Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:7][CH:6]=1)[CH3:2].O.NN>C(O)C>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][NH2:15])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(OCCCN)cc1
Yield: 51.6 %

Procedure:
A stirred mixture of 11.8 g (0.033 mole) of 4-[3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)propoxy]benzoic acid ethyl ester and 2.4 g of 85% hydrazine hydrate in 300 mL of ethanol was heated at reflux temperature for 3 hr. After cooling the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was treated with 450 mL of 2N hydrochloric acid and filtered. The filtrate was basified to pH 11 with potassium carbonate and the mixture was extracted twice with 200 mL portions of methylene chloride. The combined extract was washed with 200 mL of water and the solvent was evaporated under reduced pressure to give 3.8 g of oil that solidified on standing.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([O:20][CH3:21])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1.[Mg]>CO>[CH3:1][O:2][C:3](=[O:22])[CH:4]([O:20][CH3:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1
Reactant: COC(=O)C(=Cc1cccc(OCc2ccccc2)c1)OC
Agent: [Mg]
Solvent: CO
Product: COC(=O)C(Cc1cccc(OCc2ccccc2)c1)OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Compound from Step B was dissolved in methanol and treated with magnesium. The flask was placed in an ice bath for 5 min and then the reaction mixture was stirred at room temperature for 4 hours. Washed with HCl 3N and extracted with ether. Dry and concentrated to dryness to get the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[F-].[K+].Br[C:13]([CH3:24])([C:19](OCC)=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CN(C=O)C>[Br:9][C:5]1[CH:4]=[N:3][C:2]2[NH:1][C:19](=[O:20])[C:13]([CH3:24])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:8][C:7]=2[CH:6]=1
Reactant: Nc1ncc(Br)cc1O
Reactant: CCOC(=O)C(C)(Br)C(=O)OCC
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C)Oc2cc(Br)cnc2NC1=O
Temperature: 60 °C
Yield: 60 %

Procedure:
To an ice-cold solution of 2-amino-5-bromopyridin-3-ol (1 g, 5.29 mmol) in DMF (10 mL) was added KF (0.77 g, 13.23 mmol) followed by addition of diethyl 2-bromo-2-methylmalonate (1 mL, 5.29 mmol) and the mixture heated up to 60° C. for 4 h. After completion (by TLC), the reaction was cooled, quenched with water and extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the desired product as an off-white solid (1 g, 60%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:27]([OH:29])=[O:28])[CH2:10][O:11][C:12]1[C:13]([N+:24]([O-])=O)=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[NH2:24][C:13]1[C:12]([O:11][CH2:10][C@@H:9]([C:27]([OH:29])=[O:28])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:17][CH:16]=[CH:15][C:14]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1cccc(-c2ccccc2)c1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](COc1cccc(-c2ccccc2)c1N)C(=O)O
Reaction time: 10 h
Yield: 100.3 %

Procedure:
In an autoclave containing 280 mg of 41 (0.696 mmol), 30 mg of Pd/C (10%) and 18 mL of MeOH, hydrogenation is performed at 2 bar for 10 h at 20° C. After filtration of the catalyst on celite, the solvent is evaporated and 260 mg of expected product 42 are obtained, which product is used directly for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1.[Cl:21][CH2:22][C:23](Cl)=O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:23]([CH2:22][Cl:21])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1
Reactant: O=C(Cl)CCl
Reactant: NNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
15 g. of 7-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl hydrazine (obtained as in Preparation 2) is slowly added to 150 ml. of acetic acid with external cooling. A solution of 6 g. of chloroacetyl chloride in 75 ml. of acetic acid is then added during about ten minutes, the solution is stirred at room temperature for about 1.5 hours and 4 g. of sodium acetate added with additional stirring for about 30 minutes, the mixture then being refluxed for about 3.25 hours. This mixture is cooled, poured into ice water and concentrated to a small volume, then diluted with water, neutralized with sodium bicarbonate and extracted with chloroform. The extract is dried over anhydrous magnesium sulfate, concentrated and the residue chromatographed on 1 kg. column of silica gel with 1% methanol -- 99% chloroform. The product obtained from the column is crystallized from ethyl acetate to give pure 8-bromo-1-(chloromethyl)-6-(2-pyridyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([NH:5][C:6]1[CH:10]=[C:9]([CH3:11])[NH:8][N:7]=1)=[O:4].C1C(=O)N([Cl:21])C(=O)C1>CC#N>[Cl:21][C:10]1[C:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:12])[F:13])=[N:7][NH:8][C:9]=1[CH3:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(NC(=O)C(F)(F)F)n[nH]1
Solvent: CC#N
Product: Cc1[nH]nc(NC(=O)C(F)(F)F)c1Cl

