Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[NH:11][N:10]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.Cl.[F:19][C:20]1[CH:21]=[N:22][C:23]([C@@H:26]([NH2:28])[CH3:27])=[N:24][CH:25]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:17][C:5]1[C:6]([NH:8][C:9]2[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[NH:11][N:10]=2)=[N:7][C:2]([NH:28][C@H:26]([C:23]2[N:24]=[CH:25][C:20]([F:19])=[CH:21][N:22]=2)[CH3:27])=[N:3][CH:4]=1
Reactant: CN(C)c1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncc(Cl)c(Nc2cc(N(C)C)[nH]n2)n1)c1ncc(F)cn1
Temperature: 160 °C

Procedure:
A microwave reaction vessel was charged with N3-(2,5-dichloropyrimidin-4-yl)-N5,N5-dimethyl-1H-pyrazole-3,5-diamine (Method 36, 50 mg, 0.2 mmol), (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 50 mg, 0.23 mmol), and DIPEA (0.15 ml, 0.86 mmol) in n-BuOH (1 ml) was heated in a microwave reactor at 160° C. for 2 hours. Solvent was removed. The residue was purified by silica gel chromatography (by ISCO Combiflash with gradient 0-5% methanol in DCM with 1% NH4OH) to afford the title compound as a white solid. 1H NMR (CD3OD, 400 MHz) δ 8.77 (s, 2H), 8.26 (br, 1H), 5.35 (br, 1H), 3.49 (q, 1H), 3.11 (s, 6H), 1.72 (d, 3H); m/z 378.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[CH3:11][Sn:12](Cl)([CH3:14])[CH3:13].[Cl-].[NH4+]>CCOCC.CCCCCC>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][C:7]([Sn:12]([CH3:14])([CH3:13])[CH3:11])=[CH:8][C:4]=2[CH:3]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Cc1ccc2sccc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1ccc2sc([Sn](C)(C)C)cc2c1
Reaction time: 0.5 h

Procedure:
A solution of 7.411 g of 5-methylbenzo[b]thiophene (Maybridge, Chemical Co. Ltd., 11-78) in 35 ml of ether is added dropwise at 0° to a mixture of 40 ml of 1.5N butylithium in hexane and 40 ml of ether. After 30 minutes, a solution of 9.963 g of trimethyltin chloride in 50 ml of ether is also added dropwise at 0°. After stirring for 1 hour at 0°, 50 ml of 5% ammonium chloride solution are added. The product is obtained by extracting with 100 ml and 150 ml of ether. Distillation at 0.15 mbar and 100-106° yields 5-methyl-2-trimethylstannylbenzo[b]thiophene.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=2)=[CH:6][N:7]=1.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:9]=2)=[CH:6][N:7]=1
Reactant: BrCCc1ccccc1
Reactant: CNC(=O)c1nc(-c2cccc(O)c2)cnc1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1nc(-c2cccc(OCCc3ccccc3)c2)cnc1N
Temperature: 85 °C
Yield: 30.9 %

