Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.[Se](=O)=O.[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].C(N(CC)CC)C>C(O)C>[CH3:13][S:12][C:4]1[N:3]=[C:2](/[CH:1]=[C:21]2/[C:20](=[O:22])[NH:19][C:18](=[O:23])[S:17]/2)[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[N:5]=1
Reactant: O=C1CSC(=O)N1
Reactant: CSc1nc(C)cc(C(F)(F)F)n1
Agent: O=[Se]=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CSc1nc(/C=C2\SC(=O)NC2=O)cc(C(F)(F)F)n1
Temperature: 90 °C
Reaction time: 40 h
Yield: 27.5 %

Procedure:
A 30 mL round-bottomed vial was charged with 4-methyl-2-(methylthio)-6-(trifluoromethyl)pyrimidine (0.500 g, 2.4 mmol, 1 equiv.), ethanol (5 mL, 0.48 M), selenium dioxide (0.293 mg, 2.6 mmol, 1.1 equiv.), and the reaction mixture was shaken at 90° C. for 40 h and then RT for 14 d. The crude reaction mixture was then treated with thiazolidine-2,4-dione (0.281 g, 2.4 mmol, 1 equiv.), triethylamine (1.0 mL, 7.20 mmol, 3 equiv.) and the reaction mixture was shaken for 16 h at 80° C. The solvent was concentrated under reduced pressure and the residue was partitioned between EtOAc (30 mL) and saturated NaHCO3 (25 mL). The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified using the Biotage (SiO2, 10 g cartridge, CH2Cl2/MeOH 99:1 to 9:1) that afforded 270 mg of partially purified product that was re-purified using the Biotage (SiO2, 10 g cartridge, Hexanes/EtOAc 90:10 to 0:1 then CH2Cl2/MeOH 99:1 to 9:1) afforded 212 mg of yellow solid that was still not completely pure but was used directly in the next step without further purification.
Reaction SMILES: [OH:1]O.[Br:3][C:4]1[C:13](B(O)O)=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:17][CH3:18])[CH:10]=2)[N:5]=1.[NH4+].[Cl-]>CCOCC.O>[Br:3][C:4]1[C:13]([OH:1])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:17][CH3:18])[CH:10]=2)[N:5]=1
Reactant: COc1ccc2nc(Br)c(B(O)O)cc2c1
Reactant: OO
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: COc1ccc2nc(Br)c(O)cc2c1
Reaction time: 13 h
Yield: 100 %

Procedure:
Aqueous H2O2 (30%, 32.8 mL, 321 mmol) was added dropwise to a stirred solution of (2-bromo-6-methoxyquinolin-3-yl)boronic acid (4.64 g, 16.45 mmol) and NH4Cl (3.29 g, 61.5 mmol) in Et2O (82 mL) and water (82 mL). After 13 h, NH4Cl (3.29 g, 61.5 mmol) and aqueous H2O2 (30%, 32.8 mL, 321 mmol) were added, and the mixture was stirred for 48 h. The precipitate was collected and washed with water, then dried at 50° C. to afford the title compound (4.18 g, 100%) as a solid that was used directly in the subsequent step. LCMS (ES+) m/z 254, 256 (M+H)+,
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]2)=[CH:4][CH:3]=1.[C:21]1([CH3:30])[C:22]([C:27](Cl)=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1.C(N(CC)CC)C>C(Cl)Cl>[F:18][C:17]([F:20])([F:19])[C:10]1[CH:11]=[C:12]([C:13]([F:14])([F:15])[F:16])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:27](=[O:28])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:30])=[CH:7][CH:6]=2)[N:9]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Reaction time: 72 h
Yield: 46.3 %

