Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[C:15]([N:17]2[CH2:21][C@@H:20]([CH:22]3[CH2:24][CH2:23]3)[C@H:19]([CH2:25][N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)[CH2:18]2)=[O:16])[CH:8]=[CH:7]1.C1(=O)[NH:43]C(=O)C2=CC=CC=C12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[NH2:43][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[C:15]([N:17]2[CH2:21][C@@H:20]([CH:22]3[CH2:24][CH2:23]3)[C@H:19]([CH2:25][N:26]3[CH2:27][CH2:28][CH:29]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[CH2:30][CH2:31]3)[CH2:18]2)=[O:16])[CH:8]=[CH:7]1
Reactant: COCCCn1ccc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](C4CC4)C3)c21
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: NCCCn1ccc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](C4CC4)C3)c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.2 %

Procedure:
A mixture of 1 g (4 mmol) of 7-carboethoxy-N-(3-hydroxypropyl)indole (Example 20, Step 1), 1.23 g (8.4 mmol) of phthalimide, 2.12 g (8 mmol) of triphenylphosphine and 1.28 g (8 mmol) of diethylazodicarboxylate in 15 mL of THF was stirred for 12 h at rt. The reaction mixture was concentrated and partitioned between ether and water that had been made basic. The combined organic fractions were dried over MgSO4, filtered andthe filtrate was concentrated. The residue was purified by chromatography (silica, EtOAc:hexanes, 1:4) to give 1.09 g of the title compound. 1H NMR (CDCl3) δ7.8 (m, 2H), 7.7 (m, 4H), 7.2 (d, 1H), 7.1 (t, 1H), 4.45 (t, 2H), 4.2 (q, 2H), 3.7 (t, 2H), 2.1 (m, 2H), 1.35 (t, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[N:8][CH:9]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[N:8][CH:9]=1
Reactant: O=C(O)CCc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CCC(=O)O)nc1
Reaction time: 1.5 h
Yield: 90 %

Procedure:
A solution of 3-(5-nitropyrid-2-yl)propionic acid (4.50 g) in ethanol (140 ml) containing 10% palladium on carbon (0.45 g) was shaken under an atmosphere of hydrogen at 3.4 atmospheres pressure for 1.5 hours. The catalyst was removed by filtration and the filtrate was evaporated to dryness. The residue was recrystallised from acetonitrile to give the title compound (3.43 g) m.p. 118°-120° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B>C1COCC1>[CH2:1]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CC(=O)O)NCc1ccccc1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(CCO)NCc1ccccc1
Reaction time: 1 h
Yield: 47.2 %

