Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]([CH3:55])([CH3:54])[C:20]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]3[C:34]([O:41][C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)=[N:35][NH:36][C:37]=3[CH:38]([CH3:40])[CH3:39])=[C:28]([CH3:53])[CH:27]=2)=[O:21])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CC(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]([CH3:55])([CH3:54])[C:20]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]3[C:34](=[O:41])[NH:35][NH:36][C:37]=3[CH:38]([CH3:39])[CH3:40])=[C:28]([CH3:53])[CH:27]=2)=[O:21])=[O:18])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(OCCNC(=O)C(C)(C)C(=O)N2CCN(C(=O)OCc3ccccc3)CC2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cc1cc(OCCNC(=O)C(C)(C)C(=O)N2CCN(C(=O)OCc3ccccc3)CC2)ccc1Cc1c(C(C)C)[nH][nH]c1=O
Temperature: 50 °C
Reaction time: 48 h
Yield: 99.2 %

Procedure:
A mixture of 4-[(4-{2-[2-{[4-(benzyloxycarbonyl)-piperazin-1-yl]carbonyl}-2-(methyl)propionylamino]ethoxy}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole (0.23 g), p-toluenesulfonic acid monohydrate (0.41 g) and 2-propanol (10 mL) was stirred at 50° C. for 2 days. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (0.18 g).
Reaction SMILES: [NH2:1][OH:2].[CH3:3]/[C:4](/[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[F:19])[N:10]=[C:9]([CH3:20])[C:8]=1[C:21]#[N:22])=[CH:5]/[CH3:6].CC1SC=C(C)C=1C1N(C2C=CC(O)=CC=2F)N=C(C)C=1C#N>CO>[CH3:3]/[C:4](/[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[F:19])[N:10]=[C:9]([CH3:20])[C:8]=1[C:21](=[N:1][OH:2])[NH2:22])=[CH:5]/[CH3:6]
Reactant: NO
Reactant: C/C=C(/C)c1c(C#N)c(C)nn1-c1ccc(O)cc1F
Agent: Cc1csc(C)c1-c1c(C#N)c(C)nn1-c1ccc(O)cc1F
Solvent: CO
Product: C/C=C(/C)c1c(C(N)=NO)c(C)nn1-c1ccc(O)cc1F
Temperature: 150 °C
Yield: 47 %

