Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[Cr](=O)=O.C1C=CC=CN=1.C1C=CC=CN=1.N1C=CC=CC=1.[OH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH3:39])=[C:31]1[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1>ClCCl.[O-2].[O-2].[O-2].[Cr+6]>[CH:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH3:39])=[C:31]1[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)=[O:23]
Reactant: Cc1c(-c2cccnc2)n(CCCCCCO)c2ccccc12
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(-c2cccnc2)n(CCCCCC=O)c2ccccc12
Reaction time: 0.42 h

Procedure:
To a solution of Collins Reagent prepared with chromium trioxide (5.6 g) and pyridine (8.86 g, 112 mmol) in dichloromethane (150 ml) at 0°-5° under a nitrogen atmosphere is added all at once 1.8 g of 1-(6-hydroxyhexyl)-3-methyl-2-(3-pyridyl)-indole in dichloromethane (15 ml). The mixture is stirred for an additional 25 minutes, then filtered through celite. The filtrate is then passed through a silica gel column. The product is eluted from the silica gel with a 1:1 mixture of ethyl acetate:dichloromethane (500 ml). Concentration in vacuo yields the desired 1-(5-formylpentyl)-2-(3-pyridyl)-3-methylindole as a pale yellow oil; NMR (CDCl3) δ9.7 (t, 1H); IR (neat) 2710, 1720 cm-1.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Na+].[Na+].[Br:24]Br>C(Cl)(Cl)Cl>[Br:24][C:9]1[S:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:11][C:10]=1[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1
Reactant: BrBr
Reactant: c1ccc(-c2nc(-c3ccncc3)cs2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Brc1sc(-c2ccccc2)nc1-c1ccncc1
Reaction time: 1 h

Procedure:
To the solution of 2-phenyl-4-(pyridin-4-yl)thiazole (70 mg, 0.3 mmol) in CHCl3 was added Na2CO3 (311 mg, 2.9 mmol) and Br2 (75 μL, 1.470 mmol) at rt. After 1 h, additional charges of Na2CO3 (1 g, 9.4 mmol) and Br2 (0.5 mL, 1 mmol) were added and the reaction maintained for another hour. The reaction was diluted with CHCl3 and filtered through a pad of Celite, washing the filter cake thoroughly with CHCl3. The combined filtrates were concentrated of provide 0.5-bromo-2-phenyl-4-(pyridin-4-yl)thiazole which was carried forward without further purification: LCMS (m/z): 318.9 (MH+), tR=0.75 min.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Li+].CS(O[CH2:10][CH:11]([CH2:30][C:31]#[N:32])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=O)=O.N(CC(NC(OC)=O)CSCCCCCCCCCCCCCCCC)=[N+]=[N-]>CN(C)C=O>[N:1]([CH2:10][CH:11]([CH2:30][C:31]#[N:32])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCCCCCCCCCOCC(CC#N)COS(C)(=O)=O
Agent: CCCCCCCCCCCCCCCCSCC(CN=[N+]=[N-])NC(=O)OC
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOCC(CC#N)CN=[N+]=[N-]
Yield: 96.1 %

Procedure:
Using 4.9 g (100 mM) of lithium azide, crude product of 2-cyanomethyl-3-hexadecyloxypropyl methanesulfonate Vn1a obtained in the previous reaction in 30 ml of dimethylformamide is converted by the same procedure as described in the (52) and 3.504 g (96.1% yield) of the titled compound Vn1a is obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([C:33]([F:36])([F:35])[F:34])=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:21]4[CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH2:25][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl>C(Cl)Cl.CCOCC>[F:1][C:2]1[C:3]([C:33]([F:35])([F:34])[F:36])=[C:4]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[C:21]4[CH2:22][NH:23][CH2:24][CH2:25][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:13][CH2:14]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)N3CCC(c4cc(F)cc(F)c4C(F)(F)F)CC3)c2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(c1n[nH]c2c1CNCC2)N1CCC(c2cc(F)cc(F)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.6 %