Procedure:
To a slurry of 3-Benzylamino-3-methyl-butyric acid (1.00 g, 4.83 mmol) in THF was added borane (9.7 mmol, 9.7 mL of a 1.0 M solution in THF). After stirring for 1 h, the mixture was quenched by pouring into a mixture of 1 M HCl and crushed ice. The mixture was neutralized with K2CO3 and extracted 1× with CHCl3. The material was dried via passage through cotton and concentrated to give 441 mg (47%) of the title compound: Rf 0.40 (12:88 MeOH/CHCl3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(=O)(OC(C)(C)C)OC(C)(C)C.C([O-])([O-])=O.[K+].[K+].ClC1N=C2N(C=1[S:40](Cl)(=[O:42])=[O:41])C=CS2.CC(C)([O-])C.[K+].C([O-])(O)=O.[Na+]>C1COCC1.O.CC(C)=O>[S:40](=[C:10]1[CH:11]=[C:12]2[C:7](=[N:6][CH:5]=[C:4]2[CH2:3][CH2:2][NH2:1])[CH:8]=[CH:9]1)(=[O:42])=[O:41]
Reactant: O=S(=O)(Cl)c1c(Cl)nc2sccn12
Reactant: NCCc1c[nH]c2ccccc12
Agent: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Solvent: CC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: NCCC1=CN=C2C=CC(=S(=O)=O)C=C12
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
A solution of tryptamine (4.2 g, 26.2 mmol) in a 1:1 mixture of acetone; water is treated with di-t-butyl carbonate (6.5 g, 27.8 mmol) and K2CO3 (7.5 g, 54.4 mmol), stirred at room temperature for 16 h, concentrated in vacuo to an aqueous mixture and extracted with EtOAc. The extracts are combined, dried over MgSO4 and concentrated in vacuo. A mixture of the resultant residue (5.6 g, 21 mmol) and 6-chloroimidazo[2,1-b]thiazole-5-sulfonyl chloride (5.01 g, 19.5 mmol) in THF is treated portion-wise with potassium t-butoxide (4.3 g, 39 mmol (2 eq.) at room temperature, stirred for 16 h, poured into a saturated NaHCO3 solution and extracted with EtOAc. The extracts are combined, dried over MgSO4 and concentrated in vacuo. This resultant residue is chromatographed (silica gel, 10%-60% EtOAc in hexanes as gradient eluent) to give the protected 5-sulfonyl-tryptamine intermediate as a tan solid, 5.6 g (60% yield). A solution of said intermediate (6.8 g 14.2 mmol) in isopropanol is treated with 4N HCl in dioxane (40 mL, 11 equiv.), stirred for 4 h and filtered. The filtercake is washed with ether and air-dried to give the title product as an off-white solid 3.2 g (55% yield) mp 239-241° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [N:1]1([C:6]2[CH:18]=[CH:17][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>ClCCl.[OH-].[Na+]>[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:9]2[CH:17]=[CH:18][C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:7][CH:8]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: NCCCCCOc1ccc(-n2ccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCCCOc1ccc(-n2ccnc2)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 2.9 g of 5-[4-(1H-imidazol-1-yl)phenoxy]pentaneamine (Example 27) in 150 ml of dichloromethane and 100 ml 1N NaOH are combined and stirred vigorously as 2.8 g of 4-bromobenzoyl chloride is added. The reaction mixture is stirred at room temperature for 20 hours, the dichloromethane layer separated and dried over Na2SO4. The dichloromethane solution is diluted with 200 ml of hexane, and the solution concentrated to turbidity. Cooling the mixture at room temperature gives the desired product as white crystals, m.p. 150°-151° C.; yield, 1.4 g.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH2:16][CH2:17][N:18]([C:21](=[O:32])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([F:31])([F:30])[F:29])[CH2:19][CH:20]=3)=[N:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:32])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([F:31])([F:29])[F:30])[CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(NCCC1CC1)c1ccc(C2=CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1
Agent: [Pd]
Solvent: CO
Product: O=C(NCCC1CC1)c1ccc(C2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1
Reaction time: 24 h
Yield: 50 %

Procedure:
To a stirred solution of 1′-(2-trifluoromethylbenzoyl)-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-5-carboxylic acid (2-cyclopropylethyl)amide (0.030 g, 0.068 mmol) in methanol (5 mL) was added Pd/C (0.010 g, 12 mol %). The mixture was placed under an atmosphere of hydrogen for 24 hours and then filtered through celite. The filtrate was concentrated in vacuo. The crude product was purified by column chromatography to yield the title compound in 50% yield (0.015 g). 1H NMR (300 MHz, CDCl3) δ 8.91 (s, 1H), 8.12-8.08 (m, 1H), 7.71-7.67 (m, 1H), 7.60-7.47 (m, 2H), 7.38 (d, J=7.5 Hz, 1H), 7.31-7.22 (m, 1H), 6.62 (s, 1H), 4.95-4.85 (m, 1H), 3.55-3.41 (m, 3H), 3.18-2.84 (m, 3H), 2.07-2.02 (m, 1H), 1.92-1.65 (m, 2H), 1.52-1.45 (dd, J=6.9 and 7.0 Hz, 2H), 0.71-0.66 (m, 1H), 0.46-0.44 (m, 2H), 0.07-0.04 (m, 2H). 13C NMR (CDCl3, 75 MHz) δ 167.4, 166.0, 165.2, 147.1, 146.9, 136.6, 136.5, 132.3, 132.2, 129.1, 127.2, 121.1, 120.8, 47.4, 44.0, 41.8, 40.4, 34.3, 31.5, 30.7, 8.6, 4.2. MS (ES+) m/z 446.1 (M+1).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:13]=[C:12]([C:18]2[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.[O-]P([O-])([O-])=O.[Na+].[Na+].[Na+].[CH3:36][NH:37][C:38](=[O:41])[CH2:39]Cl>CN1C(=O)CCC1>[CH:23]([N:19]1[C:18]([C:12]2[N:11]=[C:10]3[C:9]4[CH:26]=[CH:27][C:6]([CH:4]5[CH2:3][N:2]([CH2:39][C:38]([NH:37][CH3:36])=[O:41])[CH2:5]5)=[CH:7][C:8]=4[O:17][CH2:16][CH2:15][N:14]3[CH:13]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CNC3)cc1OCC2
Reactant: CNC(=O)CCl
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CNC(=O)CN1CC(c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)C1
Yield: 28.5 %