Procedure:
A mixture of 1-(4′-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole (0.10 g, 0.34 mmol), o-toluoyl chloride (0.062 mL, 0.43 mmol), and triethylamine (0.06 mL, 0.43 mmol) in methylene chloride (7 mL) was stirred under argon for three days. The reaction mixture was diluted with methylene chloride, washed with 1N hydrochloric acid (2×50 mL), brine (2×40 mL), dried (magnesium sulfate) and concentrated to give an off-white solid. Recrystallization from methylene chloride/hexanes gave the above-named compound (0.065 g). m.p. 175° C. NMR (CDCl3, 400 MHz): δ 7.83 (d, 2H), 7.64 (br s, 1H), 7.53 (m, 3H), 7.43 (m, 1H), 7.31 (m, 2H), 7.10 (s, 1H), 2.56 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:12][CH2:13][CH3:14])[N:8]=[CH:7][N:6]=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21](=[S:30])[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]1.N1C=CC=C[CH:32]=1.C(Cl)(=O)C(Cl)=O.[Cl-].[Na+]>CN(C)C=O.O>[CH2:23]([NH:22][C:21]([N:18]1[CH2:19][CH2:20][N:15]([C:5]2[C:4]3[CH:3]=[C:2]4[N:1]=[CH:32][N:12]([CH2:13][CH3:14])[C:11]4=[CH:10][C:9]=3[N:8]=[CH:7][N:6]=2)[CH2:16][CH2:17]1)=[S:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: c1ccncc1
Reactant: CCNc1cc2ncnc(N3CCN(C(=S)NCc4ccccc4)CC3)c2cc1N
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1cnc2cc3c(N4CCN(C(=S)NCc5ccccc5)CC4)ncnc3cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of 504.4 mg (1.20 mmol) of 4-(6-amino-7-ethylamino-4-quinazolinyl)-N-benzyl-1-piperazinethiocarboxamide obtained in Example 461 in 10 ml of dimethylformamide were added 0.29 ml (3.60 mmol) of pyridine and 0.13 ml (1.49 mmol) of oxalyl chloride under ice-cooling, followed by overnight stirring at room temperature in an atmosphere of argon. Then, the resulting mixture was heated at 80° C. with stirring for 5 hours. The reaction mixture was allowed to cool to room temperature and then poured into water, and sodium chloride was added thereto. The precipitated crystals were collected by filtration, washed with water, and dried, followed by purification by silica gel chromatography to give the desired compound as colorless crystals.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[CH:17]=[C:16]([CH:18]=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[C:9]1=[O:21])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH:28]1([NH:31][C:32](=[O:50])[C:33]2[CH:38]=[C:37](B3OC(C)(C)C(C)(C)O3)[C:36]([CH3:48])=[C:35]([F:49])[CH:34]=2)[CH2:30][CH2:29]1>CN(C=O)C.O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[CH:17]=[C:16]([CH:18]=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:37]3[CH:38]=[C:33]([C:32](=[O:50])[NH:31][CH:28]4[CH2:29][CH2:30]4)[CH:34]=[C:35]([F:49])[C:36]=3[CH3:48])[CH:14]=2)[C:9]1=[O:21])(=[O:3])[CH3:2]
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(=O)OCCCn1cc(C=O)c2cc(Br)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCCn1cc(C=O)c2cc(-c3cc(C(=O)NC4CC4)cc(F)c3C)ccc2c1=O

Procedure:
3-(6-Bromo-4-formyl-1-oxoisoquinolin-2(1H)-yl)propyl acetate (Example 10c, 0.90 g), potassium carbonate (1.06 g), N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.82 g) and Pd-118 (0.050 g) in DMF (10 ml) were heated under nitrogen at 70° C. for 12 h. The cooled reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified (SiO2 chromatography, elution with ethyl acetate) to afford the subtitle compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[CH3:13])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1Cl.CC(C)([O-])C.[K+].CN(C)C(=O)C.[CH3:31][N:32]1[CH:36]=[CH:35][C:34]([NH:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([OH:48])[CH:46]=3)[N:41]=[CH:40][N:39]=2)=[N:33]1>O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[CH3:13])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[O:48][C:45]1[CH:46]=[C:47]2[C:42](=[CH:43][CH:44]=1)[N:41]=[CH:40][N:39]=[C:38]2[NH:37][C:34]1[CH:35]=[CH:36][N:32]([CH3:31])[N:33]=1
Reactant: CN(C)CCN(C)S(=O)(=O)c1cnc(Cl)c(Cl)c1
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C)CCN(C)S(=O)(=O)c1cnc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)c(Cl)c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 59.9 %