Procedure:
To a solution of tert-butyl 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (61, 94 mg, 0.19 mmol) in CH2Cl2 (3 mL) was added HCl (2.0 N solution in Et2O, 3 mL). The mixture was stirred for 18 h at ambient temperature. The reaction mixture was diluted with Et2O (20 mL), washed with saturated NaHCO3 solution, and the concentrated under reduced pressure to yield (4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone (62) as a white solid (80 mg, 97%): 1H NMR (500 MHz, DMSO-d6) δ 12.73 (s, 1H), 7.487-7.336 (m, 2H), 5.193-5.008 (m, 1H), 4.76-4.58 (br s, 1H), 3.75 (s, 2H), 3.25-3.04 (m, 2H), 2.94-2.84 (m, 1H), 2.84-2.71 (br s, 1H), 2.60-2.53 (m, 2H), 1.89-1.58 (m, 4H); ESI MS m/z 415.1 [M+H]+.
Reaction SMILES: [F:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[N:10]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12](O)=[O:13].CN1CCOCC1.C(OC(Cl)=O)C(C)C>CCOCC.C1COCC1>[CH2:6]([O:5][C:3]([CH:2]([F:1])[C:12]([CH:11]1[CH2:15][CH2:16][CH2:17][N:10]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:13])=[O:4])[CH3:7]
Reactant: CCOC(=O)CF
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CCOCC
Product: CCOC(=O)C(F)C(=O)C1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl fluoroacetate (2.0 g, 18.9 m mol) in ether (25 ml) was added dropwise with stirring to a suspension of NaH (50 percent oil dispersion)(0.91 g, 18.9 m mol) in ether (20 ml). The reaction mixture was stirred three hours at room temperature, then cooled to -15°. The mixed anhydride of Boc-Pro-OH [prepared from Boc-Pro-OH (4.1 g, 18.9 m mol) in the THF (50 ml) containing N-methylmorpholine (2.1 ml, 18.9 m mol) at -15°, by the addition of isobutylchloroformate (2.45 ml, 18.9 m mol) and stirred 5 minutes] was filtered into the chilled enolate suspension and stirred at -15° for 10 minutes. The reaction was then allowed to warm to room temperature for one hour. The solution was poured onto ice containing 2.5N H2SO4. The organic solvents were removed by evaporation and the aqueous residue extracted with ethyl acetate. The ethyl acetate solution was washed with saturated NaHCO3, saturated with NaCl, and dried over anhydrous MgSO4. The ethyl acetate was removed by evaporation and the residue was applied to a silica gel column. The product was eluted with chloroform. The solvent was removed by evaporation yielding 1.08 g of an oil. The 1H nmr (CDCl3) showed peaks shifted from TMS by ##STR5##
Reaction SMILES: C(B(CC)CC)C.[OH:8][CH:9]([CH2:14][C:15](=[O:24])[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10]([O:12][CH3:13])=[O:11].[BH4-].[Na+].[Cl-].[NH4+]>C1COCC1.CO.C(O)(=O)C>[OH:8][CH:9]([CH2:14][CH:15]([OH:24])[CH2:16][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(O)CC(=O)CC(=O)OC(C)(C)C
Agent: CCB(CC)CC
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C(O)CC(O)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A mixture of THF (133.05 ml), methanol (66.52 ml) and triethylborane (1M in THF) (72.71 ml) was stirred at room temperature for one hour in an argon atmosphere. To a solution of 1-methyl 6-tert.-butyl 2-hydroxy-4-oxoadipate (12.79 g, 51.94 mmol) in THF (312 ml) cooled to -78° C., the above boran solution was dropwise added over 45 minutes. After stirring the mixture at -78° C. for 50 minutes, sodium borohydride (2.26 g, 59.72 mmol) was added in one portion, followed by stirring at -78° C. for 3 hours. After dropwise adding a mixed solvent of acetic acid and methanol (1:1) (54 ml) to the reaction solution at -78° C. over 15 minutes, the solution was stirred for additional 15 minutes. The resulting mixture was poured in a 5 % solution of ammonium chloride (511 ml) and stirred for 15 minutes. After adjusting pH to 7.5, the organic layer was evaporated off under reduced pressure. After adding 10 % aqueous hydrogen peroxide (104 ml) and adjusting pH of the mixture to 7, a 5 % aqueous solution of sodium sulfite (312 ml) was added, followed by stirring at room temperature for 40 minutes. Then the mixture was extracted with ethyl acetate, and organic layers were colleted, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:acetone=2:1) to give pure 1-methyl 6-tert.-butyl 2,4-dihydroxyadipate (11.22 g, 45.19 mmol). Yield, 87 %.
Reaction SMILES: [F:1][C@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:15](=[O:19])[NH:14][C:13]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[N:12][C:11]1=2.N#N.C([C@@]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H](CO[C:40]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C@@H](O)C1)(=O)C(C)C>>[CH3:56][O:55][C:52]1[CH:51]=[CH:50][C:49]([C:40]([O:9][CH2:8][C@H:5]2[O:4][C@@H:3]([N:10]3[CH:18]=[N:17][C:16]4[C:15](=[O:19])[NH:14][C:13]([NH:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])=[N:12][C:11]3=4)[C@@H:2]([F:1])[C@@H:6]2[OH:7])([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)=[CH:54][CH:53]=1
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2F)c(=O)[nH]1
Reactant: COc1ccc(C(OC[C@H]2O[C@@](C(=O)C(C)C)(n3cnc4c(=O)[nH]c(N)nc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: N#N
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)C(C)C)nc43)[C@@H](F)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1

