Azzindani/Open_Reaction_Data huggingface dataset:
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][CH:20]=[CH:19][CH:18]=1)=[O:4].[Cu][C:25]#[N:26].CN(C)C=O.C(Cl)(Cl)Cl.C(O)(C)C>O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[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][CH:20]=[CH:19][CH:18]=1)=[O:4]
Reactant: N#C[Cu]
Reactant: COC(=O)c1nc(Br)c2c(Oc3ccccc3)cccc2c1O
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C#N)c2c(Oc3ccccc3)cccc2c1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.3 %

Procedure:
A mixture of 1-bromo-4-hydroxy-8-phenoxy-isoquinoline-3-carboxylic acid methyl ester (1.22 g, 3.3 mmol), copper(I) cyanide (585 mg, 6.6 mmol), and anhydrous dimethylformamide (16 mL) was refluxed for ten minutes before it was cooled to room temperature and diluted with water. To the resulting slurry was added a chloroform/isopropanol mixture (3:1, 150 mL). After stirring for 10 minutes the solid components were separated by filtration and discarded. The organic layer of the filtrate was washed with water, and brine before it was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of methanol and dichloromethane to give the title compound as a white solid (574 mg): 1H NMR (CDCl3, 200 MHz): δ=12.26 (s, 1H), 8.15 (m, 1H), 7.71 (t, J=8.2 Hz, 1H), 7.38 (m, 2H), 7.17 (m, 4H), 4.12 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.[S:13]1[CH2:17][C:16](=[O:18])[NH:15][C:14]1=[O:19].N1CCCCC1>COCCO>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:17]2[S:13][C:14](=[O:19])[NH:15][C:16]2=[O:18])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: COCCO
Product: COC(=O)c1ccc(C=C2SC(=O)NC2=O)cc1
Temperature: 25 °C
Yield: 35.1 %

Procedure:
A solution of 4-formyl-benzoic acid methyl ester (1.0 g, 6.7 mmol), thiazolidine-2,4-dione (0.78 g, 6.7 mmol) and piperidine (0.66 ml, 6.7 mmol) in 2-methoxy-ethanol (20 ml) was refluxed for 2 hrs, cooled to the room temperature and evaporated. The residue was triturated with CH2Cl2 to produce a crystalline material which was collected by filtration to afford the title compound (620 mg, 35% yield). LRMS: 263.3 (calcd.), 264.1 [MH]+ (found).
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>CCOCC>[Cl:1][C:2]1[C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: C1COCCN1
Reactant: Cc1cnc(Cl)c(Cl)n1
Solvent: CCOCC
Product: Cc1cnc(Cl)c(N2CCOCC2)n1

Procedure:
16.3 g of 2,3-dichloro-5-methyl-pyrazine and 100 ml of morpholine are warmed to 100° C. for 6 hours. The reaction mixture is then diluted with 200 ml of ether and again extracted by shaking with water. The ether phase is dried over sodium sulphate and evaporated in a waterpump vacuum. The residue is distilled in a waterpump vacuum. 2-Chloro-3-morpholinyl-5-methyl-pyrazine, boiling point 166°-167° C./15 mm Hg, is thus obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:18]I>C(O)(=O)C>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]([I:18])[C:10]=1[OH:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: II
Reactant: COc1cccc(O)c1OCc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(I)c(O)c1OCc1ccccc1
Temperature: 55 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
To a suspension of 2-benzyloxy-3-methoxy-phenol (3.80 g, 16.5 mmol) and cupric acetate monohydrate (3.28 g, 16.5 mmol) in acetic acid (45 mL) was added iodine (4.62 g, 18.2 mmol) and the reaction was heated to 55° C. and stirred overnight. After this time the reaction was quenched with 10% aqueous sodium thiosulphate (40 mL) and diluted with diethyl ether (150 mL). The resultant emulsion was filtered through celite and the organic layer was washed with water (4×40 mL) and brine (40 mL), dried over magnesium sulphate and the solvent removed under vacuum. The crude residue was purified by silica-gel flash chromatography (sequential elution—5% diethyl ether in hexane, 10%). Concentration of fractions containing the pure product as indicated by thin layer chromatography gave 2.85 g of the desired product. Later impure fractions were combined and re-chromatographed to yield a further 520 mg of material (combined mass=3.37 g, 57% yield). 1H-NMR (CDCl3) δ 7.40-7.33 (m, 5H), 7.34 (d, J=8.9 Hz, 1H), 6.34 (d, J=8.9 Hz, 1H), 6.06 (s, 1H), 5.06 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[C:8]([C:17]([C:19]2[CH:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=2)=[O:18])=[CH:7]1.[CH3:29][O-:30].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[C:8]([C:17]([C:19]2[CH:20]=[N:21][C:22]([O:30][CH3:29])=[CH:23][CH:24]=2)=[O:18])=[CH:7]1
Reactant: C[O-]
Reactant: O=C(c1ccc(Cl)nc1)c1cn(Cc2cccc(Cl)c2)c2ccccc2c1=O
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Cl)c3)c3ccccc3c2=O)cn1
Yield: 89.5 %