Procedure:
Following protocol L, 2,2,2-Trifluoro-N-(5-methyl-1H-pyrazol-3-yl)-acetamide was treated with NCS in CH3CN to yield the title compound.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:34](=[O:37])[CH2:35][CH3:36])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f13) and commercially propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2[C:18]([CH3:27])=[N:19][CH:20]=[C:21]([CH:26]=2)[C:22](OC)=[O:23])[CH:11]=3)=[O:5])[CH2:3][CH2:2]1.[AlH4-].[Li+]>O1CCCC1>[OH:23][CH2:22][C:21]1[CH:26]=[C:17]([C:12]2[CH:11]=[C:10]3[C:15]([CH:16]=[C:7]([NH:6][C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])[N:8]=[CH:9]3)=[CH:14][CH:13]=2)[C:18]([CH3:27])=[N:19][CH:20]=1
Reactant: COC(=O)c1cnc(C)c(-c2ccc3cc(NC(=O)C4CC4)ncc3c2)c1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ncc(CO)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
To a solution of Methyl 5-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-6-methylnicotinate (11.9 mg, 0.0329 mmol) in tetrahydrofuran (3 mL, 40 mmol) was added 1.0 M of lithium tetrahydroaluminate in tetrahydrofuran (0.10 mL). The reaction mixture was stirred at room temperature for 30 minutes. The reaction was then quenched with water and extracted twice with dichloromethane. The combined organic extracts were dried over MgSO4, filtered, and evaporated in vacuo. The crude material was purified via flash chromatography on silica gel (25 g silica, solvent gradient: 0-10% methanol in dichloromethane) to yield 4.5 mg (41%) of N-(7-(5-(hydroxymethyl)-2-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=2.995, M+H=334.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 9.19 (s, 1H), 8.50 (s, 1H), 8.46 (s, 1H), 8.06 (s, 1H), 7.95 (d, J=8.7 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.64 (s, 1H), 5.30 (t, J=5.4 Hz, 1H), 4.58 (d, J=5.2 Hz, 2H), 2.47 (s, 3H), 2.08 (s, 1H), 0.91-0.78 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]([C:23]2[C:24](=[O:36])[N:25]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:26]([CH3:29])[C:27]=2[CH3:28])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.CS(O[CH2:42][CH2:43][CH2:44][N:45]1[CH2:51][CH:50]([OH:52])[C:47]2([CH2:49][CH2:48]2)[CH2:46]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:52][CH:50]1[C:47]2([CH2:49][CH2:48]2)[CH2:46][N:45]([CH2:44][CH2:43][CH2:42][O:19][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([NH:20][C:21]([C:23]5[C:24](=[O:36])[N:25]([C:30]6[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=6)[N:26]([CH3:29])[C:27]=5[CH3:28])=[O:22])=[CH:3][C:2]=4[F:1])=[CH:10][CH:11]=[N:12]3)=[CH:17][CH:16]=2)[CH2:51]1
Reactant: CS(=O)(=O)OCCCN1CC(O)C2(CC2)C1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCCN5CC(O)C6(CC6)C5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 40 h
Yield: 72.9 %

Procedure:
To a solution of N-(3-fluoro-4-(7-hydroxyquinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (200 mg, 0.413 mmol) in DMA (3 mL) was added 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (154 mg, 0.619 mmol) and Cs2CO3 (268 mg, 0.826 mmol). The reaction was then stirred at rt for 40 hrs. The solvent was removed and the residue was partioned between saturated NaHCO3 aqueous solution (10 mL) and CHCl3 (25 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (100:15:1(v/v/v)EtOAc/CH3OH/Et3N) to afford a pale yellow solid (192 mg, 73%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].Cl[CH2:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([CH2:14][CH2:13][CH2:12][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]#[N:10])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: ClCCCN1CCCC1
Reactant: N#CCc1ccccc1O
Product: N#CCc1ccccc1OCCCN1CCCC1
Yield: 58 %