Procedure:
3-Amino-6-(3-hydroxyphenyl)-N-methylpyrazine-2-carboxamide (179 mg, 0.8 mmol) was taken into DMF (3 mL) followed by addition of cesium carbonate (1.3 g, 4 mmol) and 2-(bromoethyl)benzene (550 uL, 4 mmol). The mixture was heated to 85° C. for 12 hours then allowed to cool to room temperature. The mixture was diluted with an excess of ethyl acetate and washed with water (3×) then brine and dried over anhydrous magnesium sulfate. Filtration and concentration in vacuo followed by purification of the residue using silica gel flash chromatography using ethyl acetate:hexanes (2:3) as eluent. The pure fractions were combined and concentrated then dried in vacuo to give 3-amino-N-methyl-6-{3-[(2-phenylethyl)oxy]phenyl}pyrazine-2-carboxamide (86 mg, 31% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO): 8.83 (s, 1H), 8.82 (br m, 1H), 7.74 (d, 1H), 7.67 (tr, 1H), 7.38-7.31 (m, 6H), 7.26-7.22 (m, 1H), 6.95 (d tr, 1H), 4.31 (tr, 2H), 3.08 (tr, 2H), 2.85 (d, 3H); MS (EI) for C20H21N4O2: 349 (MH+).
Reaction SMILES: [P:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)([S:5][CH2:6][CH3:7])([O:3][CH3:4])=[O:2].[Cl:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([NH:23][NH2:24])=[O:22]>CO.C(Cl)Cl>[P:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[N:24][NH:23][C:21](=[O:22])[C:20]2[CH:25]=[CH:26][CH:27]=[C:18]([Cl:17])[CH:19]=2)=[CH:13][CH:14]=1)([S:5][CH2:6][CH3:7])([O:3][CH3:4])=[O:2]
Reactant: NNC(=O)c1cccc(Cl)c1
Reactant: CCSP(=O)(OC)Oc1ccc(C=O)cc1
Solvent: CO
Solvent: ClCCl
Product: CCSP(=O)(OC)Oc1ccc(C=NNC(=O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of O-methyl S-ethyl O-(4-formylphenyl) thiophosphate (0.02 mole) in methanol (50 ml) and 3-chlorobenzoylhydrazine (0.02 mole) are charged into a glass reaction vessel and the mixture is stirred at room temperature for a period of about 12 hours. After this time the reaction mixture is stripped of methanol under vacuum and the residue is dissolved in methylene chloride (100 ml) and the resulting solution is washed with water (75 ml), with aqueous sodium hydroxide (75 ml; 0.1 N) and again with water (75 ml). The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product O-methyl S-ethyl O-[4-(3-chlorobenzoylhydrazonomethyl)phenyl] thiophosphate.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH:12]([CH3:14])[CH3:13])[C:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)=[C:7]([CH3:27])[C:6]=2[C:5]([OH:28])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:35][O:36][C:37](=[O:40])[CH2:38]Br>CC(C)=O>[CH3:35][O:36][C:37](=[O:40])[CH2:38][O:28][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:27])=[C:8]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:18][CH:17]=1)[C:9]([CH:12]([CH3:13])[CH3:14])=[N:10]2
Reactant: Cc1c(Cc2ccc(-n3cccn3)cc2)c(C(C)C)nc2c(Cl)ccc(O)c12
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(Cl)c2nc(C(C)C)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 8-chloro-2-isopropyl-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-ol (0.10 g), acetone (3.0 mL), potassium carbonate (0.035 g) and bromoacetic acid methyl ester (0.025 mL) was stirred at room temperature for 20 hours. The mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (10:0 to 8:2 by volume) gave title compound as colourless oil (0.087 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[C:9]2[C:17]([O:19]CC)=O)=[CH:4][C:3]=1[F:22].[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH2:29])=[N:25]1.C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[C:9]2[C:17]([NH:29][C:26]2[CH:27]=[CH:28][N:24]([CH3:23])[N:25]=2)=[O:19])=[CH:4][C:3]=1[F:22]
Reactant: CCOC(=O)c1nc2cccnc2n1-c1ccc(Cl)c(F)c1
Reactant: Cn1ccc(N)n1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cn1ccc(NC(=O)c2nc3cccnc3n2-c2ccc(Cl)c(F)c2)n1

Procedure:
To a solution of ethyl 3-(4-chloro-3-fluorophenyl)-3H-imidazo[4,5-b]pyridine-2-carboxylate (C13) (32 mg, 0.10 mmol) and 1-methyl-1H-pyrazol-3-amine (29 mg, 0.30 mol) in toluene (3 mL) was added trimethylaluminum (2 M solution in toluene, 0.3 mL, 0.6 mmol) at room temperature. The reaction mixture was irradiated in a microwave reactor at 150° C. for 1 hour, whereupon it was partitioned between water (20 mL) and ethyl acetate (50 mL). The organic layer was washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via reversed phase HPLC (Column: Agella Venusil ASB-C18, 5 μm; Mobile phase A: 0.225% formic acid in water; Mobile phase B: 0.225% formic acid in acetonitrile; Gradient: 33% to 63% B) afforded the product as a yellow solid. Yield: 2.0 mg, 5.4 μmol, 5%. LCMS m/z 371.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.47 (br d, J=4.6 Hz, 1H), 8.32 (br d, J=8 Hz, 1H), 7.69 (dd, J=8, 8 Hz, 1H), 7.48-7.56 (m, 3H), 7.35 (br d, J=8 Hz, 1H), 6.52-6.55 (m, 1H), 3.83 (s, 3H).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C@@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]([NH:15][CH2:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O.NN>CCO>[C:26]1([CH2:25][C@@H:12]([C:13]2[O:24][C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][N:15]=2)[NH2:3])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(CNC(=O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O)c1ccccc1
Agent: NN
Solvent: CCO
Product: N[C@@H](Cc1ccccc1)c1ncc(-c2ccccc2)o1
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of the product from Example 48 Part B (160 mg, 0.4 mmol) in EtOH (10 mL) was added to hydrazine (39 mg, 1.2 mmol). The reaction mixture was refluxed for 2 h. It was cooled to rt. EtOH was removed under vacuum. The residue was re-dissolved in dichloromethane. The undissolved solid was removed by filtration. The filtrate was concentrated to yield 95 mg of the product as a yellow solid (90% yield). MS 265.1 (M+H)+.
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])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]([OH:28])=O)=[CH:21][CH:20]=[CH:19]2.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[C:32]([NH2:37])[CH:31]=1>>[NH2:37][C:32]1[CH:31]=[C:30]([Br:29])[CH:35]=[CH:34][C:33]=1[NH:36][C:26]([C:22]1[C:23]2[C:24](=[CH:25][C:16]([O:15][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)[N:9]=[CH:8][N:7]=3)=[CH:17][CH:18]=2)[CH:19]=[CH:20][CH:21]=1)=[O:28]
Reactant: COc1cc2ncnc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Reactant: Nc1ccc(Br)cc1N
Product: COc1cc2ncnc(Oc3ccc4c(C(=O)Nc5ccc(Br)cc5N)cccc4c3)c2cc1OC
Yield: 77 %