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 151 mg (0.37 mmol) of 1-(3-chloro-benzyl)-3-(6-chloro-pyridine-3-carbonyl)-1H-quinolin-4-one and 170 mg (3.15 mmol) of sodium methoxide were stirred in 2 mL of dry methanol in a sealed vessel at 75° C. for 2 h. The reaction mixture was evaporated and purified by flash chromatography to give 134 mg of a white powder. LC-MSD, m/z for C23H17ClN2O3 [M+H]+=405.1, 407.1; HPLC retention time: 2.3 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])/[C:5](/[CH2:24][CH2:25][CH2:26][O:27]CC1C=CC=CC=1)=[CH:6]\[CH2:7][C@H:8]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH3:2].C(OC(=O)/C(/CCCOCC1C=CC=CC=1)=C/C[C@H](NC(OC(C)(C)C)=O)C(OC(C)(C)C)=O)C>CO.[Pd]>[C:20]([O:19][C:17]([NH:16][C@@H:8]([CH2:7][CH2:6][CH:5]([CH2:24][CH2:25][CH2:26][OH:27])[C:4]([O:3][CH2:1][CH3:2])=[O:35])[C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)/C(=C\C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CCCOCc1ccccc1
Agent: [Pd]
Agent: CCOC(=O)/C(=C/C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CCCOCc1ccccc1
Solvent: CO
Product: CCOC(=O)C(CCCO)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of (Z)—(S)-2-(3-Benzyloxypropyl)-5-tert-butoxycarbonylamino-hex-2-enedioic acid 6-tert-butyl ester 1-ethyl ester and (E)-(S)-2-(3-Benzyloxypropyl)-5-tert-butoxycarbonylamino-hex-2-enedioic acid 6-tert-butyl ester 1-ethyl ester (270 mg, 0.55 mmol) and palladium (30.0 mg, 10% on charcoal) in methanol (30 mL) were stirred for 6 h at r.t. under a hydrogen atmosphere. Then the mixture was filtered through Celite® and concentrated under reduced pressure. The crude product was purified by column chromatography (silica, hexane/ethyl acetate gradient).
Reaction SMILES: C[O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.Br.C(O)(=O)C>O>[OH:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2cccc(C(=O)O)c2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cccc(Oc2ccc(O)cc2)c1
Temperature: 25 °C

Procedure:
A mixture of 73 g of 3-(4-methoxyphenoxy)benzoic acid, 300 ml of 48% hydrobromic acid, and 600 ml of acetic acid was heated at reflux for 48 hours. The reaction mixture was allowed to cool to ambient temperature, poured into cold water, and extracted with ethyl acetate. The organic extracts were dried and concentrated in vacuo. The residue was crystallized from ethyl/hexane providing 39.41 g of the desired subtitle intermediate, m.p. 172°-174° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:48])=O>>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([Cl:48])=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Cl)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1
Temperature: 25 °C

Procedure:
A solution of the product from Example 43C (224 mg, 0.443 mmol) in thionyl chloride (2 mL) was refluxed for 1 hour. The mixture was cooled to room temperature, toluene (5 mL) was added and the mixture concentrated under vacuum to provide the title product as a solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[C:10]([O:17][CH2:18][C:19]([O:21]CC)=O)[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:3][CH2:2]1.[NH2:24][CH2:25][CH:26]([OH:38])[CH2:27][N:28]1[CH2:37][CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29]1>CCO>[CH2:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:36][CH2:37][N:28]1[CH2:27][CH:26]([OH:38])[CH2:25][NH:24][C:19](=[O:21])[CH2:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[C:7]([N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)[CH:16]=[CH:15]2
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: CCOC(=O)COc1cccc2ccc(N3CCOCC3)nc12
Solvent: CCO
Product: O=C(COc1cccc2ccc(N3CCOCC3)nc12)NCC(O)CN1CCc2ccccc2C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 9.3 %