Procedure:
The title compound was prepared from 2-hydroxy-benzeneacetonitrile (J. Org. Chem.; 66, 3435; 2001) and 1-(3-chloropropyl)pyrrolidine, using a method similar to that of preparation 104, as a pale brown gum in 58% yield. 1H NMR (400 MHz, CD3OD) δ: 7.33-7.25 (2H, m), 7.02-6.90 (2H, m), 4.12-4.09 (2H, m), 3.75 (2H, s), 2.76-2.72 (2H, m), 2.62-2.57 (4H, m), 2.09-2.02 (2H, m), 1.87-1.78 (4H, m); LRMS APCI m/z 245 [M+H]+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)#[CH:2].Br[C:11]1[CH:25]=[CH:24][C:14]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:16])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:11]2[CH:12]=[CH:13][C:14]([C:15](=[O:16])[C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[CH:24][CH:25]=2)=[CH:4][CH:5]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: O=C(c1ccc(F)cc1)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)c1ccc(C#Cc2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
Into a 250 mL, 3-neck, round-bottom flask equipped with a magnetic stirrer, a thermocouple, and a condenser were placed 12.00 g (100.0 mMol) of 1-ethynyl-4-fluorobenzene, 27.93 g (100.0 mMol) of 4-bromo-4′-fluorobenzophenone (Rieke Metals, Inc.), 1.5 g of tetrakis(triphenylphosphine)palladium[0], and 150 mL of de-aerated triethylamine. The reaction mixture was heated to 80° C. with stirring under argon for 3 hr and then cooled to ambient overnight (16 hr) with stirring. The reaction mixture was filtered to remove a white precipitate of triethylamine hydrobromide. The triethylamine solvent was evaporated and the solids obtained were dissolved in dichloromethane. The resulting solution was washed with water (2×50 mL), 2% HCl (2×50 mL), brine, and then dried over sodium sulfate. After removal of the solvent, the crude 4-fluoro-4′-(4-fluorobenzoyl)tolane was purified by silica gel column chromatography using hexanes as the elutant. White crystals having a melting point of 190-191° C. were obtained in a yield of 81%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:18]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=2[O:16][C:15](=[O:24])[CH:14]=1.CCN(C(C)C)C(C)C.Cl.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:23][C:20]1[CH:21]=[CH:22][C:17]2[O:16][C:15](=[O:24])[CH:14]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][NH:8][C:35](=[O:42])[C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)[C:18]=2[CH:19]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: NCCCOc1cc(=O)oc2ccc(Cl)cc12
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCCOc1cc(=O)oc2ccc(Cl)cc12)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
The trifluoroacetic acid salt of 4-(3-amino-propoxy)-6-chloro-1-benzopyran-2-one (0.272 mmol, 0.10 g) is dissolved in 3 mL of DCM and is added enough DIEA to bring the pH to ˜9 as measured by wet pH paper. Isonicotinoyl chloride hydrochloride is added (0.50 mmol, 0.089 g) and the reaction is stirred at ambient temperature overnight. The reaction mixture is evaporated under reduced pressure and the crude material is purified by HPLC to obtain the title compound as the trifluoroacetic acid salt (39 mg, 30%). 1H NMR (DMSO-d6, 300 MHz) δ 8.93 (1H, br t), 8.73 (2H, br d), 7.80 (2H, m), 7.76 (1H, d, J=2.5 Hz), 7.69 (1H, dd, J=2.5, 8.75 Hz), 7.45 (1H, d, J=8.75 Hz), 5.97 (1H, s), 4.31 (2H, t, J=5.75 Hz), 3.51 (2H, q, J=6.5 Hz), 2.11 (2H, m); MS (ESI, Pos.) calcd for C18H15ClN2O4 m/z [M+H]=359.1, found 359.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](=O)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.Cl>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][CH:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(NC(=O)Cc2ccc(C(F)(F)F)cc2)cc1OC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(NCCc2ccc(C(F)(F)F)cc2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.5 %