Procedure:
A solution of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride from Example 65 (70 mg, 0.2 mmol) in NMP (2 mL) was treated with sodium phosphate tribasic (85 mg, 0.6 mmol) then N-methyl-2-chloro acetamide (24 mg, 0.22 mmol) in NMP (0.2 mL) and the mixture stirred at RT for 18 h. The mixture was loaded onto an Isolute® SCX-2 cartridge eluting with MeOH then 2M NH3 in MeOH. Appropriate fractions were combined and concentrated in vacuo, the resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH in DCM) to give 212 (24 mg, 29%). 1H NMR δ (ppm) (CDCl3): 8.50 (1H, d, J=8.29 Hz), 7.89 (1H, s), 7.68 (1H, s), 7.22 (1H, s), 7.10 (1H, dd, J=8.33, 1.81 Hz), 6.99-6.96 (1H, m), 6.03-5.94 (1H, m), 4.53-4.49 (2H, m), 4.48-4.44 (2H, m), 3.96 (2H, t, J=7.77 Hz), 3.81 (1H, t, J=7.74 Hz), 3.54 (2H, t, J=7.43 Hz), 3.35 (2H, s), 2.86 (3H, d, J=4.93 Hz), 1.60 (6H, d, J=6.63 Hz). LCMS: RT=2.53 min, M+H+=422
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=3[Cl:26])=[C:16]([C:27](OCC)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=3[Cl:26])=[C:16]([C:27]([N:42]3[CH2:43][CH2:44][CH:39]([C:36]4[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=4)[CH2:40][CH2:41]3)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC(C)(C)C)cnn2c1Nc1cc(C)ccc1Cl
Reactant: Fc1ccc(C2CCNCC2)cc1
Product: Cc1ccc(Cl)c(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(S(=O)(=O)NC(C)(C)C)cnn23)c1
Yield: 28.6 %

Procedure:
Using ethyl 3-(N-tert-butylsulfamoyl)-7-(2-chloro-5-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (2.31 g, 4.96 mmol) obtained in step 3 and 4-(4-fluorophenyl)piperidine (0.92 g, 5.14 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (0.85 g, 41%) was obtained.
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]([C:14]3[N:18]([CH3:19])[C:17]4[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=4[N:15]=3)=[O:13])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:19][N:18]1[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[N:15]=[C:14]1[C:12]([N:10]1[CH2:11][CH:8]([C:3]2[C:2]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:9]1)=[O:13]
Reactant: OB(O)c1ccccc1
Reactant: Cn1c(C(=O)N2CC(c3nccnc3Cl)C2)nc2ccccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1c(C(=O)N2CC(c3nccnc3-c3ccccc3)C2)nc2ccccc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 56.7 %

Procedure:
To a stirred solution of [3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-(1-methyl-1H-benzoimidazol-2-yl)-methanone (100 mg, 0.30 mmol) in dioxane (10 mL) was added phenylboronic acid (87 mg, 0.71 mmol), Na2CO3 (152 mg, 1.4 mmol) and H2O (2 mL). The reaction mixture was degassed with N2 and then PdCl2(dppf) (35 mg, 0.05 mmol) was added. The reaction mixture was stirred at 80° C. for 12 h. The reaction mixture was left to reach RT and filtered through a pad of CELITE® and the filter cake was washed with CH2Cl2 (20 mL×3). The combined filtrates were evaporated in vacuo and the residue was purified by column chromatography to give the desired compound (60 mg, 0.17 mmol, yield 70%)
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][C:6](=[C:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.Cl.O>O1CCCC1.[Cl-].[Na+].O>[CH:15]1([CH:12]2[CH2:13][CH2:14][C:9](=[C:6]3[CH2:7][CH2:8][C:3](=[O:2])[CH2:4][CH2:5]3)[CH2:10][CH2:11]2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COC1(OC)CCC(=C2CCC(C3CCCCC3)CC2)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCC(=C2CCC(C3CCCCC3)CC2)CC1
Yield: 107.8 %

