Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]I.[F:3][C:4]([F:25])([F:24])[C:5]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH2:21][CH2:22][CH3:23])[CH:15]=1)([O:10][CH2:11][O:12][CH3:13])[C:6]([F:9])([F:8])[F:7].S([O-])([O-])(=O)=S.[Na+].[Na+]>N1C=CC=CC=1>[F:3][C:4]([F:24])([F:25])[C:5]([C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][CH3:23])[C:17]([OH:20])=[C:18]([I:1])[CH:19]=1)([O:10][CH2:11][O:12][CH3:13])[C:6]([F:8])([F:7])[F:9]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1O
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: c1ccncc1
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cc(I)c1O
Temperature: 60 °C
Yield: 84.7 %

Procedure:
Iodine (13.3 g) was added to a mixed solution of 4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethyl)oxypropan-2-yl]-2-propylphenol (3.63 g, 10.5 mmol) in pyridine (50 mL) at room temperature, followed by heating in an oil bath at an external temperature of 60° C. overnight. A 1 mol/L sodium thiosulfate aqueous solution was added to the reaction solution at room temperature, followed by extraction with ethyl acetate-water. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 4.20 g of the title compound (yield: 85%) as a brown solid.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([OH:11])[CH2:8][CH2:9][OH:10].[CH:12]([CH:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH2:13].C(OCC)(=O)C>O1CCCC1>[CH:12]([CH:14]([O:10][CH2:9][CH2:8][CH2:7][OH:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH2:13]
Reactant: C=CC(Cl)c1ccccc1
Reactant: OCCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC(OCCCO)c1ccccc1
Reaction time: 0.25 h
Yield: 80.7 %

Procedure:
Potassium tert-butoxide (23.07 g, 0.206 mol) was added to a stirred solution of 1,3-propanediol (44.92 g, 0.591 mol) in dry tetrahydrofuran (400 ml) under an atmosphere of nitrogen. The reaction mixture was stirred for 15 min then a solution of vinylbenzylchloride (mixture of meta and para isomers) (30.00 g, 0.197 mol) in dry tetrahydrofuran (100 ml) was added dropwise over 30 min. The reaction was heated at reflux overnight then the tetrahydrofuran was removed in vacuo and the residue taken-up in water (400 ml) and diethyl ether (400 ml). The organic phase was washed with water, dried (magnesium sulfate) and concentrated in vacuo to give a liquid. The liquid was purified by column chromatography over silica gel (eluent 3:1:petrol ether/ethyl acetate, then ethyl acetate) to give the title compound (30.59 g, 0.159 mol, 81%) as a straw colored liquid.
Reaction SMILES: [Cl-].[CH3:2][S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[O:17][N:16]=[C:15]([C:18]2[N:19]=[C:20]([CH:23]3[CH2:28][CH2:27][NH2+:26][CH2:25][CH2:24]3)[S:21][CH:22]=2)[CH2:14]1)(=[O:5])=[O:4].[Si:29]([O:36][CH2:37][C:38](O)=[O:39])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].C(N(C(C)C)CC)(C)C.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C>CN(C)C=O>[CH3:2][S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[O:17][N:16]=[C:15]([C:18]2[N:19]=[C:20]([CH:23]3[CH2:28][CH2:27][N:26]([C:38](=[O:39])[CH2:37][O:36][Si:29]([C:32]([CH3:34])([CH3:33])[CH3:35])([CH3:30])[CH3:31])[CH2:25][CH2:24]3)[S:21][CH:22]=2)[CH2:14]1)(=[O:4])=[O:5]
Reactant: CS(=O)(=O)Oc1ccccc1C1CC(c2csc(C3CC[NH2+]CC3)n2)=NO1
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4OS(C)(=O)=O)C3)cs2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23 %