Procedure:
A mixture of 3 g (8.8 mmol) N-(3,4-Dimethoxy-phenyl)-2-(4-trifluoromethyl-phenyl)-acetamide and 1 g (26.3 mmol) LiAlH4 in 100 mL THF was stirred for 1 h at room temperature. Water and HCl aq. was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water, dried with MgSO4 and evaporated to dryness. The residue was purified by flash column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane. The product containing fractions were combined and evaporated to dryness to yield 0.7 g (24%) of the title compound. MS(m/e): 326.1 (MH+).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([O:34][C:35]2[C:40]([Cl:41])=[CH:39][CH:38]=[C:37]([CH2:42][NH:43][CH3:44])[C:36]=2[F:45])[CH:33]=1)[C:29]#[N:30].[NH:46]1[CH:50]=[CH:49][CH:48]=[C:47]1[C:51]([OH:53])=O.C([O-])(O)=O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[Cl:41][C:40]1[CH:39]=[CH:38][C:37]([CH2:42][N:43]([CH3:44])[C:51]([C:47]2[NH:46][CH:50]=[CH:49][CH:48]=2)=[O:53])=[C:36]([F:45])[C:35]=1[O:34][C:32]1[CH:31]=[C:28]([C:29]#[N:30])[CH:27]=[C:26]([Cl:25])[CH:33]=1
Reactant: O=C(O)c1ccc[nH]1
Reactant: CNCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(Cc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F)C(=O)c1ccc[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
HATU (0.16 g, 0.43 mmol) was added to a solution of 3-chloro-5-({6-chloro-2-fluoro-3-[(methylamino)methyl]phenyl}oxy)benzonitrile (0.10 g, 0.30 mmol) and 1H-pyrrole-2-carboxylic acid (0.05 g, 0.43 mmol) in DMF (3 mL) and the solution was stirred at RT overnight. After 16 h, ethyl acetate (100 ml) and saturated NaHCO3 solution (100 ml) were added. The organic layer was separated, washed with saturated NaHCO3 solution (2×100 ml), brine (150 mL), dried over MgSO4, filtered and concentrated. The crude material was purified by Reverse Phase HPLC to give the title compound (0.042 g, 33%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.77 (d, 1H), 7.34-7.40 (m, 1H), 7.21-7.33 (m, 3H), 7.17 (t, 1H), 7.01-7.05 (m, 1H), 6.99 (d, 1H), 6.28 (d, 1H), 4.85 (br. s., 2H), 3.33 (br. s., 3H).
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.[NH2:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([C@H:38]3[CH2:43][CH2:42][C@H:41]([N:44]4[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]4)[CH2:40][CH2:39]3)[N:19]=[C:20]([C:21]3[C:26]([F:27])=[CH:25][C:24]([NH:28]C(=O)OC(C)(C)C)=[C:23]([O:36][CH3:37])[CH:22]=3)[C:13]=12>ClCCl>[NH2:28][C:24]1[C:23]([O:36][CH3:37])=[CH:22][C:21]([C:20]2[C:13]3[C:14](=[N:15][CH:16]=[N:17][C:12]=3[NH2:11])[N:18]([C@H:38]3[CH2:43][CH2:42][C@H:41]([N:44]4[CH2:45][CH2:46][N:47]([CH3:50])[CH2:48][CH2:49]4)[CH2:40][CH2:39]3)[N:19]=2)=[C:26]([F:27])[CH:25]=1
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)c(F)cc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)c(F)cc1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of trifluoroacetic acid/dichloromethane (20:80, 7 mL) was added to a solution of trans-tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-5-fluoro-2-methoxyphenyl)carbamate (250 mg, 0.451 mmol) in dichloromethane (4.0 mL) at 0° C. After 15 minutes, the ice-bath was removed and the reaction mixture was stirred at room temperature for 4 hours. Solvent was then evaporated and the residue was dissolved in dichloromethane. Saturated sodium bicarbonate was added to adjust the pH to 8. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated give trans-3-(4-amino-2-fluoro-5-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (179 mg, 87%). 1H NMR (CDCl3) δ 1.56 (m, 2H), 2.15 (m, 7H), 2.31 (s, 3H), 2.51 (m, 4H), 2.67 (m, 4H), 3.88 (s, 3H), 4.16 (bs, 2H), 4.74 (m, 1H), 5.64 (bs, 2H), 6.56 (d, J=10.84 Hz, 1H), 6.88 (d, J=6.55 Hz, 1H), 8.33 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+ =455.2, Rt=0.63 min.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:5](=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:22][C:21]=1[Cl:26]
Reactant: Clc1ccccc1Cl
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCCCCCCCC(=O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
In a dry 250 ml three-neck flask with thermometer, reflux condenser (under nitrogen) and dropping funnel, 17.73 g of AlCl3 (0.133 mol) were suspended in 50 ml of 1,2-dichlorobenzene and cooled to 0° C. While stirring vigorously, 31.6 ml of lauroyl chloride (0.133 mol) were slowly added dropwise (1 hour). The mixture was then allowed to cool until the temperature had reached room temperature. Subsequently, the mixture was heated gradually to approximately 100-105° C., in the course of which a change in colour was evident (from ochre to dark red). Subsequently, the mixture was stirred at this temperature for 5 hours and left to stand overnight at room temperature. To separate the complex, this mixture was cautiously poured onto 200 g of ice (5% HCl) while stirring. The mixture became a mustard-coloured paste which was extracted in ethyl acetate. The organic layer was then removed in a separating funnel and washed to neutrality with saturated sodium hydrogencarbonate solution (2×50 ml) and water. After drying over sodium sulphate, the ethyl acetate was evaporated off. The remaining 1,2-dichlorobenzene was distilled off under reduced pressure. The residue was chromatographed through a column (length=20 cm, diameter=5 cm) on silica gel (Merck 0.040-0.063 nm) with dichloromethane as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:4].[Cu][C:26]#[N:27]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:26]#[N:27])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:4]
Reactant: N#C[Cu]
Reactant: COC(=O)c1nc(Br)c2c(Oc3ccc(F)cc3)cccc2c1O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C#N)c2c(Oc3ccc(F)cc3)cccc2c1O
Temperature: 25 °C
Yield: 45.8 %