Procedure:
5,6-Dichloro-N-[2-(dimethylamino)ethyl]-N-methylpyridine-3-sulfonamide (104 mg, 0.33 mmol) and potassium tert-butoxide (58 mg, 0.52 mmol) were added to an N,N-dimethylacetamide solution (1 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (50 mg, 0.21 mmol), and stirred under a nitrogen atmosphere at 100° C. for 2.5 hours. The reaction solution was cooled with ice, saline water was added, and extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Biotage NH, hexane:ethyl acetate:chloroform=2:5:1 to 2:5:2) to obtain the entitled compound (65 mg, yield: 61%) as a pale orange amorphous solid.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[F:19][C:20]1[CH:21]=[C:22]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:23][NH:24][C:25](=[O:32])[C:26]([CH3:31])([CH3:30])[C:27](O)=[O:28]>>[F:19][C:20]1[CH:21]=[C:22]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:23][NH:24][C:25](=[O:32])[C:26]([CH3:31])([CH3:30])[C:27]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:28]
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Reactant: CC(C)(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Product: CN1C(=O)C(NC(=O)C(C)(C)C(=O)NCc2cc(F)cc(F)c2)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=478.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,5-difluoro-benzyl)-2,2-dimethyl-malonamic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([O:8][CH2:9][CH:10]([CH2:15][CH3:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:7])=[CH:4][CH:3]=1.Cl[C:20](Cl)(Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:15]([CH:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:20](=[N:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH:10]([CH2:15][CH3:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:7])=[CH:17][CH:18]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=1)=[O:7])[CH3:16]
Reactant: CCCCC(CC)COC(=O)c1ccc(N)cc1
Reactant: ClC(Cl)(Cl)c1ccccc1
Product: CCCCC(CC)COC(=O)c1ccc(N=C(Nc2ccc(C(=O)OCC(CC)CCCC)cc2)c2ccccc2)cc1

Procedure:
N,N'-Bis[4-(2-ethylhexyl)oxycarbonylphenyl]benzamidine (3) was prepared from 2-ethylhexyl 4-aminobenzoate and α,α,α-trichlorotoluene; viscous, gold oil: 1H-NMR (CDCl3) 7.9-6.8 (m, 14H), 4.1 (d, 4H, J=4 Hz), 1.9-0.8 (m, 30H); IR (Neat) 3330, 1710, 1585; MS (m/e) 584 (M+), 336 (base).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][CH:3]=1.[CH:14]1([CH2:17][NH:18][C:19](=[O:36])[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:21]=2)[CH2:16]C1>CC(O)C>[CH:17]1([NH:18][C:19]([C:20]2[CH:21]=[C:22]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)=[CH:4][CH:3]=3)[C:23]([CH3:26])=[CH:24][CH:25]=2)=[O:36])[CH2:14][CH2:16]1
Reactant: Cc1nnc(-c2ccc(I)cc2)o1
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Solvent: CC(C)O
Product: Cc1nnc(-c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc2)o1