Procedure:
The title compound (42.0 mg, 77% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthoic acid (37.6 mg, 0.1 mmol) and 4-bromo-o-phenylenediamine (22.4 mg, 0.12 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 4.01 (s, 6H, 2×OCH3), 5.31 (s, 2H, benzene-NH2), 6.77 (d, J=8.3 Hz, 1H, Ar—H), 7.01 (s, 1H, Ar—H), 7.41 (s, 1H, Ar—H), 7.58-7.65 (m, 5H, Ar—H), 7.89 (d, J=7.0 Hz, 1H, Ar—H), 8.00 (s, 1H, Ar—H), 8.14 (d, J=10.2 Hz, 1H, Ar—H), 8.37 (d, J=9.1 Hz, 1H, Ar—H), 8.54 (s, 1H, Ar—H), 9.84 (s, 1H, benzene-NH). LC-MS (m/z) 545 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:14]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: BrCCc1ccccc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(O)c1ccc(NCCc2ccccc2)cc1
Temperature: -20 °C

Procedure:
A mixture of 16.5 g. of ethyl p-aminobenzoate, 10.3 g. of (2-bromoethyl)benzene and 50 ml. of hexamethylphosphoramide is heated in an oil bath at 115°-120° C. for 17 hours. The mixture is put into ice and water and extracted with ether. The ether extracts are washed with water, dried over magnesium sulfate and concentrated in vacuo to an oil. The oil is combined with 200 ml. of ethanol-water (9:1) and 20 g. of potassium hydroxide and the mixture is refluxed for 3.5 hours. After chilling the mixture is made acidic with concentrated hydrochloric acid, diluted with 150 ml. of water, chilled, diluted with water and extracted with chloroform. The chloroform extracts are washed with water, dried over magnesium sulfate and concentrated in vacuo to a gum. Ethanol is added, the mixture is chilled and filtered to give yellow crystals. The mother liquors are chilled at -20° C. to give a second crop of crystals. Recrystallization of the combined crops of crystals from hexane-ethanol gives yellow crystals, m.p. 123°- 125° C. Recrystallization from ethanol gives pale yellow crystals, m.p. 124°-126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:19]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(S(C)(=O)=O)ccc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2-chloro-5-(methylsulfonyl)benzoic acid (4 g, 0.016 mol) was dissolved in MeOH (10 ml) and thionyl chloride (1 ml) was added. The reaction was stirred for 72 h at RT. Solvents were evaporated and crude solid was dissolved in DCM and washed with saturated aqueous solution of NaHCO3. The organic solvent was dried (Na2SO4) and evaporated to obtain 0.88 g of the title compound as white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:12])[CH3:2].[C:13](Cl)(=[O:16])[CH2:14][CH3:15]>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:12])[CH3:2]
Reactant: CCN1C(=O)Cc2ccccc21
Reactant: CCC(=O)Cl
Product: CCC(=O)c1ccc2c(c1)CC(=O)N2CC

Procedure:
Prepared from readily available starting materials (N-ethyloxindole and propionyl chloride) in a manner analogous to that set forth in Preparation 18.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C:7]([CH3:22])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][O:17]S(C)(=O)=O)[N:14]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]([F:39])([F:38])[C:26]1[CH:27]=[C:28]([N:32]2[CH:36]=[C:35](O)[CH:34]=[N:33]2)[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:23])[C:7]([CH3:8])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][O:17][C:35]2[CH:34]=[N:33][N:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:38])([F:39])[F:24])[CH:27]=3)[CH:36]=2)[N:14]=1)[CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: Oc1cnn(-c2cccc(C(F)(F)F)c2)c1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOS(C)(=O)=O)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2cnn(-c3cccc(C(F)(F)F)c3)c2)cs1
Temperature: 85 °C
Reaction time: 3 h
Yield: 29.7 %