Procedure:
This compound is prepared from 9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-N2 -isobutyrylguanine by the same procedure used for the preparation of N2 -isobutyryl-5'-O-(4,4'-dimethoxytrityl)-2'-deoxyguanosine.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([CH2:14][OH:15])[CH2:3]1.C(Cl)Cl.[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20]>>[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20].[OH:15][CH2:14][C@H:4]1[NH:5][CH2:6][C@H:2]([OH:1])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Formation of the amide bond was carried out using an adaptation of General Method A, above. A mixture of commercially available (2S,4R)-tert-butyl 4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (3.26 g, 15 mmol) in 50 mL of DCM/TFA (3:2, v/v) was stirred at rt for 4 h, concentrated in vacuo to give a brown oil as a crude TFA salt of (3R,5S)-5-(hydroxymethyl)pyrrolidin-3-ol, which was dissolved in DMF (28 mL), added with biphenyl-2-carboxylic acid (3.05 g, 15.4 mmol) and HATU (5.86 g, 15.4 mmol). The resulting solution was cooled to 0° C., added with Et3N (8.8 mL, 63 mmol) dropwise and was allowed to warm to rt gradually and stirred overnight. 2M NaOH (aq.) was added and the mixture was extracted with EtOAc (3×). The combined EtOAc solution was washed with brine, dried over MgSO4 and concentrated in vacuo to a brown oil, which was purified by column chromatography on silica gel (10% MeOH in EtOAc) to provide biphenyl-2-yl((2S,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-1-yl)methanone as an off-white solid (2.0 g, 45% yield over two steps). 1H NMR (CDCl3, 400 MHz) δ 7.59-7.57 (m, 2H), 7.54-7.40 (m, 7H), 4.44 (brs, 1H), 4.10 (s, 1H), 3.77-3.72 (m, 1H), 3.62 (brs, 1H), 3.32 (brs, 1H), 3.04-2.96 (m, 1H), 2.60 (brs, 1H), 2.00-1.95 (m, 1H), 1.61 (brs, 2H). MS (ESI) 298.04 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2([CH3:16])[CH3:15].[Li]CCCC.CN([CH:25]=[O:26])C.O>O1CCCC1>[CH3:15][C:5]1([CH3:16])[C:4]2[C:9](=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:11]=[C:2]([CH:25]=[O:26])[CH:3]=2)[O:8][CH2:7][CH2:6]1
Reactant: CN(C)C=O
Reactant: CC(C)c1cc(Br)cc2c1OCCC2(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1cc(C=O)cc2c1OCCC2(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
6-Bromo-4,4-dimethyl-8-(propan-2-yl)-3,4-dihydro-2H-chromene (154 mg, 0.54 mmol) in tetrahydrofuran (5.44 mL) was cooled to −78° C. and n-BuLi (261 μL, 0.65 mmol) was added dropwise via a syringe. The reaction mixture was stirred at −78° C. for 30 minutes, and then DMF (168 μL, 2.17 mmol) was added dropwise. The resulting mixture was allowed to warm to room temperature, and stirred for 30 minutes before water was added. It was then extracted with EtOAc (2×) and the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with 0-10% EtOAc/Hexanes to obtain the desired product as a colorless oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([CH2:30][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[CH:25]=4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[CH:11][CH:10]=1)(C)(C)C.[ClH:37]>O1CCOCC1>[ClH:37].[ClH:37].[ClH:37].[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([CH2:30][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[CH:25]=4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: CCN(CC)Cc1cc(-c2ccn3c(-c4ccc(CNC(=O)OC(C)(C)C)cc4)cnc3c2)ccn1
Agent: Cl
Solvent: C1COCCO1
Product: CCN(CC)Cc1cc(-c2ccn3c(-c4ccc(CN)cc4)cnc3c2)ccn1
Reaction time: 2 h