Procedure:
Example 39 was prepared using 2-(4-iodophenyl)-5-methyl-[1,3,4]oxadiazole (Intermediate 15) and N-cyclopropyl-4methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 17) with propan-2-ol as the solvent.
Reaction SMILES: [Na].[CH3:2]CN(C(C)C)C(C)C.[OH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[O:13].[F:18][C:19]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:20]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[N:33]=[C:32]3[CH2:34][NH:35][CH2:36][CH2:37][C:31]3=[N:30][C:29]=2[NH:38][CH:39]([CH3:41])[CH3:40])[CH2:24][CH2:23]1.C=O>CO>[F:18][C:19]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:20]=1[O:21][CH:22]1[CH2:23][CH2:24][N:25]([C:28]2[N:33]=[C:32]3[CH2:34][N:35]([CH3:2])[CH2:36][CH2:37][C:31]3=[N:30][C:29]=2[NH:38][CH:39]([CH3:41])[CH3:40])[CH2:26][CH2:27]1.[C:12]([OH:13])([C:14]([F:17])([F:16])[F:15])=[O:11]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Agent: C=O
Agent: [Na]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CN(C)CC2
Reaction time: 0.5 h

Procedure:
Sodium triacetoxyhydroborate (12.3 mg, 0.058 mmol) was added to a solution of DIPEA (10 μL, 0.058 mmol), 3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (15.0 mg, 0.029 mmol) and formaldehyde (2 μL, 0.029 mmol) in MeOH (290 μL) at rt. After 30 min, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (12.3 mg, 80%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.25 (d, J=6.6 Hz, 6H), 1.90-2.00 (m, 2H), 2.07-2.16 (m, 2H), 2.96-3.05 (m, 3H), 3.08 (br s, 4H), 3.33-3.42 (m, 2H), 3.43-3.85 (m, 2H), 4.14-4.38 (m, 3H), 4.44-4.51 (m, 1H), 6.84-6.91 (m, 1H), 6.95-7.02 (m, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 418.3.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14][CH2:15][C@H:16]([NH:27]C(OC(C)(C)C)=O)[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:27][C@@H:16]([CH2:15][S:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CSCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of 0.50 g (1.023 mmol) of benzyl (R)-3-(2-benzyloxycarbonylaminoethyl-sulfanyl)-2-tert-butoxycarbonylaminopropionate in 5 ml of dichloromethane was mixed with the same volume of trifluoroacetic acid and left to stand at RT for 1 h. It was then concentrated and directly reacted further.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](SCC)=[CH:6][C:5]2=[O:15].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[CH:6][C:5]2=[O:15]
Reactant: C1COCCN1
Reactant: CCSc1cc(=O)c2cc(Br)ccc2o1
Product: O=c1cc(N2CCOCC2)oc2ccc(Br)cc12

Procedure:
Prepared from 6-Bromo-2-ethylsulfanyl-chromen-4-one (0.375 g, 1.35 mmol) and morpholine (0.54 ml, 6.25 mmol), affording a pale yellow solid. (0354 g, 1.14 mmol, 84%); m.p. 147-149° C.; ES+(m/e)=310.24 (M++1); (200 MHz, CDCl3) δ 3.44 (4H, m); 3.77 (4H, m); 5.42 (1H, s); 7.11 (1H, d); 7.57 (1H, dd); 8.20 (1H, d)
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2.[ClH:16]>C(O)(=O)C>[Cl:16][CH2:15][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2
Reactant: Cl
Reactant: Cc1cc(OCC2CO2)c2cn[nH]c2c1
Solvent: CC(=O)O
Product: Cc1cc(OCC(O)CCl)c2cn[nH]c2c1
Reaction time: 1 h

