Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:9][O:8][C:7]2[C:3](=[C:4](C(O)=O)[S:5][C:6]=2C(O)=O)[O:2]1>C(=O)([O-])[O-].[Cu+2].CN(C=O)C>[CH2:1]1[CH2:9][O:8][C:7]2[C:3](=[CH:4][S:5][CH:6]=2)[O:2]1
Reactant: O=C(O)c1sc(C(=O)O)c2c1OCCO2
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: c1scc2c1OCCO2
Temperature: 120 °C
Yield: 95.7 %

Procedure:
3,4-Ethylenedioxythiophene-2,5-dicarboxylic acid (230 g) and basic copper carbonate (23 g) were added to DMF (600 g) at room temperature. While air was slowly introduced to the reaction mixture, it as heated at 120° C. for 5 hours. After cooling, the reaction mixture was purified using the same process as described in Example 1 to obtain 3,4-ethylenedioxythiophene (136 g, purity: 97%).
Reaction SMILES: [OH-].[Na+].[CH:3]1([N:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4([C:26]([O:28]CC)=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.Cl>O1CCOCC1.O>[CH:3]1([N:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4([C:26]([OH:28])=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C1(c2ccc(OC3CCN(C4CCC4)CC3)cc2)CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C1(c2ccc(OC3CCN(C4CCC4)CC3)cc2)CCOCC1

Procedure:
Sodium hydroxide (200 mg, 5 mmol) was added to a solution of ethyl 4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-carboxylate (870 mg, 2.25 mmol) in dioxane (10 ml) and water (2 ml). The reaction mixture was heated to reflux for 16 hours under nitrogen. The reaction was not complete. More sodium hydroxide (190 mg, 4.75 mmol) in water (4 ml) was added and the reaction heated at reflux for 18 hours. 2N Hydrochloric acid (5 ml, 9.75 mmol) was added and the mixture concentrated in vacuo to a white powder (2.0 g) containing the title compound and sodium chloride. LRMS APCI+ m/z 360 [MH]+.
Reaction SMILES: [CH:1]1([C:6]2([CH2:26][CH2:27][C:28]3[CH:45]=[CH:44][C:31]([O:32][CH2:33][CH2:34][N:35](C)[C:36](=O)OC(C)(C)C)=[C:30]([CH2:46][CH3:47])[CH:29]=3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:13][C:14]3[N:24]=[C:17]4[N:18]=[C:19]([CH3:23])[CH:20]=[C:21]([CH3:22])[N:16]4[N:15]=3)[C:8](=[O:25])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2(CCC3C=CC(OCCNC(=O)OC(C)(C)C)=C(CC)C=3)CC(O)=C(CC3N=C4N=C(C)C=C(C)N4N=3)C(=O)O2)CCCC1>>[CH:1]1([C:6]2([CH2:26][CH2:27][C:28]3[CH:45]=[CH:44][C:31]([O:32][CH2:33][CH2:34][NH:35][CH3:36])=[C:30]([CH2:46][CH3:47])[CH:29]=3)[O:7][C:8](=[O:25])[C:9]([CH2:13][C:14]3[N:24]=[C:17]4[N:18]=[C:19]([CH3:23])[CH:20]=[C:21]([CH3:22])[N:16]4[N:15]=3)=[C:10]([OH:12])[CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)ccc1OCCN(C)C(=O)OC(C)(C)C
Agent: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)ccc1OCCNC(=O)OC(C)(C)C
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)ccc1OCCNC