Procedure:
Dissolve {4-[7-(2-diethylaminomethyl-pyridin-4-yl)-imidazo[1,2-a]pyridin-3-yl]-benzyl}-carbamic acid tert-butyl ester (0.24 g, 0.49 mmol) in dioxane (10 mL) under nitrogen. Add 4 M HCl in dioxane (5 mL) to the reaction and stir for 2 hours. Concentrate to dryness and use crude as the tri-HCl salt (0.321 g, crude). MS (ES), m/z 386.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22](O)=[O:23])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][C:22]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:23])=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1CCNCC1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(CCCC(=O)O)cc2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2ccc(CCCC(=O)N3CCCCC3)cc2)=C(C)C1=O
Yield: 32.1 %

Procedure:
4-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]-n-butyric acid (50 mg, 0.14 mmol) obtained in Example 26 and piperidine (0.015 ml, 0.15 mmol) were used, and a method similar to that described in Example 24 was employed to obtain the title compound (19 mg, 0.045 mmol, yield 32%).
Reaction SMILES: N1C=CC=N1.[OH-].[Na+].Cl[C:9]1[N:13]2[N:14]=[C:15](Cl)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.O>COCCOC>[N:11]1[N:10]=[CH:9][N:13]2[C:12]=1[CH:17]=[CH:16][CH:15]=[N:14]2
Reactant: Clc1ccc2nnc(Cl)n2n1
Agent: [Na+]
Agent: [OH-]
Agent: c1cn[nH]c1
Solvent: COCCOC
Solvent: O
Product: c1cnn2cnnc2c1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
0.61 g of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H)-pyrazole and 5.3 cm3 of a 1N aqueous solution of sodium hydroxide are added to a mixture of 0.5 g of commercial 3,6-dichloro-1,2,4-triazolo[4,3-b]pyridazine in 15 cm3 of 1,2-dimethoxyethane. The reaction mixture is stirred at a temperature in the region of 20° C. for 30 minutes before the addition of 92 mg of palladium dichlorobis(triphenylphosphine). The reaction mixture is then stirred at 65° C. for 30 minutes, and then brought back to a temperature in the region of 20° C. and poured into 20 cm3 of water. The mixture obtained is extracted with 3×100 cm3 of dichloromethane and the combined organic phases are washed with 2×100 cm3 of a saturated aqueous solution of sodium chloride. The resulting organic phase is dried over sodium sulphate, filtered and concentrated by evaporation under reduced pressure. The yellow powder thus obtained is purified by chromatography on silica gel (eluent: 98/2 CH2Cl2/MeOH). 0.2 g of 3-chloro-6-(1-methyl-1H)-pyrazol-4-yl)-1,2,4-triazolo[4,3-b]pyridazine is thus obtained in the form of a beige powder, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](C3C=CN=C(Cl)C=3)=[CH:14][C:6]1=2.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[C:38]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[CH:39]=[CH:40][CH:41]=2)O1>>[Cl:1][C:2]1[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([N:42]4[CH2:43][CH2:44][O:45][CH2:46][CH2:47]4)[CH:37]=3)=[CH:14][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(-c4ccnc(Cl)c4)cc32)c1Cl
Reactant: CC1(C)OB(c2cccc(N3CCOCC3)c2)OC1(C)C
Product: Fc1ccc(F)c(CN2CCNc3ncc(-c4cccc(N5CCOCC5)c4)cc32)c1Cl

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-(2-chloropyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was coupled to 4-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-morpholine as in General Procedure 4B to give the title compound as a yellow solid. LCMS: m/z=457.05 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.21 (4H, t, J=4.8 Hz), 3.29 (2H, t, J=4.7 Hz), 3.52 (2H, t, J=4.2 Hz), 3.89 (4H, t, J=4.8 Hz), 4.52 (2H, s), 5.09 (1H, bs), 6.84 (1H, dd, J=8.0, 1.9 Hz), 7.00 (3H, m), 7.10 (2H, m), 7.29 (1H, m), 7.72 (1H, d, J=1.8 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)=[C:4]([N+:16]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[NH2:16][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[S:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccc(Sc2cccc(O)c2)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: Cc1ccc(Sc2cccc(O)c2)c(N)c1