Procedure:
A solution of 2.7 g. 4-(2,3-epoxypropoxy)-6-methylindazole in 10 ml. glacial acetic acid is introduced, while stirring, into 10 ml. glacial acetic acid which has been saturated with hydrogen chloride at ambient temperature. After 1 hour at ambient temperature, the reaction mixture is poured into 300 ml. water and neutralised with sodium bicarbonate, a viscous oil thereby separating out, which solidifies after stirring for a comparatively long time or upon triturating with toluene. When recrystallized from toluene, with the use of fullers' earth, there is obtained 4-(3-chloro-2-hydroxypropoxy)-6-methyl-indazole in the form of colorless needles; m.p. 171°-172° C.
Reaction SMILES: CN(C=O)C.[C:6]1([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH2:21][NH:22][C:23]4[CH:24]=[CH:25][N:26]=[C:27]5[C:32]=4[N:31]=[CH:30][C:29]([OH:33])=[CH:28]5)=[N:19][N:20]=3)[N:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[C:35]([F:40])([F:39])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>O>[F:39][CH:35]([F:40])[O:33][C:29]1[CH:28]=[C:27]2[C:32]([C:23]([NH:22][CH2:21][C:18]3[N:16]4[N:17]=[C:12]([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=5)[CH:13]=[CH:14][C:15]4=[N:20][N:19]=3)=[CH:24][CH:25]=[N:26]2)=[N:31][CH:30]=1
Reactant: Oc1cnc2c(NCc3nnc4ccc(-c5ccccc5)nn34)ccnc2c1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)Oc1cnc2c(NCc3nnc4ccc(-c5ccccc5)nn34)ccnc2c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 17.7 %

Procedure:
DMF (0.5 mL) and water (0.1 mL) were added to a pressure vessel containing 8-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-ol (50 mg, 135 μmol), sodium 2-chloro-2,2-difluoroacetate (47 mg, 311 μmol), cesium carbonate (62 mg, 190 μmol). The reaction mixture was stirred at 100° C. for 18 h, cooled to RT and concentrated in vacuo. Purification by MPLC (DCM/MeOH+1% NH4OH: 100/0 to 90/10) afforded the title compound (10 mg, 17% yield). MS m/z=420.1 [M+H]+. Calc'd for C, 21; H, 15; F, 2; N, 7O, : 419.40.
Reaction SMILES: [ClH:1].[CH2:2]([C:5]1[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=1)[C:3]#[CH:4].[N:11]([CH2:14][C:15]([CH3:23])=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N+:12]=[N-:13]>>[ClH:1].[CH3:23][C:15](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:14][N:11]1[CH:4]=[C:3]([CH2:2][C:5]2[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=2)[N:13]=[N:12]1
Reactant: C#CCc1c[nH]c(N)n1
Reactant: CC(=Cc1ccccc1)CN=[N+]=[N-]
Agent: Cl
Product: CC(=Cc1ccccc1)Cn1cc(Cc2c[nH]c(N)n2)nn1
Yield: 91.2 %