Procedure:
To 4-[4-(5-{2-[(methylsulphonyl)oxy]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidinium chloride (500 mg) in dimethylformamide (6 ml) under argon were added {[tert-butyl(dimethyl)silyl]oxy}acetic acid (225 mg), diisopropylethylamine (582 mg) and 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU, 542 mg). The reaction mixture was stirred at room temperature for 18 hours. Then ice-cold sodium hydrogencarbonate solution was added thereto, the mixture was filtered, and the aqueous phase was removed and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Purification by column chromatography gave 2-(3-{2-[1-({[tert-butyl(dimethyl)silyl]oxy}acetyl)piperidin-4-yl]-1,3-thiazol-4-yl}-4,5-dihydro-1,2-oxazol-5-yl)phenyl methanesulphonate (150 mg, 22%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][CH2:29][C:30](OC)=[O:31])[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[CH2:34]([CH2:36][NH2:37])[OH:35]>>[OH:35][CH2:34][CH2:36][NH:37][C:30](=[O:31])[CH2:29][O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:18]([NH:17][C:13]1[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[N:9]=[CH:10]3)=[N:19][CH:20]=[N:21]2
Reactant: NCCO
Reactant: COC(=O)COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Product: O=C(COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12)NCCO
Yield: 85.2 %

Procedure:
Using the same procedure as in Example 5, methyl [(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]acetate (250 mg, 0.55 mmol) was reacted with ethanolamine (0.333 ml, 5.5 mmol) to give the title compound as a white solid (220 mg, 85%), except that the reaction was run at 45° C. for 2 days. NMR Spectrum 3.30 (m, 2H), 3.49 (m, 2H), 4.79 (m, 1H), 4.89 (s, 2H), 5.77 (s, 2H), 6.96 (m, 2H), 7.29 (m, 1H), 7.37 (d, 1H), 7.77-7.69 (m, 3H), 7.84 (m, 1H), 8.16 (s, 1H), 8.42 (br t, 1H), 8.57-8.53 (m, 3H), 10.87 (br s, 1H); Mass spectrum MH+ 470.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]#[C:24][CH2:25][N:26]([CH3:28])[CH3:27])=[C:10]1[C:29]([O:31][CH2:32][CH3:33])=[O:30].[H][H]>N1C=CC=CC=1.[Pd]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][N:26]([CH3:28])[CH3:27])=[C:10]1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)C1=C(COCC#CCN(C)C)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(COC/C=C\CN(C)C)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 17.7 %

Procedure:
A solution of 4-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}-1-dimethylaminobut-2-yne (1.10 g) in pyridine (75 ml) was stirred at room temperature in the presence of 5% palladium on calcium carbonate under one atmosphere of hydrogen for 45 minutes. The mixture was evaporated and the residue twice taken up in toluene and evaporated. The residue was purified by chromatography on SiO2 (20 g) using dichloromethane plus 1-5% of 10% 0.880 aqueous ammonia in methanol as eluant. Appropriate fractions were combined and evaporated. The residue was dissolved in methanol (20 ml) and the solution treated with fumaric acid (74 mg). The mixture was then evaporated and the residue crystallised from ethyl acetate to give the fumarate salt of the title compound (0.195 g) as a hemihydrate, m.p. 142°-146°.
Reaction SMILES: [CH:1]([S:3]([N:6]1[CH2:9][CH:8]([C:10]2[CH:31]=[CH:30][C:13]3[C:14]4[N:15]=[C:16]([C:22]5[N:23]([CH:27]([CH3:29])[CH3:28])[N:24]=[CH:25][N:26]=5)[S:17][C:18]=4[CH2:19][CH2:20][O:21][C:12]=3[CH:11]=2)[CH2:7]1)(=[O:5])=[O:4])=[CH2:2].[CH3:32][NH:33][CH3:34]>>[CH:27]([N:23]1[C:22]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:12]4[CH:11]=[C:10]([CH:8]5[CH2:7][N:6]([S:3]([CH2:1][CH2:2][N:33]([CH3:34])[CH3:32])(=[O:5])=[O:4])[CH2:9]5)[CH:31]=[CH:30][C:13]=4[C:14]=3[N:15]=2)=[N:26][CH:25]=[N:24]1)([CH3:28])[CH3:29]
Reactant: CNC
Reactant: C=CS(=O)(=O)N1CC(c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)C1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(S(=O)(=O)CCN(C)C)C3)ccc1-2
Reaction time: 72 h
Yield: 50.3 %