Procedure:
2-Methyl-2-[(4-{2-[(methylsulfonyl)oxy]ethyl}-1,3-thiazol-2-yl)thio]propionic acid tert-butyl ester (1.0 g) synthesized in Example 5 and 1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-4-ol (600 mg) were dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (363 mg) was added, and the mixture was stirred at 85° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 4:1) to give the title compound (400 mg) as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)C>[CH2:13]1[CH:14]2[N:10]([CH2:2][CH:3]=[C:4]([C:3]3[C:4]4[C:9](=[CH:8][N:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:5]2)[CH2:11][CH2:12]1
Reactant: C1CCNC1
Reactant: c1cc2cc[nH]c2cn1
Solvent: CCO
Product: C1=C(c2c[nH]c3cnccc23)CC2CCCN2C1

Procedure:
from 6-azaindole (250 mg, 2.1 mmol), 1,2,3,5,6,8,8a-heptahydrohydro-7-oxo-indolizine (324 mg, 2.3 mmol) and pyrrolidine (1.2 g, 16.9 mmol) in ethanol (2 mL) heating at reflux for 6 hrs.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=[C:4]([CH3:24])[N:3]=1.Cl.[NH2:26][OH:27].C([O-])(O)=O.[Na+]>>[CH3:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:26]/[OH:27])/[CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=[C:4]([CH3:24])[N:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2ccccc2)c2ccccn2)cc(C)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(CC(c2ccccc2)c2ccccn2)=N/O)cc(C)n1

Procedure:
In analogy to example 1, step 2, from 1-(2,6-dimethyl-pyridin-4-yl)-3-phenyl-3-pyridin-2-yl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a light yellow foam, MS (ESI+): m/z=332.3 ([M+H]+).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]([CH:9]([CH3:11])[CH3:10])[CH:7]=[N:6][C:5]=1[CH3:12].[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:13][C:14]1[N:19]=[C:18]([S:20][CH2:3][C:4]2[N:8]([CH:9]([CH3:11])[CH3:10])[CH:7]=[N:6][C:5]=2[CH3:12])[N:17]=[C:16]([OH:21])[CH:15]=1
Reactant: Cc1ncn(C(C)C)c1CCl
Reactant: Cc1cc(O)nc(S)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(O)nc(SCc2c(C)ncn2C(C)C)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 19.8 %

Procedure:
A mixture of 5-(chloromethyl)-4-methyl-1-(propan-2-yl)-1H-imidazole hydrochloride (824 g, 3.9 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (970 mg, 7.0 mmol), and potassium carbonate (1.2 g, 9.0 mmol) in acetone (30 mL) was stirred at room temperature for 2 days. The solid material was removed by filtration. The filtrate was recovered and evaporated. The crude product was purified by flash chromatography (0-8% MeOH/DCM), affording 6-methyl-2-({[4-methyl-1-(propan-2-yl)-1H-imidazol-5-yl]methyl}-sulfanyl)pyrimidin-4-ol (215 mg, 28% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.36 (d, 3H, J=6.7 Hz), 2.09 (s, 3H), 2.19 (s, 3H), 4.31 (m, 1H), 4.45 (s, 2H), 6.00 (s, 1H), 7.66 (s, 1H); M+279. The product was used without further purification.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:14][N:15]([CH3:29])[C:16]([C:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]=1[CH2:27][CH3:28])=[O:17])[CH:8]=[CH:7]2>C(O)(=O)C>[Br:1][C:5]1[C:4]([OH:3])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([CH2:14][N:15]([CH3:29])[C:16]([C:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]=1[CH2:27][CH3:28])=[O:17])=[CH:10]2
Reactant: BrBr
Reactant: CCc1oc2ccccc2c1C(=O)N(C)Cc1ccc2cc(O)ccc2c1
Solvent: CC(=O)O
Product: CCc1oc2ccccc2c1C(=O)N(C)Cc1ccc2c(Br)c(O)ccc2c1
Reaction time: 8 h
Yield: 95 %