Procedure:
To a stirred mixture of ethyl 2-((2-morpholinoquinolin-8-yl)oxy)acetate (100 mg, 0.316 mmol) in EtOH (2 mL) was added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl) propan-2-ol (65 mg, 0.316 mmol). The mixture was stirred at 120° C. for 0.5 hour under microwave conditions then after evaporation of solvent, the reaction mixture was purified by prep-HPLC to afford the title product (14 mg, Yield 10%). 1H NMR (400 MHz, MeOD) δ=8.04 (d, J=9.3 Hz, 1H), 7.43-7.36 (m, 1H), 7.23-7.16 (m, 3H), 7.10-7.00 (m, 3H), 6.97 (d, J=4.8 Hz, 1H), 4.77 (s, 2H), 3.96 (t, J=6.3 Hz, 1H), 3.87-3.83 (m, 4H), 3.77-3.72 (m, 4H), 3.63-3.53 (m, 2H), 3.52-3.45 (m, 1H), 3.40 (d, J=6.3 Hz, 1H), 2.83 (d, J=5.8 Hz, 2H), 2.75-2.67 (m, 2H), 2.56-2.37 (m, 2H). LCMS (m/z): 477.2 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].[CH3:18][O:19][C:20]1[CH:42]=[CH:41][C:23]([CH2:24][O:25][C:26](ON=C(C(OCC)=O)C(OCC)=O)=[O:27])=[CH:22][CH:21]=1>O.C(O)(C)(C)C>[CH3:18][O:19][C:20]1[CH:42]=[CH:41][C:23]([CH2:24][O:25][C:26]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:27])=[CH:22][CH:21]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)C(=NOC(=O)OCc1ccc(OC)cc1)C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccc(COC(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
L-Phenylalanine (330 mg.) and sodium bicarbonate (202 mg.) were dissolved in water (10 ml.) under heating and allowed to stand. A solution of diethyl 2-(4-methoxybenzyloxycarbonyloxyimino)malonate (1.0 g.) in tert-butyl alcohol (10 ml.) was added to the solution with stirring at room temperature and water (10 ml.) was added thereto, the mixture was then stirred for 2 hours at room temperature. The reaction mixture was brought to pH 9 by adding water (20 ml.) and saturated sodium bicarbonate aqueous solution (10 ml.), and water (10 ml.) was added thereto. The resulting mixture was then washed twice with ethyl acetate (20 ml.). The aqueous layer was adjusted to pH 7 with a 10% citric acid aqueous solution, washed twice with ethyl acetate (30 ml.), adjusted to pH 3.5 with a 10% citric acid aqueous solution and extracted three times with ethyl acetate (30 ml.). The extract was washed with a sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give N-(4-methoxybenzyloxycarbonyl)-L-phenyalanine (410 mg.), oil.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:17]=[C:16]([CH2:27][CH:28]([C:31]3[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=3)[C:29]#[N:30])[CH:15]=2)[CH:10]=[CH:11][C:12]=1[Cl:13].[Cl-].[NH4+].[N-:40]=[N+:41]=[N-:42].[Na+]>O.C(O)=O>[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2[N:18]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[N:17]=[C:16]([CH2:27][CH:28]([C:29]3[NH:42][N:41]=[N:40][N:30]=3)[C:31]3[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=3)[CH:15]=2)[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: COc1ccc(-n2nc(CC(C#N)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O=CO
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-n2nc(CC(c3cccc(C)c3)c3nnn[nH]3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 90 °C
Yield: 63 %