Procedure:
To a suspension of 8-(1-ethenesulfonyl-azetidin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (75 mg, 0.17 mmol) in IMS (2 mL) was added dimethylamine (2M in MeOH, 158 μL, 0.32 mmol) and the reaction mixture was stirred for 72 hours. The mixture was concentrated in vacuo to low volume and partitioned between DCM and water. The layers were separated and the organic layer was washed with water followed by brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was combined with a previous batch of the desired compound and purified by flash chromatography (SiO2, 0-2% MeOH in DCM) to give 455 as a white solid (43 mg, 34%). LCMS: RT=8.51 min, [M+H]+=503. 1H NMR δ (ppm) (CDCl3): 8.36 (1 H, d, J=8.20 Hz), 7.90 (1 H, s), 7.16 (1 H, dd, J=8.24, 1.92 Hz), 7.03 (1 H, d, J=1.88 Hz), 5.93-5.83 (1 H, m), 4.39 (2 H, t, J=5.04 Hz), 4.26 (2 H, t, J=8.23 Hz), 4.10 (2 H, t, J=7.33 Hz), 3.81-3.74 (1 H, m), 3.40 (2H, t, J=5.05 Hz), 3.22-3.14 (2 H, m), 2.81 (2H, t, J=7.47 Hz), 2.29 (6 H, s), 1.61 (6 H, d, J=6.63 Hz)
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[OH:6].[Cl:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[O:30])[CH:24]=[C:25]([Cl:27])[CH:26]=1>C(Cl)Cl>[CH3:19][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]([O:6][C:29](=[O:30])[NH:28][C:23]1[CH:24]=[C:25]([Cl:27])[CH:26]=[C:21]([Cl:20])[CH:22]=1)[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:9][CH:8]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: CN(C)CCC(O)c1ccc(-c2ccncc2)cc1
Solvent: ClCCl
Product: CN(C)CCC(OC(=O)Nc1cc(Cl)cc(Cl)c1)c1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-dimethylamino-1-(4-pyridin-4-yl-phenyl)-propan-1-ol (100 mg, 0.37 mmol) in CH2Cl2 (2 mL) was added 3,5-dichloro-phenylisocyanate (70 mg, 0.37 mmol) and the mixture was stirred at room temperature for 16 h. The mixture was concentrated to give a light brown oil, which was then purified by silica gel chromatography (5–10% MeOH/DCM gradient) to afford the title compound (3,5-dichloro-phenyl)-carbamic acid 3-dimethylamino-1-(4-pyridin-4-yl-phenyl)-propyl ester as a white solid, 131 mg (91%). 1H NMR (300 MHz, CD3OD): δ 8.77 (dd, 2H), 7.72 (d, 2H), 7.58 (m, 3H), 7.48 (d, 2H), 7.12 (t, 1H), 5.94 (t, 1H), 2.49 (m, 2H). 2.36 (s, 6H), 2.33 (m, 1H), 2.21 (m, 1H); MS(ESI): 444.1 (M+1), 446.1 (M+3).
Reaction SMILES: [Mg].II.[CH2:4]([O:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[B:18](OC)([O:21]C)[O:19]C.S(=O)(=O)(O)O>C(OC1C=CC(Br)=CC=1)CCCCC.C1COCC1>[CH2:4]([O:10][C:11]1[CH:16]=[CH:15][C:14]([B:18]([OH:21])[OH:19])=[CH:13][CH:12]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: COB(OC)OC
Reactant: CCCCCCOc1ccc(Br)cc1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(B(O)O)cc1
Temperature: 25 °C

Procedure:
In a baked-out apparatus filled with argon, magnesium turnings (1.89 g; 78 mmol) were treated with a crystal of iodine and covered with dried THF. Subsequently, a few drops of 4-hexyloxybromobenzene were added to the static solution. The Grignard reaction commenced very quickly and the 4-hexyloxybromobenzene (total amount: 20 g; 78 mmol) was subsequently added dropwise while stirring at such a rate that the mixture boiled gently; during this addition, the mixture was diluted with THF (total of about 100 ml). The mixture was refluxed for 3 hours (only a few flakes of magnesium remaining in the solution) and was subsequently allowed to cool. The Grignard soltuion was transferred in a countercurrent of protective gas to a 250 ml dropping funnel and added dropwise at −70° C. to a solution of trimethyl borate (8.9 g; 9.6 ml; 86 mmol) in 50 ml of dry THF while stirring, with a precipitate being formed. The mixture was allowed to warm to RT overnight and the reaction mixture was poured into a mixture of 100 g of ice and 3 ml of concentrated sulfuric acid while stirring. The organic phase was separated off and the aqueous phase was extracted with 3×100 ml of chloroform, the combined organic phases were evaporated. The crude product was subsequently recrystallized from hexane.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:17])[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9](=[O:12])[C:10]=1[CH3:11])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[CH3:20][OH:21].Cl>C(Cl)Cl>[C:1]([C:5]1[C:10]([CH3:11])=[C:9]([O:12][CH:20]2[CH2:10][CH2:5][CH2:1][CH2:2][O:21]2)[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1=C(C(C)(C)C)C(=O)C(C(C)(C)C)=CC1=O
Reactant: CO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(OC2CCCCO2)cc(C(C)(C)C)c(O)c1C(C)(C)C
Reaction time: 3 h
Yield: 81 %