Procedure:
A solution of 4-(4'-cyclohexylcyclohexylidene)cyclohexanone dimethyl ketal (0.016 mol) and 1.0N HCl (100 ml) in tetrahydrofuran (125 ml) was left at room temperature for 2.5 hours at which time TLC indicated hydrolysis to be complete. Water and brine were added to the reaction solution and the mixture was extracted with ether (4×). The pooled ether extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to give 4.49 g of white solid. This solid was chromatographed (790 g of 40-63 μm silica gel, 4.51 of 5% ethyl acetate-hexane followed by 10% ethyl acetate-hexane) with 4-(4'-cyclohexylcyclohexylidene)cyclohexanonedimethyl ketal (0.56 g, 10%) eluted first followed by the title compound. Recrystallization of the title compound from hexane gave colorless crystals, mp 81°-81.5° C.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][N:12]1[C:34](=[O:35])[N:15]2[N:16]=[CH:17][C:18]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[C:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C:14]2=[N:13]1)(=O)C.O(C)[Na].C(O)(=O)C>CO>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][N:12]1[C:34](=[O:35])[N:15]2[N:16]=[CH:17][C:18]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[C:19]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[C:14]2=[N:13]1
Reactant: CC(=O)Oc1ccccc1Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Agent: CO[Na]
Solvent: CO
Solvent: CC(=O)O
Product: O=c1n(Cc2ccccc2O)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reaction time: 8 h
Yield: 79 %

Procedure:
2-((7,8-Bis(4-chlorophenyl)-3-oxo-[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl)methyl)phenyl acetate, prepared as described in 25A, (1.13 g), was dissolved in 25 mL of CH3OH. A solution of NaOCH3 (121 mg, 2.24 mmol) in a small amount of CH3OH (2 mL) was added to the reaction, and then, the reaction was stirred overnight. After this time, 0.3 mL of acetic acid was added to the reaction. The reaction was stirred for an additional 10 min, and then the resultant solution was concentrated under reduced pressure. The crude residue was purified using silica gel column chromatography using an automated system, eluting with a gradient of 0% to 60% EtOAc/hexanes for 30 min followed by 60% EtOAc/hexanes for an additional 15 min. The title compound, 2-(2-hydroxybenzyl)-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (818 mg, 79% yield) was obtained as yellow solid. MS [M+H]+=463; 1H NMR (CDCl3, 400 MHz) δ 8.54 (s, 1H), 8.14 (s, 1H), 7.32-7.17 (m, 8H), 7.04-7.00 (m, 2H), 6.94 (dd, 1H), 6.81 (td, 1H), 5.13 (s, 2H).
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:5]=[C:6]([CH:24]=[C:25]([Br:27])[CH:26]=1)[CH2:7][O:8][C@@H:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@H:10]1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(N(C(C)C)CC)(C)C.Cl[CH2:38][C:39]1[NH:40][C:41](=[O:44])[NH:42][N:43]=1>CN(C)C=O.ClCCl>[Br:3][C:4]1[CH:5]=[C:6]([CH:24]=[C:25]([Br:27])[CH:26]=1)[CH2:7][O:8][C@@H:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@H:10]1[N:18]1[CH2:23][CH2:22][N:21]([CH2:38][C:39]2[NH:40][C:41](=[O:44])[NH:42][N:43]=2)[CH2:20][CH2:19]1
Reactant: Brc1cc(Br)cc(CO[C@@H]2Cc3ccccc3[C@H]2N2CCNCC2)c1
Reactant: O=c1[nH]nc(CCl)[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]nc(CN2CCN([C@@H]3c4ccccc4C[C@H]3OCc3cc(Br)cc(Br)c3)CC2)[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
After reconversion to the base, the compound obtained in Step C of Example 1 (2.14 mmol) is dissolved in 30 ml of dimethylformamide. There are added 0.75 ml (4.28 mmol) of diisopropylethylamine and 314 mg (2.35 mmol) of 5-(chloromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one prepared according to the method described in Tetrahedron Letters,2000, 41, 8661. The mixture is stirred for 12 hours at ambient temperature and then evaporated to dryness. The residue obtained is taken up in dichloromethane, washed, dried, filtered and evaporated. The oil obtained is purified by flash chromatography on silica to yield the expected product.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:29])[N:10]([CH:12]1[CH2:16][CH2:15][N:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[N:25]=3)[N:20]=[CH:19][CH:18]=2)[CH2:13]1)[CH3:11])(C)(C)C.Cl.C(N(CC)CC)C.[O:39]=[C:40]1[CH2:45][O:44][C:43]2[CH:46]=[CH:47][C:48]([CH:50]=O)=[N:49][C:42]=2[NH:41]1.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.O1CCOCC1.CO.ClCCl.CO>[CH3:11][N:10]([CH:12]1[CH2:16][CH2:15][N:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[N:25]=3)[N:20]=[CH:19][CH:18]=2)[CH2:13]1)[C:9](=[O:29])[CH2:8][NH:7][CH2:50][C:48]1[CH:47]=[CH:46][C:43]2[O:44][CH2:45][C:40](=[O:39])[NH:41][C:42]=2[N:49]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: COc1ccc2nccc(N3CCC(N(C)C(=O)CNC(=O)OC(C)(C)C)C3)c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COc1ccc2nccc(N3CCC(N(C)C(=O)CNCc4ccc5c(n4)NC(=O)CO5)C3)c2n1
Reaction time: 1 h