Procedure:
To a 48-mL pressure vessel (Chemglass) were added N,N-dimethylformamide (25.0 mL), 3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionitrile (2.76 g, 5.97 mmol, 1.0 equiv), ammonium chloride (1.58 g, 29.8 mmol, 5.0 equiv) and sodium azide (1.94 g, 29.8 mmol, 5.0 equiv). The screw-cap vessel was sealed and then placed in an oil bath heated to 90° C. for 48 h. The reaction mixture was cooled to room temperature, pH-adjusted with formic acid, diluted with water (100 mL), and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with water (3×50 mL) then brine (50 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude material was purified by flash chromatography (5% methanol/dichloromethane) to yield the title compound (1.9 g, 63%). HPLC: Rt=3.09 (Method A). MS (ESI): mass calculated for C26H22Cl2N6O, 504.12; m/z found, 505.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 7.57 (d, J=8.5 Hz, 1H), 7.41 (d, J=2.2 Hz, 1H), 7.23-7.16 (m, 3H), 7.09-7.07 (m, 3H), 7.01 (dd, J=8.5, 2.2 Hz, 1H), 6.96 (d, J=9.0 Hz, 2H), 6.46 (s, 1H), 4.86 (dd, J=9.0, 6.6 Hz, 1H), 3.77 (s, 3H), 3.62 (dd, J=14.8, 9.3 Hz, 1H), 3.35 (dd, J=14.8, 6.6 Hz, 1H), 2.28 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH2:25]([O:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)[CH3:26].O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[CH2:25]([O:27][C:28]1[N:33]=[CH:32][C:31]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)=[CH:30][CH:29]=1)[CH3:26]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: CCOc1ccc(B(O)O)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: CCOc1ccc(-c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3cc(C)nn23)cn1
Temperature: 110 °C
Yield: 40.1 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 100 mg, 0.290 mmol), 6-ethoxypyridin-3-ylboronic acid (63 mg, 0.377 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (21 mg, 29 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.966 mL of 1,4-dioxane and 0.483 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (50-60% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (50.2 mg, 40%). Melting point (183.5-185.5° C.). 1H NMR (DMSO-d6) δ: 11.13 (s, 1H), 8.85 (dd, J=2.5, 0.5 Hz, 1H), 8.34 (dd, J=8.6, 2.5 Hz, 1H), 7.95 (d, J=8.8 Hz, 2H), 7.92 (s, 1H), 7.55 (d, J=8.6 Hz, 2H), 6.98 (dd, J=8.8, 0.8 Hz, 1H), 6.32 (s, 1H), 5.11 (br. s., 1H), 4.37 (q, J=6.9 Hz, 2H), 2.34 (s, 3H), 1.39 (s, 6H), 1.31 (t, 3H); ESI-MS: m/z 432.2 (M+H)+. Melting point (183.5-185.5° C.).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:7][OH:8])[S:5][CH:6]=1.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[N:3]=[C:4]([CH2:7][OH:8])[S:5][CH:6]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1OCc1ccccc1
Reactant: OCc1nc(Br)cs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: OCc1nc(-c2ccccc2OCc2ccccc2)cs1
Temperature: 90 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
To a mixed solution of the compound (900 mg, 4.6 mmol) obtained in Example 30a, 2-benzyloxyphenylboronic acid (1.3 g, 5.6 mmol) and 2M aqueous sodium carbonate solution (2.8 mL, 5.6 mmol) in 1,2-dimethoxyethane-ethanol (v/v=3/1, 12 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (380 mg, 0.46 mmol), and the mixture was stirred at 90° C. overnight. The resulting salt was filtered and removed, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by column chromatography (hexane-hexane/ethyl acetate=60/40) to give the title compound (1.2 g, 88%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20](C3C=NC=CC=3)[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[N:6]4[CH:7]=[CH:2][CH:3]=[N:4][CH2:5]4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c(-c3cccnc3)cccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cccc(N3C=CC=NC3)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-pyridin-3-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([N:25]=[C:26]=[S:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:26]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[S:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: S=C=NCc1ccccc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=S)NCc4ccccc4)cc23)CC1
Yield: 68.6 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 14.63 mg (0.098 mMol) benzyl isothiocyanate, 17.0 mg (86%) of the title compound were recovered.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[I:10]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCOCC1.CC(N(C)C)=O>[I:10][C:7]1[CH:6]=[C:5]([CH3:9])[C:3]([NH2:4])=[C:2]([CH3:1])[CH:8]=1
Reactant: Cc1cccc(C)c1N
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: Cc1cc(I)cc(C)c1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a solution of 2,6-dimethyl aniline (25 gm) in 1,4-dioxane (200 ml) and dimethylacetamide (20 ml) was added iodine (79 gm) slowly at 0° C. The solution was stirred for 1 hour at 0° C. and the temperature was raised to room temperature. The solution was stirred for 1 hour at room temperature and then added a saturated solution of sodium thiosulfate. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried with anhydrous sodium sulfate and the solvent was evaporated in vacuum to obtain 45 gm of 4-iodo-2,6-dimethyl benzenamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])=[C:6]([C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])=[C:6]([C:8]2[N:9]=[C:10]([NH2:15])[N:11]=[C:12]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=3)[CH:13]=2)[CH:7]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CN(C)CCCOc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Product: CN(C)CCCOc1ccc(Br)cc1-c1cc(Nc2ccc(Cl)cc2)nc(N)n1
Yield: 55 %

