temp. for 3 h., then evaporated. The residue was dissolved in dichloromethane/water and the phases were separated. The aqueous phase was extracted (3×) with dichloromethane and the organic fractions were dried and evaporated.
Reaction SMILES: C([Li])CCC.[CH3:6][C@@H:7]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:10][C:9](=[O:18])[NH:8]1.[F:19][C:20]([F:27])([F:26])[CH2:21][CH2:22][C:23](Cl)=[O:24]>CCCCCC.O1CCCC1>[CH3:6][C@@H:7]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:10][C:9](=[O:18])[N:8]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]([F:27])([F:26])[F:19]
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: O=C(Cl)CCC(F)(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
A solution of n-butyllithium (2.0 mole) in hexane was added to a stirred solution of (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone (353 g) in dry tetrahydrofuran (2500 ml) at -78° C. under an inert atmosphere. The solution was stirred at -70° c. for 15 min, then 4,4,4-trifluorobutyryl chloride (320 g) was added over 30 min at -60° C. and the mixture warmed to room temperature and stirred overnight. The mixture was evaporated and the residue was partitioned between diethyl ether and water. The ethereal layer was washed (1N hydrochloric acid, brine (twice)), dried (MgSO4), and evaporated to yield crude product (604 g, about 100%). Filtration through 3000 ml of silica gel using 1:1 methylene chloride:hexanes as the eluent afforded a white solid. Recrystallization from methylene chloride:hexanes afforded (4R,5S)-4-methyl-3-(4,4,4-trifluorobutyryl)-5-phenyl-2-oxazolidinone (519 g, 86%); m.p. 93°-95° C.; partial NMR (300 MHz, CDCl3): 0.91 (d, 3H, CH3), 2.45-2.65 (m, 2H, CF3CH2), 3.18-3.40 (m, 2H, CH2CO), 4.78 (m, 1H, 4-H oxazolidinone), 5.70 (d, 1H, 5-H oxazolidone), 7.30-7.44 (m, 5H, Ar).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1>C1(C)C=CC=CC=1.C(#N)C>[CH2:20]([O:19][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:37]([NH:36][C:33]4[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=4)=[O:38])=[CH:28][CH:27]=3)=[CH:8][CH:9]=[N:10]2)=[CH:15][C:14]=1[C:17]#[N:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N#Cc1cc2c(Oc3ccc(N)cc3)ccnc2cc1OCc1ccccc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2cc1OCc1ccccc1
Temperature: 120 °C
Yield: 91.5 %

Procedure:
4-(4-Aminophenoxy)-7-(benzyloxy)-6-cyanoquinoline (7.776 g, 21.2 mmol) was dissolved in a toluene (400 ml) and acetonitrile (200 ml) mixed solvent, and then 4-fluorophenyl isocyanate (3.68 ml, 31.7 mmol) was added and the mixture was heated to reflux at 120° C. for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was suspended in tetrahydrofuran (150 ml), and then hexane (150 ml) was added, sonication was performed, and the precipitated crystals were filtered out and dried under reduced pressure to obtain N-(4-(7-(benzyloxy)-6-cyano-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea (9.81 g, 19.4 mmol, 91.9%) as light brown crystals. These were dissolved in trifluoroacetic acid (100 ml) and thioanisole (9.13 ml, 77.7 mmol) under a nitrogen atmosphere, and the solution was stirred at 60° C. for 12 hours. The reaction solution was concentrated under reduced pressure, and after adding tetrahydrofuran (50 ml) and then 1N aqueous sodium hydroxide (150 ml) and water (150 ml) to the residue, the mixture was stirred and the precipitated crystals were filtered out and washed with water, diethyl ether and ethyl acetate and dried at 70° C. to obtain the title compound (3.646 g, 8.36 mmol, 43.0%) as yellow crystals. negative ESI-MS 413 (M−Na)−
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[O:11][CH:10]=[CH:9][C:8](=[O:13])[C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C>[Pd].C(O)C>[OH:13][CH:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:12]=2[O:11][CH2:10][CH2:9]1
Reactant: COc1cccc2c(=O)ccoc12
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cccc2c1OCCC2O

Procedure:
A solution of 8-methoxy-4-benzopyranone (31.6 g), triethylamine (4.9 ml) and 10% palladium on carbon (3.1 g) in absolute ethanol (1.7 l) is stirred under an atmosphere of hydrogen (P=52 lbs.) overnight. The resulting solid is filtered, washed with diethyl ether and evaporated in vacuo yielding the desired product as a solid.
Reaction SMILES: Cl[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([OH:5])=[O:4].[OH-:16].[K+].Cl>O>[OH:16][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([OH:5])=[O:4]
Reactant: [OH-]
Reactant: CCCCCCCCCCC(Cl)C(=O)O
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCCCCCCCCCC(O)C(=O)O