Procedure:
The title compound was prepared analogously to example A(71) where tert-butyl 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-ethylphenoxy]ethyl(methyl)carbamate (Example A(69)) was substituted in place of tert-butyl 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-ethylphenoxy]ethylcarbamate in that example. 1H NMR (300 MHz, MeOD): δ 1.16 (t, J=8.54 Hz, 3H) 1.32-2.35 (m, 11H), 2.40 (s, 3H), 2.59-2.75 (m, 14H), 2.92 (t, J=16.54 Hz, 2H), 3.84 (t, J=7.54 Hz, 2H), 6.55 (d, J=2.08 Hz, 1H), 6.65 (d, J=2.56 Hz, 1H), 6.95 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[C:5]2[S:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].C(N(CC)CC)C.[NH2:29][CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[N:34]1[CH:35]=[CH:36][C:31]([CH2:30][NH:29][C:11]([C:6]2[NH:7][C:8]3[C:4]([C:5]=2[S:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[O:13])=[CH:32][CH:33]=1
Reactant: O=C(O)c1[nH]c2ccc(Cl)cc2c1S(=O)c1ccccc1
Reactant: NCc1ccncc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccncc1)c1[nH]c2ccc(Cl)cc2c1S(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 5-chloro-3-phenylsulfinylindole-2-carboxylic acid (0.096 g, 0.3 mmol), triethylamine (0.061 g, 0.6 mmol), 4-aminomethylpyridine (0.043 g, 0.4 mmol) in dry dimethylformamide was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) (0.155 g, 0.35 mmol). The mixture was stirred at room temperature under nitrogen for three days. Following evaporation, the residue was partitioned between ethyl acetate and water. The ethyl acetate phase was separated and washed with dilute hydrochloric acid. The acidic extract was neutralized with aqueous sodium bicarbonate and the product extracted into ethyl acetate. The ethyl acetate extract was washed well with aqueous sodium bicarbonate, then brine, and dried over magnesium sulfate. Evaporation afforded a solid residue which was recrystallized from ethyl acetate to give the title compound, mp 233°-235° C. Anal. Calcd for C21H16ClN3O2S: C, 61.54; H, 3.93; N, 10.25. Found: C, 61.39; H, 3.95; N, 10.36. NMR (DMSO-d6) δ9.62 (1H, t, J=6 Hz), 8.53 (2H, d, J=6 Hz), 7.80 (1H, d, J=2 Hz), 7.67 (2H, m), 7.64 (2H, d, J=9 Hz), 7.44-7.54 (3H, m), 7.33 (3H, m), 4.60 (2H, dq, J=9, 6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18](O)=[O:19])[N:9]=2)=[CH:4][CH:3]=1.C[Si](C=[N+:26]=[N-:27])(C)C.O.NN>CO.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]3[CH2:14][CH2:15]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:26][NH2:27])=[O:19])[N:9]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Agent: NN
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: NNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reaction time: 1 h

Procedure:
50 mg (0.17 mmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid [preparation according to WO 2007/134862 Example 88A] were dissolved in 0.4 ml of methanol and diluted with 0.6 ml of toluene, and 128 μl (0.26 mmol) of trimethylsilyldiazomethane solution (2 M in hexanes) were then added dropwise until a slight yellow color remained. The reaction was stirred for 1 h and then evaporated to dryness. The residue was taken up in 1 ml of ethanol, 43 mg (0.85 mmol) of hydrazine hydrate were added and the mixture was stirred under reflux for 2.5 h. After cooling, the solution was concentrated under reduced pressure and the residue was dried under high vacuum. This gave 54 mg (96% of theory) of the title compound in a purity of 93% as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15]([C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[O:16])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[F:30]>>[Cl:23][C:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[C:4]([NH:14][C:15]([C:17]3[CH:18]=[N:19][CH:20]=[N:21][CH:22]=3)=[O:16])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cncnc1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(F)c(Cl)c2)c1)c1cncnc1

Procedure:
The title compound was synthesized in analogy to Example 39, using pyrimidine-5-carboxylic acid[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 52 a) and B-(3-chloro-4-fluorophenyl)-boronic acid (CAN 144432-85-9) as starting materials; LC-MS (UV peak area/ESI) 93.5%, 425.0449 (M−H)−.
Reaction SMILES: [F:1][C:2]1[C:10](F)=[C:9]([F:12])[C:8]([F:13])=[C:7]([CH3:14])[C:3]=1[C:4]([OH:6])=[O:5].[OH-].[K+].NCCNCCNCCNCCNCCN.[H][H]>C(O)C.[OH-].[Pd+2].[OH-].O>[F:13][C:8]1[C:7]([CH3:14])=[C:3]([C:2]([F:1])=[CH:10][C:9]=1[F:12])[C:4]([OH:6])=[O:5]
Reactant: [H][H]
Reactant: Cc1c(F)c(F)c(F)c(F)c1C(=O)O
Agent: [Pd+2]
Agent: NCCNCCNCCNCCNCCN
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1c(F)c(F)cc(F)c1C(=O)O
Yield: 80.1 %

Procedure:
To a solution of 1.04 g of 2,3,4,5-tetrafluoro-6-methylbenzoic acid in 15 ml of ethanol were added 840 mg of potassium hydroxide, 232 mg of pentaethylene hexamine and 200 mg of 20% palladium hydroxide. The mixture was stirred in a hydrogen atmosphere at room temperature for 3 hours. After addition of water, the reaction mixture was filtrated through celite and the filtrate was washed with diethyl ether. The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid and extracted with dichloromethane. After evaporating the solvent, the residue was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:3) to give 761 mg of 3,4,6-trifluoro-2-methylbenzoic acid (yield: 80%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[Br-:12].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>O1CCCC1>[Br:12][CH2:10][C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Br:1])=[O:11]
Reactant: [Br-]
Reactant: CC(=O)c1ccc(F)cc1Br
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.8 %

Procedure:
To 1-(2-Bromo-4-fluoro-phenyl)-ethanone (2.5 g, 11.52 mmol) in anhydrous tetrahydrofuran (53 mL) under argon was added phenyltrimethylammonium tribromide (4.33 g, 11.52 mmol, 1.0 eq) at 0° C. The reaction mixture was stirred at ambient temperature for 16 h, concentrated, and re-dissolved in ethyl acetate. The organic layer was washed with water (2×150 mL) and brine (1×100 mL), dried (MgSO4), filtered, and evaporated in vacuo. Purification using MPLC chromatography (Biotage) gave 2.14 g (63%) of 2-bromo-1-(2-bromo-4-fluoro-phenyl)-ethanone as a clear oil. 1H-NMR (CD2Cl2) δ 7.57 (dd, J=9.6 Hz, 1H), 7.44 (dd, J=8, 2 Hz, 1H), 7.21 (m, 7.21-7.14, 1H), 4.51 (s, 2H); TLC Rf=0.38, 15% ethyl acetate-hexanes.
Reaction SMILES: CS(C)=O.[S:5]1[CH:9]=[CH:8][N:7]=[C:6]1[NH:10][C:11](=O)[O:12]C1C=CC=CC=1.[NH2:20][C:21]1[CH:44]=[CH:43][C:24]([O:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:38][CH2:39][CH:40]4[CH2:42][O:41]4)=[C:33]([C:36]#[N:37])[CH:34]=3)[N:29]=[CH:28][CH:27]=2)=[CH:23][C:22]=1[F:45]>O>[C:36]([C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][C:32]=1[O:38][CH2:39][CH:40]1[CH2:42][O:41]1)[N:29]=[CH:28][CH:27]=[C:26]2[O:25][C:24]1[CH:43]=[CH:44][C:21]([NH:20][C:11]([NH:10][C:6]2[S:5][CH:9]=[CH:8][N:7]=2)=[O:12])=[C:22]([F:45])[CH:23]=1)#[N:37]
Reactant: O=C(Nc1nccs1)Oc1ccccc1
Reactant: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1OCC1CO1
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)ccnc2cc1OCC1CO1
Temperature: 80 °C
Yield: 11.8 %

Procedure:
After adding dimethylsulfoxide (1 ml) and phenyl N-(2-thiazolyl)carbamate (94 mg) to 4-(4-amino-3-fluorophenoxy)-7-oxiranylmethoxyquinoline-6-carbonitrile (100 mg), the mixture was heated at 80° C. for 90 minutes. Water was added and the precipitated crystals were filtered out to obtain the title compound (16 mg) as light yellow crystals.
Reaction SMILES: N[C:2]1[CH:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.N([O-])=[O:13].[Na+].C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O.O>[OH:13][C:2]1[CH:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(C(F)(F)F)nc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Oc1ccc(C(F)(F)F)nc1
Temperature: -8 °C
Yield: 72.1 %

Procedure:
3-Amino-6-trifluoromethylpyridine (9.86 g, 61 mmol) was dissolved in concentrated sulphuric acid (70 ml) and diluted with water (70 ml), then cooled to −8° C. A solution of sodium nitrite (5.18 g, 75 mmol) in water (50 ml) was slowly added, and the mixture warmed to 0° C. for 15 minutes. The solution was then poured into sulphuric acid (10 M, 250 ml) and heated to 110° C. for 1 h. After cooling, the pH was adjusted to 6 with saturated sodium bicarbonate solution, and the solution extracted with ethyl acetate (2×300 ml). The extracts were dried (MgSO4) and concentrated to give the product as a yellow solid (7.15 g, 44 mmol, 72% yield).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:20]([CH3:22])[CH3:21]>CN(C=O)C>[CH:20]([O:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:22])[CH3:21]
Reactant: CC(C)Br
Reactant: Oc1ccc(Br)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(Br)c2ccccc12
Temperature: 25 °C

Procedure:
The following is an adaptation of the method of Bringmann. A solution containing 4-bromo-1-naphthol (10.0 g, 0.045 mol), potassium carbonate (31 g, 0.224 mol), and 2-bromopropane (27.6 g, 0.224 mol) in DMF was heated at reflux for 1 h under a nitrogen atmosphere. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The resultant residue was subjected to silica gel chromatography using a 50% ethyl acetate-hexane mixture as the eluent to provide 4-isopropoxy-1-bromonaphthalene.
Reaction SMILES: ClC1N=C(N2CCOCC2)C2SC(C3C=C(C=CC=3)[C:14](O)=[O:15])=CC=2N=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH:14]=[O:15])[CH2:29][CH2:28]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Product: CN1CCN(C=O)CC1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (60 mg) was reacted with 1-methylpiperizine via General Procedure B to yield 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone. Crude 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone (71 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 22.4 mg of 339. MS (Q1) 540.1 (M)+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[N:9][N:10]=[C:4]2[CH:3]=1.[Br:11]N1C(=O)CCC1=O>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:11][CH2:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[N:9][N:10]=[C:4]2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccn2nnnc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: BrCc1ccn2nnnc2c1

Procedure:
7-Methyl tetrazolo [1,5-a]pyridine [Boyer, et al., J. Am. Chem. Soc., 82, 2218 (1960](23 g, 173 mmole), N-bromosuccinimide (30.6 g, 173 mmole) and benzoyl peroxide (100 mg) in 1.5 liters of benzene is refluxed overnight. More N-bromosuccinimide (15.3 g, 86.5 mole) is added and the reflux is maintained for several hours. The mixture is cooled and washed with 100 ml 20% sodium hydroxide and then with water. It is dried over calcium chloride, evaporated to dryness to yield 36.4 g of a mixture of 7-bromomethyltetrazolo [1,5-a]pyridine (63%) 7-dibromomethyltetrazolo [1,5-a]pyridine (24%) and 7-methyltetrazolo [1,5-a]pyridine (13%). Two triturations of this mixture with 500 ml of ether-hexane 1:1 (v/v) affords 25 g of a mixture consisting of 82% monobromo derivative, 13% dibromo derivative and 5% of starting material. This mixture is used for the next step.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[C:19]([C:20]#[C:21][C:22]3[CH:23]=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=3)=[C:18]([CH3:29])[N:17]=[C:16]([NH2:30])[N:15]=2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[C:19]([C:20]#[C:21][C:22]3[CH:23]=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=3)=[C:18]([CH3:29])[N:17]=[C:16]([NH2:30])[N:15]=2)[CH2:9]1
Reactant: Cc1nc(N)nc(N2CCCC(NC(=O)OC(C)(C)C)C2)c1C#Cc1ccc(N)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(N2CCCC(N)C2)c1C#Cc1ccc(N)nc1
Temperature: 25 °C

Procedure:
3.3 g (7.8 mmol) of {1-[2-amino-5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-piperidin-3-yl}-carbamic acid tert-butyl ester are dissolved in DCM (50 mL) and 26 mL TFA are added. The reaction mixture is stirred over night at RT. The reaction mixture is adjusted to neutral pH using concentrated aqueous Na2CO3 solution and the DCM is evaporated at reduced pressure. The residue is washed with water, taken up in acetonitrile and freeze dried. The crude product is used without further purification in the next step.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=[C:9]([CH3:23])[CH:8]=1.ClC1C=CC=CC=1C(O)=O.CC1C=C(OC)C=CC=1N>>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=[C:9]([CH3:23])[CH:8]=1
Reactant: COc1ccc(Nc2ccccc2C(=O)O)c(C)c1
Agent: BrB(Br)Br
Agent: COc1ccc(N)c(C)c1
Agent: O=C(O)c1ccccc1Cl
Product: Cc1cc(O)ccc1Nc1ccccc1C(=O)O

Procedure:
2-(4-Hydroxy-2-methylphenylamino)benzoic acid [XI; R=H, R"=2-CH3, OH at 4-position], m.p. 209°-211° C. (decompn.) was prepared by boron tribromide demethylation of 2-(4-methoxy-2-methylphenylamino)benzoic acid, in turn prepared by reaction of 2-chlorobenzoic acid with 2-methyl-4-methoxyaniline.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]([O:26][CH3:27])([O:24][CH3:25])[C:16](=[O:23])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Cl-].[NH4+]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:27][O:26][C:15]([O:24][CH3:25])([O:14][CH3:13])[C:16](=[O:23])[CH2:17][CH:18]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: BrCc1ccccc1
Reactant: COC(=O)CCC(=O)C(OC)(OC)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Product: COC(=O)C(CC(=O)C(OC)(OC)OC)Cc1ccccc1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
Under nitrogen atmosphere at -78° C., 4.29 ml of 1.5 M n-butyl lithium (hexane solution) was added, while stirring, to 0.98 ml of diisopropylamine dissolved in 13 ml of anhydous tetrahydrofuran. The stirring was conducted for 15 minutes. To the resultant was added, taking 5 minutes, 1.18 g of dimethyl 2-oxoglutarate dimethyl acetal dissolved in 7 ml of anhydrous tetrahydrofuran, followed by stirring for 15 minutes. To the mixture was added, taking 5 minutes, a solution of 0.76 ml of benzyl bromide and 0.28 ml of hexamethylphosphoramide in 7 ml of anhydrous tetrahydrofuran. The mixture was stirred for 30 minutes at -78° C. The temperature of the reaction solution was raised up to -20° C. under stirring taking 2 hours, followed by addition of saturated aqueous solution of ammonium chloride, which was subjected to extraction with ethyl acetate. The extract solution was washed with water, dried (MgSO4), followed by evaporating off the solvent. The residue was subjected to a silicagel column chromalography, followed by elution with hexane-ethyl acetate (5:1→2:1) to give 1.64 g of dimethyl 4-benzyl-2-oxoglutarate dimethyl acetal as a pale yellow oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:16])[O-])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:30]2[CH2:29][CH2:28][N:27]([C:21]3[CH:20]=[C:19]([O:18][CH3:17])[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=3)[CH2:32][CH2:31]2)=[S:16])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1
Reactant: COc1nc2c(cc1NC([O-])=S)CCCC2
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=S)Nc3cc4c(nc3OC)CCCC4)CC2)c1
Yield: 56 %