Procedure:
Following the method described in Example 4, 4-[5-bromo-2-(3-dimethylamino-propoxy)-phenyl]-6-chloro-pyrimidin-2-ylamine and 4-chloro-phenylamine provided the title compound (55% yield) as its hydrochloride salt. 1H NMR (CD3OD) δ 2.28-2.32 (m, 2H, CH2), 2.92 (s, 6H, CH3), 3.28-3.36 (m, 2H, CH2), 4.25 (m, 2H, CH2), 6.51 (s, 1H, Ar), 7.20-7.22 (m, 1H, Ar), 7.41-7.43 (m, 2H, Ar), 7.73-7.76 (m, 2H, Ar), 7.85-7.86 (m, 2H, Ar).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([Cl:26])=[CH:10][C:11]([O:24][CH3:25])=[C:12]([NH:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[O:17])[CH:13]=1.CCN(CC)CC.[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>C(Cl)Cl>[Cl:26][C:9]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:13][C:12]([NH:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:34](=[O:37])[CH:35]=[CH2:36])[CH2:20][CH2:19]2)=[O:17])=[C:11]([O:24][CH3:25])[CH:10]=1
Reactant: COc1cc(Cl)c(-c2ccccc2Cl)cc1NCC(=O)N1CCNCC1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N1CCN(C(=O)CNc2cc(-c3ccccc3Cl)c(Cl)cc2OC)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
To a solution of the crude 2-(5-(2-Chlorophenyl)-4-chloro-2-methoxyphenylamino)-1-(piperazin-1-yl)ethanone (0.304 mmol) and Et3N in DCM (5 mL) at 0° C., acryloyl chloride (27.5 mg, 0.304 mmol) was slowly added and the resulting mixture was stirred at room temperature for 1 h. The mixture was quenched with saturated NaHCO3 solution and extracted with DCM. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford the desired product (80 mg, 58.7% yield, 2 steps). 1H NMR (400 MHz, DMSO-d6) δ: 7.55-7.52 (m, 1H), 7.45-7.39 (m, 2H), 7.32-7.29 (m, 1H), 6.97 (s, 1H), 6.80 (dd, J=10.4, 16.4 Hz, 1H), 6.54 (s, 1H), 6.12 (dd, J=2.0, 16.8 Hz, 1H), 5.70 (dd, J=2.0, 10.4 Hz, 1H), 5.35 (bs., 1H), 3.93 (d, J=4.0 Hz, 2H), 3.89 (s, 1H), 3.55-3.49 (m, 8H). ESI-MS m/z: 448.2[M+H]+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[C@@:21]([OH:32])([CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)[C@@H:22]([CH3:25])[CH2:23][OH:24].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[C@:21]([OH:32])([C@@H:22]([CH3:25])[CH2:23][O:24][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1
Reactant: C[C@@H](CO)[C@](O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](COS(C)(=O)=O)[C@](O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Yield: 101 %

Procedure:
61 mg (0.61 mmole) of triethylamine and 64 mg (0.56 mmole) of methanesulfonyl chloride were added at 0° C., whilst stirring, to a solution of 74 mg (0.231 mmole) of (2S*,3R*)-3-(2,4-dichlorophenyl)-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1,3-butanediol in 2 ml of methylene chloride. Fifteen minutes later the reaction mixture was mixed with a dilute aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, and the solvent was removed by evaporation under reduced pressure, to give 92 mg of a crude product.