Procedure:
Hydroxylamine (50 wt % solution in water, 0.5 mL, 8.11 mmol) was added to (Z)-5-(but-2-en-2-yl)-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (22 mg, 0.08 mmol) dissolved in MeOH (1.0 mL) or Hydroxylamine (50 wt % solution in water, 0.24 mL, 3.97 mmol) was added to 5-(2,4-dimethylthiophen-3-yl)-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (13 mg, 0.04 mmol) dissolved in MeOH (0.8 mL). The reaction was heated at 150° C. in the microwave for 15 min. Purification using preparative HPLC gave 5-((Z)-but-2-en-2-yl)-1-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-3-methyl-1H-pyrazole-4-carboximidamide (E51) (11.44 mg, 46%), ES/MS m/z: 305.08 (M+H), 303.13 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.22 (m, 1H), 6.76-6.71 (m, 2II), 5.65 (m, 1H), 2.30 (s, 3H), 1.83 (s, 3H) and 1.39 (d, 3H, J=6.7 Hz) or 5-(2,4-dimethylthiophen-3-yl)-1-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-3-methyl-1H-pyrazole-4-carboximidamide (E52) (4.31 mg, 30%) ES/MS m/z: 361.05 (M+H), 359.17 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.14 (t, 1H, J=8.8 Hz), 6.83 (q, 1H, J=1.0 Hz), 6.66 (m, 1H), 6.61 (dd, 1H, J=11.9, 2.7 Hz), 2.38 (s, 3H), 2.16 (s, 3H) and 1.94 (d, 3H, J=1.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[N:12]=[C:11]3[CH:19]2[CH2:21][CH2:20]2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[C:13](=[O:18])[N:12]=[C:11]3[CH:19]2[CH2:21][CH2:20]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1nc(C2CC2)c2cc(-c3cccc(Cl)c3)ccc2[nH]1
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)nc(C3CC3)c3cc(-c4cccc(Cl)c4)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 6-(3-chlorophenyl)-4-cyclopropyl-1H-quinazolin-2-one (0.5 g, 1.68 mmol) in anhydrous DMF was added potassium hexamethylsilyl amide (0.45 g, 2.1 mmol) at ambient temperature under nitrogen. The reaction mixture was stirred at ambient temperature for 30 minutes, treated with p-methoxy benzyl chloride (0.35 mL, 2.5 mmol), and heated at 55° C. for 5 hours. The mixture was then cooled to room temperature and quenched with a saturated aqueous ammonium chloride solution (10 mL). Methylene chloride (50 mL) was added and organic layer was separated. The aqueous layer was extracted with methylene chloride (2×20 mL) and the combined organic layers were washed with brine and dried (MgSO4). After removal of solvent, the residue was separated on a flash chromatography (silica gel, hexane:ethyl acetate/1:1) to afford 6-(3-chlorophenyl)-4-cyclopropyl-1-(4-methoxybenzyl)-1H-quinazolin-2-one as an off-white solid: mp 173-174° C.; 1H-NMR (DMSO-d6) δ 8.65 (d, 1H, J=1.8 Hz), 8.10 (dd, 1H, J=8.9, 1.8 Hz), 7.93 (d, 1H, J=1.6 Hz), 7.79 (d, 1H, J=7.6 Hz), 7.53 (d, 2H, J=8.4 Hz), 7.46 (t, 1H, J=8.1 Hz), 7.21 (d, 2H, J=8.6 Hz), 6.88 (d, 2H, J=8.6 Hz), 5.41 (s, 2H), 3.73 (s, 3H), 3.18 (m, 1H), 1.18-1.27 (m, 4H); MS (CI) m/z 417([M+H]+, 100%); Anal. Calc. For C25H21ClN2O2: C, 72.02, H, 5.08, N, 6.72. Found: C, 71.88, H, 4.91, N, 6.70.
Reaction SMILES: [N:1]([CH2:4][CH2:5][OH:6])=[N+:2]=[N-:3].CCN(CC)CC.[Br:14][C:15]([CH3:20])([CH3:19])[C:16](Br)=[O:17]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:1]([CH2:4][CH2:5][O:6][C:16](=[O:17])[C:15]([Br:14])([CH3:20])[CH3:19])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCO
Reactant: CC(C)(Br)C(=O)Br
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(Br)C(=O)OCCN=[N+]=[N-]

Procedure:
2-Azidoethanol (17.40 g, 0.2 mol), freshly distilled methylene chloride (150 mL), and Et3N (21.21 g, 0.21 mol) were added into a three-neck round-bottom flask equipped with a condenser and a dropping funnel. Under nitrogen atmosphere and magnetic stirring, freshly distilled anhydrous methylene chloride (150 mL), DMAP (1.7 g, 14 mmol), and freshly distilled anhydrous Et3N (46.5 g, 0.46 mol) were sequentially added. After the flask was immersed into an ice—water bath, 2-bromoisobutyryl bromide (48.28 g, 0.21 mol) was added dropwise into the previous solution. Twenty-four hours later, the reaction mixture was washed successively with 1 M HCl (3×200 mL) solution and deionized water (1×200 mL). The organic phase was dried over anhydrous MgSO4 overnight. After filter and removal of methylene chloride on a rotary evaporator, the obtained residues were distilled under reduced pressure to give a colorless viscous liquid. The yield was: 33.4 g, 70%. 1H NMR (CDCl3, δ, ppm): 4.24 (t, 2H, N3CH2CH2), 3.52 (t, 2H, N3CH2), 1.96 (s, 6H, (CH3)2Br).
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([OH:19])=[C:10]([CH:18]=1)[C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])(=[O:4])[CH3:3].[CH3:20]O>>[C:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([OH:19])=[C:10]([CH:18]=1)[C:11]([CH2:13][CH2:14][C:15]([O:17][CH3:20])=[O:16])=[O:12])(=[O:4])[CH3:3]
Reactant: CC(=O)Nc1ccc(O)c(C(=O)CCC(=O)O)c1
Reactant: CO
Agent: Cl
Product: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1O
Temperature: 0 °C
Yield: 59 %