Procedure:
2,6-di-tert-butyl-3-methyl-1,4-benzoquinone (49 g) was dissolved in methylene chloride (300 ml) and sodium borohydride (15 g) was added to the solution under a nitrogen atmosphere. After adding methanol (30 ml) dropwise, the mixture was stirred for 3 h, poured into 5% HCl under ice cooling, and subjected to extraction with methylene chloride. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was dissolved in methylene chloride (200 ml) and, after adding 3,4-2H-dihydropyran (26 ml) and a catalytic amount of paratoluenesulfonic acid, the mixture was stirred overnight at room temperature. The reaction mixture was washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 2,6-di-tert-butyl-3-methyl-4-tetrahydropyranyloxyphenol [54.4 g (yield, 81%)] as a colorless oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-])=O)=[N:7][CH:8]=1.C(O)(=O)C.C(=O)(O)[O-].[Na+]>[Fe].O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1
Reactant: CSc1ccc([N+](=O)[O-])nc1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CSc1ccc(N)nc1
Yield: 83.2 %

Procedure:
5-(methylthio)-2-nitropyridine (270 g), iron powder (600 g), acetic acid (500 mL) and water (2 L) were heated to reflux for 4 hours. Then saturated sodium bicarbonate solution (6 L) was added into the reaction mixture. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, and dried with anhydrous sodium sulfate. After filtration, the residual solution was removed under reduced pressure to obtain the target compound (185 g). 1H-NMR (300 MHz, CDCl3): δ 2.39 (3H, s), 4.49 (2H, brs), 6.47 (1H, d), 7.50 (1H, dd), 8.11 (1H, d). LC-MS m/z: 141 [M++1].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.C(O)(=O)C(O)=O.[OH:26][C@H:27]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29]>C(Cl)Cl>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[N:3]=[C:2]2[N:33]1[CH2:32][CH2:31][N:30]([C:28](=[O:29])[C@H:27]([OH:26])[CH2:36][CH:37]([CH3:38])[CH3:39])[CH2:35][CH2:34]1
Reactant: CC(C)C[C@@H](O)C(=O)N1CCNCC1
Reactant: Oc1ccccc1-c1nc(Cl)c2cc(F)ccc2n1
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Product: CC(C)C[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)CC1
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a mixture of 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (200 mg, 0.72 mmol) and CH2Cl2 (7 mL) was added (R)-2-hydroxy-4-methyl-1-(piperazin-1-yl)pentan-1-one oxalate (275 mg, 0.95 mmol). The reaction was complete after two hours. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 mixture of CH2Cl2:hexanes gave (R)-1-(4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one (289 mg, 91%). LC/MS: m/z 439.30 (M+H)+ at 3.00 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.46 (m, 1H), 8.02 (m, 1H), 7.84 (m, 2H), 7.40 (m, 1H), 6.97 (m, 2H), 4.92 (d, J=7.2 Hz, 1H), 4.38 (m, 1H), 3.98 (m, 4H), 3.76 (m, 4H), 1.80 (m, 1H), 1.42 (m, 2H), 0.92 (q, J=3.8 Hz, 6H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[F:18][C:19]1[CH:24]=[C:23]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: Fc1cccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-fluoro-phenylboronic acid to give [1-(3-fluoro-phenyl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 305(MH+).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][NH:5][C:4]2[CH:8]=[CH:9][C:10]([OH:12])=[CH:11][C:3]1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19]([O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:12][C:10]1[CH:9]=[CH:8][C:4]2[NH:5][CH2:6][CH2:7][O:2][C:3]=2[CH:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1ccc2c(c1)OCCN2
Reactant: COc1cc2nccc(Cl)c2cc1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc4c(c3)OCCN4)c2cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 83.5 %