Procedure:
0.1 Mole of alpha-chlorolauric acid prepared in the foregoing manner was admixed with 500 mls. water and 0.4 moles of KOH in a suitable reaction vessel and stirred overnight at a temperature of 98°-100° C. The reaction mixture was poured into a separatory funnel, to which was added hydrochloric acid (40 ml. conc. HCl in 200 ml. H2O). The mixture was extracted with chloroform. The chloroform layer was removed and the CHCl3 evaporated to yield alpha-hydroxylauric acid.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:15])([F:14])[C:5]([F:13])([F:12])[C:6](F)([F:10])[CH2:7][CH2:8]I>O1CCCC1>[F:10][C:6]([C:5]([F:13])([F:12])[C:4]([F:15])([F:14])[F:3])=[CH:7][CH2:8][NH:2][CH3:1]
Reactant: CN
Reactant: FC(F)(F)C(F)(F)C(F)(F)CCI
Solvent: C1CCOC1
Product: CNCC=C(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.55 g of methylamine is condensed in a solution of 2.6 ml of 1,1,1,2,2,3,3 heptafluor-5-iodo-pentane in 20 ml of anhydrous tetrahydrofuran at −40° C., and it is stirred overnight at room temperature in a pressurized reactor. After the pressurized reactor was opened at −30° C., it is allowed to come to room temperature to allow excess methylamine to evaporate off. Then, the reaction solution is mixed with diethyl ether, washed with saturated common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 1.26 g of (3,4,4,5,5,5-hexafluoro-pent-2-enyl)-methyl-amine is obtained as a crude product.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:13])[C:8]([OH:12])=[CH:9][CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.[CH2:15](O)[CH3:16].[CH2:18]([NH:20][CH2:21]C)[CH3:19].C=O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:13])[C:8]([OH:12])=[C:9]([CH2:21][N:20]([CH2:15][CH3:16])[CH2:18][CH3:19])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1
Reactant: CCNCC
Reactant: CCO
Reactant: Cc1cc(=O)oc2c(Cl)c(O)ccc12
Agent: C=O
Solvent: ClC(Cl)Cl
Product: CCN(CC)Cc1cc2c(C)cc(=O)oc2c(Cl)c1O

Procedure:
21 g of 4-methyl-7-hydroxy-8-chlorocoumarin are mixed with 180 ml of ethanol, 20 ml of chloroform, 9.5 of of diethylamine and 11.2 g of 35% aqueous formaldehyde solution. The mixture is refluxed for 20 hours, being kept in constant agitation meanwhile; the ethanol and chloroform are evaporated in vacuum. The residue is solubilized in the methylenechloride-ethyl acetate-methanol mixture (7+3+1) and the solution is used for a chromatographic separation on silica, eluting with the same mixture of solvents. 4-methyl-6-diethylaminomethyl-7-hydroxy-8-chlorocoumarin is thus obtained. It is then treated with ethyl acetate and then, by adding gaseous hydrochloric acid, crystalline hydrochloride is formed. The precipitate is separated and crystallized from ethyl acetate. After filtering and drying the crystals, hydrochloride of 4-methyl-6-diethylaminomethyl-7-hydroxy-8-chlorocoumarin is obtained.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:29]=[CH:30][CH:31]=1)[CH2:14][NH:15][C:16]1[C:25]2[C:20](=[C:21]([C:26]([NH2:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][N:17]=1.C(N(CC)CC)C>C(Cl)Cl>[NH:7]([C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:29]=[CH:30][CH:31]=1)[CH2:14][NH:15][C:16]1[C:25]2[C:20](=[C:21]([C:26]([NH2:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][N:17]=1)=[O:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1cccc2c(NCc3cccc(NC(=O)Nc4ccccc4)c3)ncnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
Phenyl isocyanate (240 μL, 0.5 M in anhydrous DCM, 0.11 mmol, 1.1 equiv.) was added to a solution of 4-[(3-aminobenzyl)amino]quinazoline-8-carboxamide (32 mg, 0.1 mmol, 1.0 equiv.) and triethylamine (40 μL, 0.3 mmol, 3.0 equiv.) in anhydrous DCM (2 mL). The resulting mixture was stirred at rt overnight. The title compound was obtained by pre-HPLC in 34% yield. Mass: M+H+: 413.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)=[CH:7][C:6]([CH2:19][CH2:20][CH3:21])=[C:5]([CH3:22])[N:4]=1.[F:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([F:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:25]=[C:24]([F:23])[CH:29]=[C:28]([F:30])[CH:27]=3)[CH2:36][CH2:35]2)=[O:18])=[CH:7][C:6]([CH2:19][CH2:20][CH3:21])=[C:5]([CH3:22])[N:4]=1
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Reactant: CCCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCCc1cc(NC(=O)N2CCN(c3cc(F)cc(F)c3)CC2)c(OC)nc1C
Yield: 57 %

Procedure:
Phenyl N-(2-methoxy-6-methyl-5-propylpyridin-3-yl)carbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)[N:3]=2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccc(F)cc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-fluoro-phenylboronic acid to give [1-(4-fluoro-phenyl)-6-methoxy-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 335(MH+).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[N:26]=1>>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[N:26]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc(Br)n1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: COc1cccc(C2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)n1
Yield: 98 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 2-bromo-6-methoxypyridine, the title compound was formed in 98% yield ! as a white solid, mp 193°-195° C. (dec). free base: 1H NMR (CDCl3, 300 MHz) 7.57 (dd, J=7.6, 7.6 Hz, 1H), 7.23 (m, 4H), 6.94 (m, 5H), 6.63 (d, J=8.0 Hz, 1H), 4.75 (s, 1H), 4.28 (s, 1H), 3.95 (s, 3H), 3.49 (s, 2H), 2.94 (m, 2H), 2.77 (m, 2H), 2.64 (d, J=1.2 Hz, 2H), 2.04 (m, 2H), 1.63 (m, 2H) MS (CI, CH4) m/z 413 (M+1,100), 441 (M+29,12), 395 (18) hydrochloride salt: