Azzindani/Open_Reaction_Data huggingface dataset:
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.[NH2:21][CH2:22][CH:23]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][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:21][CH2:22][CH:23]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:40])[CH3:39])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])=[O:19])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(CN)c1ccccc1C(F)(F)F
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Product: CC(C)(C)OC(=O)NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O)c1ccccc1C(F)(F)F

Procedure:
Analogously to the procedure of Example 63, 43 mg (146 μmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid [for the preparation see Example 88A in WO 2007/134862] were reacted with 49 mg (161 μmol) of tert-butyl {2-amino-1-[2-(trifluoromethyl)phenyl]ethyl}carbamate. This gave 59 mg (69% of theory) of the title compound.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][O:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].N1CCCC1>C(O)C>[CH:22](=[C:18]1[O:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCC=O
Reactant: O=C1COC(=O)N1CCCCSc1cccc2nccn12
Solvent: CCO
Solvent: C1CCNC1
Product: CCCCCCCCCC=C1OC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.527 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]oxazolidine-2,4-dione and 1.11 ml (5.0 mmol) of decanal in 20 ml of ethanol, 0.04 ml (0.5 mmol) of pyrrolidine was added, followed by refluxing for 20 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate 3/1→ethyl acetate). The resulting residue was crystallized from n-hexane to yield 0.13 g (5.8%, white crystal) of the desired product.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:22])[C:13]([CH3:21])([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH3:14])=[CH:8][CH:7]=1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:47]I>C(Cl)Cl>[I:47][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:22])[C:13]([CH3:21])([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH3:14])=[CH:8][CH:7]=1
Reactant: CC(C)(C(=O)c1ccc(OCCCO)cc1)N1CCOCC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C(=O)c1ccc(OCCCI)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
16.2 g (53 mmol) of 1-[4-(3-hydroxy-propoxy)-phenyl]-2-methyl-2-morpholin-4-yl-propan-1-one, 8.97 g (132 mmol) of imidazole and 34.5 g (132 mmol) of triphenyl phosphine are dissolved in 150 ml of methylene chloride. To the solution are added 27.0 g (106 mmol) of iodine and stirred at room temperature for 1 hour. 100 ml of methylene chlorideare added to the reaction mixture and washed with sodium sulfite aqueous solution and water, and dried over MgSO4. After methylene chloride is distilled off, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (1:3) as an eluent, and an oily product is obtained. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 1.31 (s, 6H), 2.30 (m, 2H), 2.57 (m, 4H), 3.38 (t, 2H), 3.69 (m, 4H), 4.11 (t, 2H), 6.91 (d, 2H), 8.60 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[CH:12]=[N:13][OH:14].C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[CH2:12][NH:13][OH:14]
Reactant: ON=Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: ONCc1ccccc1Nc1c(Cl)cccc1Cl
Yield: 90.9 %

Procedure:
To a solution of 2-[(2,6-dichlorophenyl)amino]benzaldehyde oxime (4.0 g, 13.6 mmol) in glacial acetic acid (20 ml) is added sodium cyanoborohydride (2.05 g,33 mmol) in small portions over a period of two hours. The reaction mixture is diluted with ethyl acetate (200 ml) and neutralized with 1N NaOH. The organic layer is collected and the solvent is evaporated. 2-[(2,6-Dichlorophenyl)amino]-N-hydroxybenzenemethanamine (3.5 g, 91%) is isolated as an oil by flash chromatography (silica, 3:1 chloroform/ethyl acetate). The compound is not further purified, but used directly in the next reaction.
Reaction SMILES: [CH2:1]([N:19]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]#N)=[CH:41][CH:40]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Cl)CCl.[CH3:51][OH:52].[OH2:53]>>[CH2:1]([N:19]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([O:52][CH3:51])=[O:53])=[CH:41][CH:40]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O
Reactant: CO
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)Cc1ccc(C#N)cc1
Solvent: ClCCCl
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 73.6 %

Procedure:
The nitrile (15 g.), ethylene dichoride (200 ml.), methanol (50 ml.) and water (20 ml.) are combined and stirred at room temperature. Hydrogen chloride gas is bubbled into the mixture for three hours after which the yellow solution is refluxed for three hours. Methanol (50 ml.) and water (10 ml.) are added and hydrogen chloride bubbled into the mixture for one hour and refluxing continued for 14 hours. Methanol (10 ml.) and water (2 ml.) are added and hydrogen chloride bubbled in for one hour. The mixture is refluxed for four hours, cooled to room temperature and made alkaline by addition of saturated aqueous sodium bicarbonate solution. The ethylene dichloride phase is separated and the aqueous phase extracted with chloroform (2× 100 ml.). The combined organic solutions are washed with water (100 ml.), dried (Na2SO4) and evaporated to give 1-(dioctadecylamino)methyl-4-carbomethoxy benzene (14.0 g., 73.6% yield).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[N:25]=[C:24]([NH2:26])[C:23]([NH2:27])=[CH:22][C:21]=4[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[N:3]=1.[CH2:38](OC(OCC)OCC)C>>[CH3:1][C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[N:25]=[C:24]5[N:26]=[CH:38][NH:27][C:23]5=[CH:22][C:21]=4[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:16][CH:15]=3)[CH2:11][CH2:12]2)[C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[N:3]=1
Reactant: CCOC(OCC)OCC
Reactant: Cc1nc2ccccc2n1C1CCN(Cc2ccc(-c3nc(N)c(N)cc3-c3ccccc3)cc2)CC1
Product: Cc1nc2ccccc2n1C1CCN(Cc2ccc(-c3nc4nc[nH]c4cc3-c3ccccc3)cc2)CC1
Reaction time: 1 h

Procedure:
6-(4-{[4-(2-Methyl-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl)-5-phenylpyridine-2,3-diamine (4-4, 0.055 g, 0.11 mmol) was heated at reflux in triethylorthoformate. After 3 h the reaction was concentrated and stirred in 1M HCl for 1 h. The solution pH was adjusted to 7 with saturated aqueous Na2CO3. The mixture was extracted 3× with DCM. The residue was purified by flash column chromatography (elute with a gradient of 95:5 DCM/MeOH to 90:10). The resulting impure product was dissolved in 2 ml of formic acid and the resulting solution was heated to reflux for 2 h. The reaction was concentrated, diluted with saturated aqueous NaHCO3, and extracted 3× with DCM. The extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (elute with a gradient of 95:5 DCM MeOH to 90:10) to afford 5-(4-{[4-(2-Methyl-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl)-6-phenyl-1H-imidazo[4,5-b]pyridine (6-1). 1H NMR (CDCl3) δ 8.20 (s, 1H), 7.93 (s, 1H), 7.42 (d, 2H, J=11.0 Hz), 7.37 (d, 2H, J=10.8 Hz), 7.37-7.21 (m, 6H), 4.20 (m, 1H), 3.65 (s, 2H), 3.14 (m, 2H), 2.65 (s overlapping with m, 5H), 2.23 (m, 2H), 1.80 (m, 2H). MS m/z (M+H)=499.16.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][N:8]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:20][C@H:19]([C:21]([O:23]C)=O)[O:18][C:17]4=[O:25])=[CH:12][C:11]=3[F:26])[CH2:9][C:2]=12.[NH3:27]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][N:8]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:20][C@H:19]([C:21]([NH2:27])=[O:23])[O:18][C:17]4=[O:25])=[CH:12][C:11]=3[F:26])[CH2:9][C:2]=12
Reactant: COC(=O)[C@H]1CN(c2ccc(N3Cc4cccnc4C3)c(F)c2)C(=O)O1
Reactant: N
Solvent: CO
Product: NC(=O)[C@H]1CN(c2ccc(N3Cc4cccnc4C3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The methyl (5R)-3-[4-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxylate (Step 1) is suspended in saturated ammonia in methanol (25 mL), stirred at ambient temperature for 4 h and filtered to give the title compound, mp 257° C. (dec.); MS (ESI+) for C17H15N4O3F m/z 343 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CO[CH:11](O)[C:12]([F:15])([F:14])[F:13].[C:17]([OH:20])(=O)[CH3:18].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:11]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:18][C:17]=2[OH:20])[C:12]([F:13])([F:14])[F:15])[CH:3]=1
Reactant: CC(=O)O
Reactant: COC(O)C(F)(F)F
Reactant: Oc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: Oc1ccc(Cl)cc1C(c1cc(Cl)ccc1O)C(F)(F)F
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A mixture of 4-chlorophenol (51.2 g), trifluoroacetaldehyde methyl hemiacetal (26 g) and acetic acid (16 ml) was stirred at a temperature of 14° C. and concentrated sulfuric acid (60 ml) was added slowly and the temperature of the mixture was kept below 25° C. The mixture was then stirred for a period of 2 hours at a temperature of 40° C. and the mixture poured into water. The product was recrystallised from cyclohexane/diethyl ether to give 1,1-bis(5-chloro-2-hydroxyphenyl)-2,2,2-trifluoroethane (25 g), m.p. 144° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2OCC)[N:5]=[C:4]([NH2:18])[N:3]=1.[Cl:19]C1C(Cl)=CC=CC=1B(O)O.NC1N=C(Cl)C=C(Cl)N=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([Cl:14])[C:13]=2[Cl:19])[N:5]=[C:4]([NH2:18])[N:3]=1
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: CCOc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Agent: Nc1nc(Cl)cc(Cl)n1
Product: Nc1nc(Cl)cc(-c2cccc(Cl)c2Cl)n1

Procedure:
4-Chloro-6-(2,3-dichloro-phenyl)-pyrimidin-2-ylamine was prepared according to the method described for 4-chloro-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-2-ylamine (Example 53) using 2,3-dichlorophenyl boronic acid and 2-amino-4,6-dichloropyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:32]1([CH3:63])[C:33]([C:38]([CH2:40][N:41]2[C:47]3[CH:48]=[C:49]([CH3:52])[CH:50]=[CH:51][C:46]=3[N:45]([C:53]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=3)=[O:54])[CH2:44][CH:43]([NH2:61])[C:42]2=[O:62])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=1>O1CCCC1>[C:32]1([CH3:63])[C:33]([C:38]([CH2:40][N:41]2[C:47]3[CH:48]=[C:49]([CH3:52])[CH:50]=[CH:51][C:46]=3[N:45]([C:53]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=3)=[O:54])[CH2:44][CH:43]([NH:61][C:14]([NH:1][C:2]3[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=3)=[O:16])[C:42]2=[O:62])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(N)CN2C(=O)c1ccccn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)c3ccccn3)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Reaction time: 2 h
Yield: 123.7 %

Procedure:
Ethyl 3-aminobenzoate (310 mg) was dissolved in tetrahydrofuran (50 ml), triphosgene (187 mg) was added under ice-cooling, triethylamine (161 μl) was added five times every 3 minutes,a solution of 1-(2-toluoylmethyl)-2-oxo-3-amino-5-(2-pyridylcarbonyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (730 mg) in tetrahydrofuran (23 ml) was added thereto, and the reaction mixture was allowed to come to room temperature, stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, water (50 ml) was added, extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(chloroform:ethyl acetate=10:1), to thereby obtain 483 mg of the titled compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:8]=2)[N:3]1[CH2:22][C:23]#[N:24].[N:25]([Si](C)(C)C)=[N+:26]=[N-:27].C([Sn](=O)CCCC)CCC.CN(C)C=O>C(OCC)(=O)C.C(OCC)C>[N:24]1[NH:25][N:26]=[N:27][C:23]=1[CH2:22][N:3]1[C:4]2[C:9](=[CH:8][C:7]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][CH:13]=3)=[CH:6][CH:5]=2)[CH2:10][CH2:11][C:2]1=[O:1]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CCN1C(=O)CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc2N1Cc1nn[nH]n1
Temperature: 160 °C
Yield: 80 %

Procedure:
A Biotage microwave vial was charged with 2-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetonitrile (66 mg, 0.20 mmol), azidotrimethylsilane (46 mg, 0.40 mmol), dibutyltin oxide (8 mg, 0.03 mmol), and anhydrous N,N-dimethylformamide (2.5 mL), and the vial capped. The reaction mixture was heated to 160° C. and irradiated for 25 minutes. LCMS showed only ca 63% conversion. Additional azidotrimethylsilane (46 mg, 0.40 mmol) was added, and heated again at 160° C. for an additional 30 minutes. LCMS showed the disappearance of starting material. The reaction mixture was diluted with ethyl acetate (30 mL), washed with 30% aqeuous ammonium chloride (2×10 mL), brine (20 mL), and dried over sodium sulfate. The solvent was removed from the solution under reduced pressure to give a pale yellow solid. Ethyl ether (3 mL) was added, sonicated, filtered, washed with ethyl ether (10 mL), dried to afford 1-((2H-tetrazol-5-yl)methyl)-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one as a white solid (59 mg, 0.16 mmol, 80%). LCMS mz 374.0 (M+H), anal HPLC>97% purity, 1HNMR (400 MHz, CD3CN) δ 7.83 (m, 4H); 7.65 (d, J=2.0 Hz, 1H); 7.62 (dd, J=8.4 and 2.1 Hz, 1H); 7.30 (d, J=8.6 Hz, 1H); 5.46 (s, 2H); 3.11 (m, 2H); 2.77 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[N:12]([CH2:19][CH3:20])[C:11]3=[O:21])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:23]1[NH:31][C:26]2=[N:27][CH:28]=[CH:29][CH:30]=[C:25]2[N:24]=1.O>CN1C(=O)CCC1>[CH2:19]([N:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[N:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[N:1]([C:23]2[NH:31][C:26]4=[N:27][CH:28]=[CH:29][CH:30]=[C:25]4[N:24]=2)[CH2:2][CH2:3]3)[C:11]1=[O:21])[CH3:20]
Reactant: CCn1c(=O)n(-c2ccc3c(c2)CCN3)c2ncccc21
Reactant: Clc1nc2cccnc2[nH]1
Solvent: CN1CCCC1=O
Solvent: O
Product: CCn1c(=O)n(-c2ccc3c(c2)CCN3c2nc3cccnc3[nH]2)c2ncccc21
Temperature: 150 °C
Reaction time: 2 h
Yield: 12.7 %

Procedure:
Under nitrogen atmosphere, a mixture of 3-(2,3-dihydro-1H-indol-5-yl)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) and 2-chloro-3H-imidazo[4,5-b]pyridine (60.3 mg) in NMP (4 mL) was stirred at 150° C. for 2 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by prep. HPLC. Crystallization from EtOH/H2O to give the title compound (18.0 mg).
Reaction SMILES: O[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].[C:17]([O:20][C@H:21]([CH3:45])[CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C:35](=[O:36])[C:34]2[N:33]([CH3:37])[CH:32]=[N:31][C:30]=2[N:29]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH2:44])[C:27]1=[O:28])(=[O:19])[CH3:18]>CN(C)C=O>[C:17]([O:20][CH:21]([CH3:45])[CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C:35](=[O:36])[C:34]2[N:33]([CH3:37])[CH:32]=[N:31][C:30]=2[N:29]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:8]2[C@@H:16]3[C@@H:11]([NH:12][C:13]([NH:15]3)=[O:14])[CH2:10][S:9]2)[C:27]1=[O:28])(=[O:19])[CH3:18]
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(ncn2C)n(CCCCCCN)c1=O
Solvent: CN(C)C=O
Product: CC(=O)OC(C)CCCCn1c(=O)c2c(ncn2C)n(CCCCCCNC(=O)CCCC[C@H]2SC[C@@H]3NC(=O)N[C@@H]32)c1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 34.7 %

Procedure:
Disopropylcarbodiimide (113.5 mg, 0.55 mmol) was added to a solution of biotin (122 mg, 0.5 mmol), (R)-1-(5-acetoxyhexyl)-3-(6-aminohexyl)-7-methylxanthine(227 mg, 0.5 mmol) and 4-N,N-dimethylaminopyridine (73.3 mg, 0.6 mmol) in dimethylformamide. After stirring at room temperature for 6 hours, dimethylformamide was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 20% methanol/ethyl acetate to provide (R)-1-(5-acetoxyhexyl)-3-(N-biotinyl-6-aminohexyl)-7-methylxanthine (110 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:17])[N:9]([CH3:16])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:18]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:18][C:15]1[N:14]=[CH:13][N:12]2[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=3[C:8](=[O:17])[N:9]([CH3:16])[CH2:10][C:11]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1Cc2cncn2-c2cccc(Cl)c2C1=O
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2c(Cl)ncn2-c2cccc(Cl)c2C1=O

Procedure:
1.30 g (5.25 mmol) of 7-chloro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one are stirred at 90° for 30 minutes in 10 ml of dimethylformamide with 800 mg (6 mmol) of N-chlorosuccinimide. Subsequently, the mixture is poured into water and extracted with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulphate and evaporated. By column chromatography on silica gel there is obtained 3,7-dichloro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 211°-212°.
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH3:36])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([C:20](OC(C)(C)C)=O)[CH2:15][C:14]=2[C:13]([C:27]2[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=2[F:35])=[N:12]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]>C(O)(C(F)(F)F)=O.C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:37])([CH3:36])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:27]2[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=2[F:35])=[N:12]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C(=O)OC(C)(C)C)C2)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C
Reaction time: 2 h
Yield: 49 %

Procedure:
A solution of (S)-tert-butyl 1-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-ylcarbamoyl)-3-(2,4,5-trifluorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (0.92 g, 1.76 mmol) in TFA/DCM (1:1) was stirred at room temperature for 30 min. The reaction mixture was diluted with toluene and evaporated under vacuum. The resulting residue was dissolved in THF, to which formaldehyde (37%, 0.65 mL) and sodium triacetoxyborohydride (424 mg) was added sequentially. After stifling at room temperature for 2 h, THF was evaporated under vacuum. The residue was extracted between EtOAc and saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated to dryness. The crude mixture was purified by column with a gradient of from 10% to 40% ethanol in MeCN to give (S)—N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-5-methyl-3-(2,4,5-trifluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-1-carboxamide 37 as a solid (412 mg, 49% yield for two steps). 1H NMR (CDCl3) δ 7.86 (d, J=9.4 Hz, 1H), 7.47-7.54 (m, 1H), 6.98-7.04 (m, 1H), 5.85 (br, 1H), 4.11 (d, J=9.4 Hz, 1H), 3.39 (s, 2H), 3.16-3.20 (m, 2H), 2.84 (d, J=4.8 Hz, 3H), 2.73 (t, J=6.2 Hz, 2H), 2.47 (s, 3H), 1.05 (s, 9H). LCMS (+ESI) m/z=438 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].CO[CH2:18][CH2:19]OC>C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([CH:18]=[CH2:19])=[N:3][CH:4]=1
Reactant: Cc1cc(Br)ncc1Br
Reactant: COCCOC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: C=Cc1cc(C)c(Br)cn1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a solution of 2,5-dibromo-4-picoline (9.00 g, 35.9 mmol) in DME (96 mL), 2,4,6-trivinyl-cyclotriboroxane pyridine complex (8.63 g, 35.9 mmol) and 2 N aq. K2CO3-solution (36 mL) is added. The mixture is degassed and put under argon before Pd(PPh3)4 (746 mg, 0.646 mmol) is added. The mixture is stirred at 80° C. for 15 h, before it is cooled to rt, diluted with diethyl ether (50 mL), washed with sat. aq. NaHCO3-solution (2×30 mL), dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 5-bromo-4-methyl-2-vinyl-pyridine (7.04 g) as a yellow oil; LC-MS: tR=0.75 min; [M+1]+=198.22; 1H NMR (CDCl3): δ 2.41 (s, 3H), 5.50 (d, J=10.8 Hz, 1H), 6.21 (d, J=17.3 Hz, 1H), 6.74 (dd, J=17.3, 10.8 Hz, 1H), 7.22 (s, 1H), 8.59 (s, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3](B(O)O)=[N:2]1.Br[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])=[CH:12][CH:11]=1.Br[C:29]1[CH:30]=C2C(=C[CH:37]=1)CN(C(NC1C=CC(C(=O)NCCC)=CC=1)=O)C2>>[CH2:37]([N:1]1[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20]3)=[O:18])=[CH:12][CH:11]=2)[CH:3]=[N:2]1)[CH2:29][CH3:30]
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(Br)cc3C2)cc1
Reactant: OB(O)c1cc[nH]n1
Reactant: O=C(Nc1ccc(Br)cc1)N1Cc2ccccc2C1
Product: CCCn1cc(-c2ccc(NC(=O)N3Cc4ccccc4C3)cc2)cn1

Procedure:
The title compound was prepared as described in Example 280, substituting 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 1H-pyrazol-3-ylboronic acid and N-(4-bromophenyl)isoindoline-2-carboxamide for 5-bromo-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.85 (t, J=7.3 Hz, 3H), 1.69-1.93 (m, 2H), 4.05 (t, J=6.9 Hz, 2H), 4.77 (s, 4H), 7.26-7.40 (m, 4H), 7.42-7.49 (m, 2H), 7.52-7.61 (m, 2H), 7.79 (s, 1H), 8.07 (s, 1H), 8.33 (s, 1H); MS (ESI(+)) m/e 347 (M+H)+.