Procedure:
A mixture of 1-bromo-8-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (400 mg, 1.02 mmol) and copper(I) cyanide (183 mg, 2.04 mmol) in anhydrous dimethylformamide (4 mL) was refluxed for ten minutes before it was cooled to room temperature and quenched with water. The slurry was stirred with chloroform/isopropanol (3:1, 70 mL) and water for ten minutes and filtered. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash column chromatography on silica gel with a gradient of methanol and dichloromethane to give the title compound as a white solid (158 mg): MS: (+) m/z 339.07 (M+1).
Reaction SMILES: [ClH:1].CS(NC1C=CC=CC=1)(=O)=O.Cl.[OH:14][C:15]1[CH:25]=[CH:24][C:23]([CH:26]([O:32][CH:33](C)[CH3:34])[CH2:27][NH:28][CH:29]([CH3:31])[CH3:30])=[CH:22][C:16]=1[NH:17][S:18]([CH3:21])(=[O:20])=[O:19]>C(O)C>[ClH:1].[OH:14][C:15]1[CH:25]=[CH:24][C:23]([CH:26]([O:32][CH2:33][CH3:34])[CH2:27][NH:28][CH:29]([CH3:30])[CH3:31])=[CH:22][C:16]=1[NH:17][S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: CC(C)NCC(OC(C)C)c1ccc(O)c(NS(C)(=O)=O)c1
Agent: CS(=O)(=O)Nc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOC(CNC(C)C)c1ccc(O)c(NS(C)(=O)=O)c1

Procedure:
A 1-g sample of 2'-hydroxy-5'-[1-chloro-2-isopropylamino)ethyl]methanesulfonanilide hydrochloride is added to 10 mL of absolute ethanol and heated at reflux for 30 minutes. The mixture is evaporated to dryness, and the residue is washed with ethyl ether thus yielding the product compound. The same procedure is used to prepare 2'-hydroxy-5'-[1-isopropoxy-2-(isopropylamino)ethyl]methanesulfonanilide hydrochloride, m.p. 121-123, by substituting isopropanol for ethanol in the above reaction.