Procedure:
A solution of 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ol hydrochloride (0.626 g, 3.34 mmol), cesium carbonate (4.35 g, 13.3 mmol), and 6-(benzyloxy)-4-chloro-7-methoxyquinoline (1.00 g, 3.34 mmol) in DMF (10.0 mL) was stirred at 80° C. for 18 h. An additional 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ol hydrochloride (0.626 g, 3.34 mmol) and cesium carbonate (4.35 g, 13.3 mmol) were added, and the mixture stirred at 80° C. for 3 days. The reaction mixture was partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford an orange-brown oil. This material was purified twice via column chromatography (RediSep 80 g column, gradient elution with 0-5% methanol-dichloromethane) to afford an orange oil. Trituration with methanol and filtering the resulting suspension afforded 7-(6-(benzyloxy)-7-methoxyquinolin-4-yloxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.156 g, 83.6% yield) as an orange glass. MS (MH+) 415.1; Calculated 414 for C25H22N2O4.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>O1CCOCC1>[ClH:24].[N:11]1([C:14]2[CH:23]=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc3ccccc3n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc2nc(N3CCNCC3)cnc2c1

Procedure:
Prepared in analogy to example 1.6(d) from 4-quinoxalin-2-yl-piperazine-1-carboxylic acid tert.-butyl ester and dioxane saturated with gaseous hydrochloric acid.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[C:1]([N:5]([C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NNC(=O)c1ccccn1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1ccccn1)C(=O)c1ccccc1
Reaction time: 8 h

Procedure:
A solution of N'-t-butyl-N-(2-pyridinecarbonyl)hydrazine (1.0 g, 0.00518 mol) in 20 ml of toluene at 23° C. was treated sequentially with 50% sodium hydroxide (1.3 g) and benzoyl chloride (0.728 g). The mixture was stirred overnight. The solids were removed by filtration and washed with water to afford N'-t-butyl-N-(2-pyridinecarbonyl)-N'-benzoylhydrazine.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][C:8]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[CH:10][N:9]=1)(=O)C>>[OH:6][CH2:7][C:8]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[CH:10][N:9]=1
Reactant: COc1ccnc(COC(C)=O)c1OC
Agent: [Na+]
Agent: [OH-]
Product: COc1ccnc(CO)c1OC
Reaction time: 2 h
Yield: 93.6 %

Procedure:
After adding 15 ml of 2N sodium hydroxide solution, 4.8 g of 2-acetoxymethyl-3,4-dimethoxypyridine are stirred vigorously at 80° C., whereupon a homogeneous solution forms from the initial two-phase mixture. After 2 hours, the solution is allowed to cool and is extracted five times with 30 ml of methylene chloride each time, the combined organic phases are washed twice with 5 ml of 0.3N sodium hydroxide solution each time, dried over potassium carbonate, filtered and concentrated and the distillation residue is stirred with petroleum ether. 3.6 g (96% of theory) of 2-hydroxymethyl-3,4-dimethoxypyridine are obtained as a colourless solid of m.p. 87°-89° C.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])[N:8]=1)=O.[NH:23]([C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=1)N>>[CH3:31][C:27]1[CH:26]=[C:25]([N:23]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=4)[C:17]#[N:18])[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:30]=[CH:29][N:28]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C#N)c2)ccc1=O
Reactant: Cc1cc(NN)ccn1
Product: Cc1cc(-n2nccc2-c2nn(-c3cccc(C#N)c3)ccc2=O)ccn1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-benzonitrile (A-19) and 4-hydrazino-2-methylpyridine according to the method described for example 91. MS: M=355.2 (M+H)+
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].C(O[CH:14](N(C)C)[N:15]([CH3:17])[CH3:16])(C)(C)C>>[CH3:14][N:15]([CH3:17])[CH:16]=[C:7]1[CH2:6][CH2:5][CH2:4][CH:3]([OH:8])[C:2]1=[O:1]
Reactant: O=C1CCCCC1O
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=C1CCCC(O)C1=O

Procedure:
2-Hydroxy-cyclohexanone (114 mg, 1.0 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (188 mg) as a yellow oil which was used directly in the next step.