Procedure:
({[1-(6-Methoxy-[1,5]naphthyridin-4-yl)-pyrrolidin-3-yl]-methyl-carbamoyl}-methyl)-carbamic acid tert-butyl ester (272 mg, 0.66 mmol) was dissolved in a minimum amount of chloroform and treated with 4N HCl in dioxane (3 mL). After stirring 1 h, the reaction mixture was concentrated to dryness and azeotroped with toluene. The resulting HCl salt (302 mg, 0.66 mmol) was dissolved in methanol/dichloromethane (8 mL, 1:3) and treated with triethylamine (0.46 mL, 3.3 mmol) and 3-Oxo-3,4-dihydro-2H -pyrido[3,2-b ][1,4]oxazine-6-carbaldehyde (117 mg, 0.66 mmol) and stirred for 72 hours. The solution was diluted with a small amount of methanol and treated with sodium borohydride (25 mg, 0.66 mmol.) After stirring 90 minutes, the reaction mixture was diluted with chloroform and poured into saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with chloroform. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, concentrated and chromatographed in chloroform/methanol/ammonia. The resulting solid was converted to a di-HCl salt of the title compound as an off-white solid (27 mg, 8.6%): LC-MS m/z 478 (M+H)+; 1H NMR (CDCl3, 400 MHz) δ 8.25 (d, 1H, J=6 Hz), 8.02 (d, J=9 Hz, 1H), 7.29 (m, 1H), 7.11 (d, J=9 Hz, 1H), 6.99 (d, J=8 Hz, 1H), 6.62 (d, J=6 Hz, 1H), 5.23 (m, 1H), 4.63 (m, 2H), 4.18 (m, 3H), 4.01 (m, 3H), 3.81 (m, 2H), 3.68 (s, 1H), 3.57 (s, 1H), 3.00 (s, 2H), 2.26 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]([C:8]#[N:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C=CC=CC=1.[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:18]=1[C:19](Cl)=[O:20]>ClCCl.C(OCC)(=O)C>[C:8]([CH:2]([NH:1][C:19](=[O:20])[C:18]1[C:17]([F:16])=[CH:25][CH:24]=[CH:23][C:22]=1[F:26])[C:3]([O:5][CH2:6][CH3:7])=[O:4])#[N:9]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CCOC(=O)C(N)C#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(C#N)NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a solution of ethyl 2-amino-2-cyanoacetate (1 eq) in 6 mL of dichloromethane was added pyridine (1.5 eq) and 2,6-difluorobenzoyl chloride (1 eq) at 0° C. The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate, washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc: hexanes=1:1) to give the titled compound (84%). LC/MS (m/z): 269.1 (MH+), Rt: 0.69 min.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][N:30]([C:33](=[O:36])[CH2:34][CH3:35])[CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: CCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f21) and commercially propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3Br)[CH2:5][C:4]=2[N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>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.C(O)C>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[CH2:5][C:4]=2[N:3]=1
Reactant: OB(O)c1cccnc1
Reactant: Nc1ncc2c(n1)CC(c1ccc(F)cc1Br)CC2=O
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: CCO
Product: Nc1ncc2c(n1)CC(c1ccc(F)cc1-c1cccnc1)CC2=O
Temperature: 150 °C

Procedure:
To a microwave vessel was added 2-amino-7-(2-bromo-4-fluoro-phenyl)-7,8-dihydro-6H-quinazolin-5-one (30 mg, 0.089 mmol), example 2/i stage 2, pyridine-3-boronic acid (22 mg, 0.11 mmol), potassium carbonate (51 mg, 0.22 mmol) and tetrakis(triphenylphosphine)palladium (9 mg, 5 mol %), in a 2:1 mixture of ethanol:toluene (1 ml) and the suspension thoroughly degassed. The reaction mixture was then heated in a CEM microwave at 300 W, 150° C. with a 5 min ramp time and a hold time of 30 min. On completion of the reaction the solution was filtered through celite and then the cake further washed with fresh methanol. The combined washings were evaporated to give a pale yellow residue which was triturated with fresh diethyl ether and the desired product removed by filtration as a pale yellow solid.