Procedure:
Hydrogen chloride gas was passed through a gently boiling solution of 3-(5-acetamido-2-hydroxybenzoyl)propionic acid (1.2 g, 0.0048 mole) in dry methanol (20 ml) until esterification was complete. The reaction mixture was poured into ice-water and extracted with chloroform. The extract was washed with sodium bicarbonate solution and water, dried and evaporated to give methyl 3-(5-acetamido-2-hydroxybenzoyl)propionate (0.75 g, 59%, m.p. 145°-147°). (Found: M+, 265. C13H15NO5 requires: M, 265).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:9]1[N:18]=[C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:30])[CH:15]=2)[N:10]=1>O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:9]1[N:18]=[C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:30])[CH:15]=2)[N:10]=1
Reactant: Clc1ccc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCCOc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Temperature: 100 °C

Procedure:
A mixture comprising 20 ml of ethylene glycol monomethyl ether and 70 mg of 55% sodium hydride was heated to 100° C., followed by the addition of a mixture comprising 500 mg of 2,6-dichloro-4-(3,4-methylenedioxybenzyl)aminoquinazoline and 5 ml of ethylene glycol monomethyl ether. The obtained mixture was heated under reflux for 2 hours and poured into 50 ml of water. The obtained mixture was extracted with 50 ml of ethyl acetate twice. The organic layers were together washed with 70 ml of an aqueous solution of sodium chloride twice, dried over magnesium sulfate and concentrated under a reduced pressure to give a crystalline residue. This residue was reprecipitated from ethyl acetate/n-hexane to give 420 mg of the title compound.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([O:16]C)=O)#[N:6].Cl>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].C(OCC)C>[C:5]12([CH2:2][CH2:1]1)[C:7]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:13][C:14](=[O:16])[NH:6]2
Reactant: CC[Mg]Br
Reactant: COC(=O)Cc1ccccc1C#N
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCOCC
Product: O=C1Cc2ccccc2C2(CC2)N1
Reaction time: 1 h

Procedure:
A diethyl ether solution (38 mL) of 2 M ethylmagnesium bromide was dropwise added at room temperature to a diethyl ether (200 mL) solution of methyl 2-cyanophenylacetate (10 g) and titanium tetraisopropoxide (17.9 g), and stirred for 1 hour. Aqueous 1 N hydrochloric acid solution was added to the reaction liquid, and the organic layer was separated. The aqueous layer was extracted with chloroform, the organic layer was washed with saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure. The crude product was purified through basic silica gel column chromatography (hexane/ethyl acetate) to give the entitled compound as a colorless solid (1.8 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]2([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O[CH:31](N(C)C)[N:32]([CH3:34])[CH3:33])(C)(C)C>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([C:11]2([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:16][CH2:15][C:14](=[O:17])/[C:13](=[CH:31]/[N:32]([CH3:34])[CH3:33])/[CH2:12]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)NC1(c2cccc(C(C)(C)C)c2)CCC(=O)CC1
Solvent: Cc1ccccc1
Product: CN(C)/C=C1\CC(NC(=O)OC(C)(C)C)(c2cccc(C(C)(C)C)c2)CCC1=O
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a stirred solution of tert-butyl 1-(3-tert-butylphenyl)-4-oxocyclohexylcarbamate (691 mg, 2.0 mmol) in Toluene (5 mL) was added tert-butoxybis(dimethylamino)methane (454 μL, 2.2 mmol). The reaction was stirred at 85° C. overnight. The reaction was concentrated and used crude in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][S:13][CH2:14][CH:15]([C:22](=[O:29])[C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:16][C:17]([O:19]CC)=[O:18])=[O:9])=[CH:4][CH:3]=1.[OH-].[Li+]>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][CH2:12][S:13][CH2:14][CH:15]([C:22](=[O:29])[C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:16][C:17]([OH:19])=[O:18])=[O:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(CSCCNC(=O)c1ccc(F)cc1)C(=O)c1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CC(CSCCNC(=O)c1ccc(F)cc1)C(=O)c1cccnc1
Yield: 97.5 %