Procedure:
A solution of bromine in 50 mL glacial acetic acid was added dropwise under nitrogen over 3 h to a solution of 2-ethyl-benzofuran-3-carboxylic acid (6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (1.5 g, 4.17 mmol), prepared in the previous step, in 150 mL glacial acetic acid at room temperature. The reaction stirred for 17 h (overnight). The solvent was removed under reduced pressure. The residue was dissolved in methylene chloride, extracted with 5% sodium bicarbonate, dried (MgSO4) and solvent removed under reduced pressure to give 2-ethyl-benzofuran-3-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (1.74 g, 95%) as a brown solid, mp 176-178° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(N(CC)CC)C>C(Cl)(Cl)Cl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Reactant: CCOC(=O)CCCCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCCCCNc1c([N+](=O)[O-])cnc2cccnc12
Temperature: 0 °C

Procedure:
A suspension of 4-chloro-3-nitro[1,5]naphthyridine (9.0 g, 42.9 mmol) in chloroform (180 mL) was cooled to approximately 0° C. Ethyl 6-aminohexanoate hydrochloride (12.6 g, 64.4 mmol) and triethylamine (16.6 mL, 119 mmol) were sequentially added with stirring, and the reaction was stirred for 15 minutes. The mixture was diluted with chloroform (180 mL), washed with 1% aqueous sodium carbonate (3×125 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide ethyl 6-(3-nitro[1,5]naphthyridin-4-ylamino)hexanoate as a yellow oil.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:35]=[C:34]3[C:30]([C:31]([NH:44][C:45](=[O:49])[CH2:46][CH2:47][CH3:48])=[N:32][N:33]3COCC[Si](C)(C)C)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)#[N:20]>O1CCCC1.C(OCC)(=O)C>[C:19]([C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:35]=[C:34]3[C:30]([C:31]([NH:44][C:45](=[O:49])[CH2:46][CH2:47][CH3:48])=[N:32][NH:33]3)=[CH:29][CH:28]=2)=[CH:25][CH:26]=1)#[N:20]
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(C#N)cc3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(C#N)cc3)ccc12
Yield: 42.8 %

Procedure:
3.0 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 400 mg of N-[6-(4-cyanophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 10 cm3 of tetrahydrofuran, and the mixture is refluxed for 18 hours. The reaction medium is diluted with 20 cm3 of ethyl acetate and the organic phase is washed successively with 20 cm3 of saturated sodium hydrogen carbonate solution, with 2×20 cm3 of water and with 20 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and then concentrated under reduced pressure (2 kPa; 50° C.). The crude product obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3 cm), eluting with a methylene chloride/methanol gradient (100/0 to 98/2 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); 120 mg of N-[6-(4-cyanophenyl)-1H-indazol-3-yl]butanamide are obtained in the form of a solid melting at 242° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH:10]=1.[CH2:27]([N:29]([CH2:44][CH3:45])[CH2:30][CH2:31][N:32]([CH2:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](O)=[O:39])[CH3:33])[CH3:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:38](=[O:39])[C:37]2[CH:41]=[CH:42][CH:43]=[C:35]([CH2:34][N:32]([CH2:31][CH2:30][N:29]([CH2:44][CH3:45])[CH2:27][CH3:28])[CH3:33])[CH:36]=2)=[C:3]([C:9]2[CH:10]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:24])[F:26])[CH:18]=3)[N:12]=[CH:13][N:14]=2)[CH:4]=1
Reactant: CCN(CC)CCN(C)Cc1cccc(C(=O)O)c1
Reactant: Nc1ccc(Cl)cc1-c1cc(NCc2cccc(C(F)(F)F)c2)ncn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCN(C)Cc1cccc(C(=O)Nc2ccc(Cl)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ncn2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 11.8 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 6-(2-amino-5-chlorophenyl)-N-(3-(trifluoromethyl)benzyl)pyrimidin-4-amine 65b (200 mg, 0.53 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), 3-(((2-(diethylamino)ethyl)(methyl)amino)methyl)benzoic acid (130 mg, 0.49 mmol, 1.00 equiv), HATU (300 mg, 0.79 mmol, 1.50 equiv), and N,N-diisopropylethylamine (270 mg, 2.09 mmol, 5.00 equiv). The resulting solution was stirred for 2 days at 25° C. in an oil bath. The reaction was then quenched with 50 mL of water. The resulting solution was extracted with 2×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×50 mL of saturated NH4Cl, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 36.1 mg (9%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 8.73 (s, 1H), 8.60 (d, J=9.3 Hz, 1H), 8.41 (s, 1H), 8.19 (m, 1H), 7.92 (m, 3H), 7.64 (m, 7H), 7.14 (s, 1H), 4.73 (d, J=5.7 Hz, 2H), 3.35 (s, 2H), 3.14 (d, J=6.9 Hz, 4H), 1.18 (t, J=7.2 Hz, 6H). MS (ES, m/z): 625 [M+H]+.