Procedure:
Phenyl N-[(2-methoxy-5,6,7,8-tetrahydroquinolin-3-yl)thiocarbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7]([C:9]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=O)[N:4]=[CH:3][CH:2]=1.[NH:17]([C:21]1[NH:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1)[C:18]([NH2:20])=[NH:19].[OH-].[Na+]>CO>[N:25]1[C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[NH:22][C:21]=1[N:17]=[C:18]1[NH:20][C:7]2([C:5]3[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=3)[NH:20][C:18](=[N:17][C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)[NH:19][C:9]2([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:16]=2)[NH:19]1
Reactant: N=C(N)Nc1nc2ccccc2[nH]1
Reactant: O=C(C(=O)c1ccccn1)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: c1ccc(C23NC(=Nc4nc5ccccc5[nH]4)NC2(c2ccccn2)NC(=Nc2nc4ccccc4[nH]2)N3)nc1
Reaction time: 96 h
Yield: 71.7 %

Procedure:
A mixture of 2,2′-pyridil (15.8 g, 74.4 mmol) and 2-guanidinobenzimidazole (19.5 g, 111.7 mmol) in methanol (440 mL) was treated with a solution of sodium hydroxide (2.97 g, 74.4 mmol) in 74 mL and the resulting mixture was left standing at room temperature for 4 days. The crystalline material was filtered and dried under vacuum to yield 21.1 g of the title compound as off-white crystals (72%). mp: 305-307° C. (dec); HPLC retention time 4.5 min (reversed phase, Beckman ultrasphere ODS 4.6 mm×25 cm column, 20 min gradient elution with 20:80 to 60:40 acetonitrile:water containing 0.1% TFA@2 mL/min); 1H NMR (300 MHz, d6-DMSO) d 11.5 (br s, NH, 2 H), 10.0 (br s, NH, 2 H), 8.6 (br s, NH, 2 H), 8.38 (d, J=4.2 Hz, 2 H), 7.55 (t,J=7.8 Hz, 2 H), 7.29 (d, J=7.8 Hz, 2 H), 7.27-7.21 (m, 4 H), 7.14 (br s, 2 H), 6.98 (dd, J=5.8, 3.2 Hz, 4 H); MS (ESI) m/z 527 [M+H]+; Anal. Calcd. for C28H22N12. ⅔H2O: C, 62.44; H, 4.37, N, 31.21; Found: C, 62.72; H, 4.08; N, 30.86.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[CH:15][CH2:14][N:13]2[C:30](O)=[O:31])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.Cl.[NH2:45][OH:46].C(N(CC)CC)C.NO.Cl>C(Cl)Cl.O.C1COCC1>[OH:46][NH:45][C:30]([N:13]1[CH2:14][CH:15]=[C:16]([S:19]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)(=[O:21])=[O:20])[CH:17]=[CH:18][N:12]1[S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:10])=[O:11])=[O:31]
Reactant: COc1ccc(S(=O)(=O)C2=CCN(C(=O)O)N(S(=O)(=O)c3ccc(OC)cc3)C=C2)cc1
Reactant: NO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(S(=O)(=O)C2=CCN(C(=O)NO)N(S(=O)(=O)c3ccc(OC)cc3)C=C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The 1,5-di-[(4-methoxyphenyl)sulfonyl]-diazepine-2-carboxylic acid (0.60 g, 1.24 mmol) is dissolved in methylene chloride (15 mL) at room temperature followed the addition of oxalyl chloride (0.32 mL, 2.54 mmol) and slow addition of DMF (0.09 g, 1.24 mmol). This solution is stirred for 30 minutes at room temperature. In a separate flask, hydroxylamine hydrochloride (0.34 g, 5.0 mmol) in water (5 mL) and THF (7 mL) is stirred at 0° C., and then triethylamine (1.0 mL, 6 equiv) is added. This solution is stirred for 15 minutes. The acid chloride solution is added to the hydroxylamine solution at 0° C. and then warmed up to room temperature and stirred for 3 hours. The solution is acidified to pH-1 with 1N HCl, poured into water and extracted with methylene chloride. The organic extracts are dried (Na2SO4) and concentrated down to an oil. The oil is purified by HPLC with a reverse phase column using 65% (95% water, 5% acetonitrile, 0.1 % formic acid) and 35% (80% acetonitrile, 20% water) as the eluent. MS (ESI): 500 (M+H+), 517 (M+NH4+).