Procedure:
A solution of ethyl 3-({2-[(4-fluorophenyl)carbonylamino]ethylthio}methyl)-4-oxo-4-(3-pyridyl)butanoate (100 mg) and lithium hydroxide (1 eq) was stirred a temperature in ethanol-water (1:1, 2 mL) till the starting material disappeared. The solution was acidified and purified on preparative HPLC (C-18 prep column, 10% to 90% acetonitrile in water both containing 0.1% TFA) to give 91 mg of 3-({2-[(4-fluorophenyl)carbonylamino]ethylthio}methyl)-4-oxo-4-(3-pyridyl)butanoic acid. The acid (91 mg) was treated with ethyl chloroformate (1.1 eq) and triethylamine (1.1 eq) in tetrahydrofuran (2.5 mL) at room temperature for 10 minutes. Piperidine (1.1 eq) was added to the reaction mixture and stirred at room temperature overnight. The solution was concentrated and purified on preparative HPLC (C-18 prep column, 10% to 90% acetonitrile in water both containing 0.1% TFA) to give 66 mg of the title compound; ESMS (M+1)+458.
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].I[CH:31]1[CH2:34][O:33][CH2:32]1.C([O-])(O)=O.[Na+]>CC(O)C.Cl.N[C@@H]1CCCC[C@H]1O>[C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:31]2[CH2:34][O:33][CH2:32]2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: IC1COC1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(B(O)O)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: N[C@@H]1CCCC[C@H]1O
Solvent: CC(C)O
Product: CC(C)(C)[Si](C)(C)OCCc1cccc(C2COC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 138.4 %

Procedure:
18.3 g of 3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-benzeneboronic acid, 510 mg of NiI2, 19.9 g of sodium bis(trimethylsilyl)amide, and 250 mg of trans-2-aminocyclohexanol hydrochloride were added to 14.0 ml of 2-propanol and the mixture was stirred for 10 minutes at room temperature. Then, a solution of 10.0 g of 3-Iodo-oxetane in 6.0 ml of 2-propanol was added and the reaction mixture kept at 80° C. under microwave irradiation for 30 minutes. The reaction mixture was then poured into 100 ml of a saturated aqueous NaHCO3-solution and extracted three times using 100 ml of EA each. The organic layer was then dried using MgSO4 and evaporated. Chromatography on silica gel using EA/HEP (gradient) yielded 22.0 g of the title compound, colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].N1C=CC=NC=1.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[N:34][CH:35]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[N:8]=[C:7]([C:32]2[CH:33]=[N:34][CH:35]=[C:30]([C:29]([F:40])([F:39])[F:28])[CH:31]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(NCc2ccc(F)cc2F)nc(Cl)n1
Reactant: OB(O)c1cncc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: c1cncnc1
Product: COC(=O)c1cc(NCc2ccc(F)cc2F)nc(-c2cncc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.31 %