Procedure:
4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.127 g, 0.809 mmol) was reacted with (3-Azido-2-methyl-propenyl)-benzene (0.168 g, 0.971 mmol) following the general procedure for click reactions outlined above to produce 4-[1-(2-Methyl-3-phenyl-allyl)-1H[1,2,3]triazol-4-ylmethyl]-1H-imidazol-2-ylamine hydrochloride (0.244 g, 91%) of a pale yellow solid. 1H NMR (300 MHz, D2O) δ 7.94 (s, 1H), δ 7.40-7.35 (m, 5H), δ 6.56 (s, 1H), δ 5.10 (s, 2H), δ 3.99 (s, 2H), δ 1.76 (s, 3H) ppm; 13C δ 145.8, 138.1, 136.9, 136.5, 136.4, 132.8, 128.3, 128.0, 127.6, 125.3, 123.4, 49.3, 23.8, 23.4; HRMS (ESI) calcd for C16H18N6 (M+) 295.1665, found 295.1665.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:33])([CH3:32])[C:13]([NH:15][C@H:16]1[C:22](=[O:23])[NH:21][C:20]2[CH:24]=[CH:25][C:26]3[C:31]([C:19]=2[CH2:18][CH2:17]1)=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:36]([O:40][C:41]([NH:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[C:51]1[CH:56]=[CH:55][C:54]([CH2:57]O)=[CH:53][CH:52]=1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:33])([CH3:32])[C:13]([NH:15][C@H:16]1[C:22](=[O:23])[NH:21][C:20]2[CH:24]=[CH:25][C:26]3[C:31]([C:19]=2[CH:18]([CH2:57][C:54]2[CH:53]=[CH:52][C:51]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=4[CH2:44][NH:43][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:42])=[CH:56][CH:55]=2)[CH2:17]1)=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO)cc1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2c(ccc3ccccc23)NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CC2C[C@@H](NC(=O)C(C)(C)NC(=O)OCc3ccccc3)C(=O)Nc3ccc4ccccc4c32)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 2-benzyloxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]prop-anamide (Step A) in dry dimethylformamide under nitrogen at 0° C. is added of 60% sodium hydride/oil dispersion (1.05 eq.). After stirring for 15 minutes, a solution of 2′-[(t-butoxycarbonylamino)methyl]-1,1′-biphenyl-4-methanol, methanesulfonate ester (Step F) in dimethylformamide is added by cannula. The flask which originally contained the methanesulfonate ester is rinsed with dimethylformamide which is added to the reaction mixture. After stirring at 0° C. for 15 minutes, the reaction mixture is diluted with ethyl acetate and 50% saturated ammonium chloride. The mixture is transferred to a separatory funnel and the aqueous layer is separated. The organic layer is washed with 100 mL of saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer is dried over magnesium sulfate, filtered and the solvent removed under vacuum. The residue is purified by flash chromatography on silica gel eluting with ethyl acetate/hexane to afford the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][O:64][CH2:65][C@@H:66]1[CH2:70][CH2:69][CH2:68][NH:67]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:67]1[CH2:68][CH2:69][CH2:70][C@H:66]1[CH2:65][O:64][CH3:63])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: COC[C@@H]1CCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@@H]1CCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (S)-2-methoxymethyl-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[CH:14][O:13][CH:12]=2)=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17])(=O)[CH3:2].I[C:20]1[CH:21]=[C:22](C=C[CH:28]=1)[C:23]([OH:25])=[O:24].C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[C:23]([C:22]1[CH:2]=[C:1]([NH:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH:15]=[CH:14][O:13][CH:12]=3)=[CH:7][C:6]=2[N+:16]([O-:18])=[O:17])[CH:28]=[CH:20][CH:21]=1)([OH:25])=[O:24]
Reactant: O=C(O)c1cccc(I)c1
Reactant: CC(=O)Nc1ccc(-c2ccoc2)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(O)c1cccc(Nc2ccc(-c3ccoc3)cc2[N+](=O)[O-])c1

Procedure:
A mixture of 1e from Example 19 (5 g, 24.5 mmol), 3-iodobenzoic acid (6.69 g, 27 mmol), potassium carbonate (3.79 g, 27.5 mmol) and a catalytic amount of copper-bronze in 30 ml dry N-methyl-2-pyrrolidone is heated to 180° C. overnight. After cooling water is added and the mixture is washed twice with ethyl acetate. The aqueous phase is rendered acidic with diluted hydrochloric acid and the oily precipitate is filtered off. This precipitate is extracted with ethyl acetate, and the extract is purified by column-chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (1:1) as the eluent. Yield: 2.56 g (32%). Mp 203-205° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=2)[N:4]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(O)C>ClCCl>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=3)[N:4]=[C:3]([CH2:2][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[N:12]=2)[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: C1CCNCC1
Reactant: COc1ccc(-c2nc(CCl)nc3cc(OC)c(OC)cc23)cc1OC
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(-c2nc(CN3CCCCC3)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.6 %

Procedure:
A mixture of 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline (2.0 g), piperidine (2.27 g) and ethanol (40 ml)-dichloromethane (10 ml) was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and dichloromethane (50 ml) was added to the residue. The dichloromethane layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-ethyl acetate (1/1, v/v) gave 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-piperidinomethylquinazoline (1.46 g, 65%) which was then recrystallized from ethyl acetate-hexane. Colorless needles. mp. 130°-132° C.