Procedure:
The product from Example 52a was reduced with SnCl2 following the procedure from Example 1f giving the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:11][C:12]1[NH:16][N:15]=[N:14][N:13]=1>>[NH:13]1[C:12]([NH:11][C:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[O:10])=[N:16][N:15]=[N:14]1
Reactant: Cc1cccnc1C(=O)O
Reactant: Nc1nnn[nH]1
Product: Cc1cccnc1C(=O)Nc1nnn[nH]1
Yield: 9 %

Procedure:
1.49 g of 3-methyl-2-pyridinecarboxylic acid, 1.8 g of N,N'-carbonyldiimidazole and 1.2 g of 5-aminotetrazole are treated in the same manner as described in Example 2. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and ethanol, whereby 0.2 g of N-(5-tetrazolyl)-3-methyl-2-pyridinecarboxamide is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:14][C:13](=[O:15])[CH:12]=[C:11]([OH:16])[CH:10]=1.[N+:17]([O-])([OH:19])=[O:18]>CC(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:14][C:13](=[O:15])[C:12]([N+:17]([O-:19])=[O:18])=[C:11]([OH:16])[CH:10]=1
Reactant: O=c1cc(O)cc(-c2c(Cl)cccc2Cl)[nH]1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2c(Cl)cccc2Cl)cc(O)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 14 h

Procedure:
6-(2,6-Dichlorophenyl)-4-hydroxy-1H-pyridin-2-one (253 mg, 0.990 mmol, prepared as described in the previous step) was placed in a 8 mL vial equipped with a stir bar and AcOH (4 mL) was added. Concentrated HNO3 (0.540 mL, 12.0 mmol) was added via syringe and the vial was capped and stirred at 60° C. for 14 hr. The resulting mixture was cooled to room temperature and poured onto crushed ice (20 mL). The precipitate was isolated by filtration and washed with H2O (10 mL). The solid was air-dried to yield 6-(2,6-Dichloro-phenyl)-4-hydroxy-3-nitro-1H-pyridin-2-one as a yellow powder. The filtrate was extracted with EtOAc (3×10 mL) and the combined extracts were washed with H2O (20 mL), dried over MgSO4 and filtered. The solvent was removed under reduced pressure to yield an additional crop of 6-(2,6-dichloro-phenyl)-4-hydroxy-3-nitro-1H-pyridin-2-one. 1H-NMR (400 MHz, CD3OD) δ: 7.48-7.61 (m, 3H), 6.13 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.C(O)C>ClCCl>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(O)c1ccc(O)cc1
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(COC(=O)c2ccc(O)cc2)cc1

Procedure:
4-Hydroxybenzoic acid (1.38 g) was esterified by alkylation with 4-methoxybenzyl chloride by the method described in Example A-I-1, step a. The title compound (2.06 g) was obtained after silica gel column chromatography (0, 1, 2, 3% ethanol in dichloromethane). Rf (2% MeOH/CHCl3) 0.40.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([NH:16][CH2:17][C:18](O)=[O:19])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:18]([CH2:17][NH:16][C:9](=[O:10])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1cccc(I)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(I)c1
Yield: 60 %

Procedure:
1.15 g of 3-iodoaniline and 097 g of N-BOC-glycine are dissolved in 25 ml of methylene chloride and treated portionwise at 0° with 1.14 g of dicyclohexylcarbodiimide. The separated urea is filtered off and the filtrate is concentrated. Recrystallization from toluene yields tert.butyl [(3-iodo-phenyl-carbamoyl)-methyl]-carbamate as colourless crystals. Yield: 60%. M.p.=126°-128°.
Reaction SMILES: [Cl:1][C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>CN(C=O)C.O>[Cl:1][C:2]1[N:11]([CH2:32][C:31]2[CH:30]=[CH:29][C:28]([C:26](=[O:27])[C:25]3[CH:36]=[CH:37][C:22]([Cl:21])=[CH:23][CH:24]=3)=[CH:35][CH:34]=2)[C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.2 %

Procedure:
To a solution of 8-chlorotheophylline (2.15 g) in DMF (20 ml) was added potassium carbonate (1.66 g) as well as 4-(4-chlorobenzoyl)benzyl bromide (3.10 g) and the mixture was stirred at room temperature for 20 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was washed with ether to provide the title compound as white powder (3.34 g, 75%). 1H-NMR (CDCl3) 6: 3.41(3H,s), 3.57(3H,s), 5.64(2H,s), 7.41-7.52(4H,m), 7.68-7.80(4H,m).