Procedure:
To a 20 ml microwave vial with stir bar was added the 2-Chloro-6-(2,4-difluoro-benzylamino)-pyrimidine-4-carboxylic acid methyl ester, the pyrimidine from above (500 mg, 1.597 mmol), 5-trifluoromethylpyridine 3-boronic acid (566.9 mg, 2.076 mmol), palladium acetate (17.9 mg, 0.0798 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (98.2 mg, 0.239 mmol) and potassium carbonate (661 mg, 4.791 mmol). Reagents were suspended in dioxane (10 ml)/water (1 ml) and run in microwave reactor at 120° C. for 30 minutes. The reaction was cooled to room temperature, diluted with water (60 ml) and EtOAc (100 ml) and extracted with EtOAc (50 ml). The combined organic layer was washed with water (100 ml) and brine solution then dried over anhydrous sodium sulphate and evaporated. The residue was purified by column chromatography to get the title compound.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[S:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1.O>CO.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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>[S:20]1[CH:24]=[CH:23][C:22]([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:21]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccsc2)C1
Yield: 69.8 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 3-thiopheneboronic acid (117 mg, 0.912 mmol) in methanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (140 mg, 69.7%) as an oil.
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]1.[Cl:20][C:21]1[C:26](Cl)=[N:25][CH:24]=[CH:23][N:22]=1.O>CN(C=O)C>[Cl:20][C:21]1[C:26]([O:19][C@H:16]2[CH2:15][CH2:14][C@H:13]([NH:12][C:4]3[S:3][C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[N:5]=3)[CH2:18][CH2:17]2)=[N:25][CH:24]=[CH:23][N:22]=1
Reactant: Clc1nccnc1Cl
Reactant: O[C@H]1CC[C@H](Nc2nc3ccccc3s2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nccnc1O[C@H]1CC[C@H](Nc2nc3ccccc3s2)CC1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
Sodium hydride (60% dispersion, 0.41 g, 10.2 mmol) was added to a solution of trans-4-(benzo[d]thiazol-2-ylamino)cyclohexanol (as prepared according to Scheme 5) (1.10 g, 4.43 mmol) in DMF (20 mL) under argon. The mixture was stirred for 45 min and then 2,3-dichloropyrazine (0.66 g, 4.43 mmol) was added via syringe. This mixture was heated to 60° C. for 16 h, cooled to room temperature, then water was added slowly. The resulting suspension was filtered and the collected solid was purified by silica gel chromatography to give N-(trans-4-(3-chloropyrazin-2-yloxy)cyclohexyl)benzo[d]thiazol-2-amine (0.92 g, 2.54 mmol, 57% yield) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH2:9][C:10]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[N:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:4][CH2:3]1.[CH:26]([N-]C(C)C)([CH3:28])[CH3:27].[Li+].C(=O)CC.C(N(CC)CC)C.[OH-].[Na+].Cl>O1CCCC1.N1C=CC=CC=1.CO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[C:9](=[CH:27][CH2:26][CH3:28])[C:10]([N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[N:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(C2=Nc3ccccc3N=C(N3CCN(C)CC3)C2)CC1
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC=C1C(N2CCN(C)CC2)=Nc2ccccc2N=C1N1CCN(C)CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
A suspension of 2,4-bis(4-methyl-1-piperazinyl)-3H-[1,5]benzodiazepine (45.396 g, 133.3 mmol) in tetrahydrofuran (560 ml) under constant flow of argon was cooled to −10° C. A solution of lithium diisopropylamide (LDA) (2M, 100 ml, 200 mmol) was added over a period of 20 min, maintaining the temperature at −10° C. The obtained deep red solution was stirred for 30 min. Propionaldehyde (14.6 ml, 200 mmol) was added dropwise. Triethylamine (148 ml, 1.067 mol) and pyridine (0.54 ml, 6.7 mmol) were added successively. Trifluoroacetacetic anhydride (93.1 ml, 667 mmol) was added over a period of 50 min, maintaining the temperature at −10° C. The reaction mixture was stirred for 1 h and allowed to warm to −5° C. Methanol (213 ml) and while strongly agitated NaOH (5M, 200 ml, 1.000 mol) were added maintaining the temperature at −5° C. The reaction mixture was allowed to warm to room temperature and stirred over night. The solution was made acidic with 5M HCl to a pH of 3.5. Two phases were formed and the lower layer was extracted with 600 ml and twice with 100 ml of dichloromethane. The aqueous phase was treated with brine (200 ml) and toluene (400 ml) and made alkaline with 5M NaOH to a pH of 10. The phases were separated and the aqueous phase was extracted with toluene (2×200 ml). Combined toluene phases were dried over anhydrous Na2SO4 and the solvent was evaporated at reduced pressure to give 48.38 g (95%) of the title compound as an amber resin. The product obtained was characterised using 1H-NMR spectroscopy and was found to be identical to the product obtained by method A.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].CCO[C:22]([CH3:24])=O>C1(C)C=CC=CC=1.O>[CH:9]1[C:10]2[C:5](=[C:22]([CH2:24][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[C:9]([CH3:15])=[N:8][C:7]=3[OH:16])[CH:3]=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Reactant: CCOC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2c(C)nc(O)c(Cc3cccc4cnccc34)c2cc1OC
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (158 mg, 721 μmol) in toluene (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.86 mL, 1.72 mmol) at RT followed by MDE 32016 (185 mg, 864 μmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (10 mL) before extraction with EtOAc (50 mL). The organic phase was isolated and the aqueous phase was further extracted with CH2Cl2 (50 mL). Both organic phases were washed with brine (10 mL), combined, dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 94:6) gave 48 mg of 4-(isoquinolin-5-ylmethyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol. The free base was dissolved in MeOH (3 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (4.5 mL). The reaction mixture solution was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 4-(isoquinolin-5-ylmethyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol dihydrochloride 22 as a brown solid (58 mg, 19% yield).