Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]1[CH2:13][CH2:14][N:15](CC2C=CC=CC=2)[CH2:16][CH:17]=1)#[N:2].C([O-])=O.[NH4+]>[Pd].CO>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)#[N:2]
Reactant: N#Cc1ccc2[nH]cc(C3=CCN(Cc4ccccc4)CC3)c2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: N#Cc1ccc2[nH]cc(C3CCNCC3)c2c1
Yield: 55.1 %

Procedure:
A mixture of 0.92 gm (2.9 mMol) 5-cyano-3-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, 1.85 gm (29.3 mMol) ammonium formate and 0.26 gm 5% palladium on carbon in 40 mL methanol were stirred at reflux for 45 minutes. The reaction mixture was then filtered through a pad of Celite and the filtrate concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with dichloromethane containing 20% methanol and 2% ammonium hydroxide. Fractions shown to contain product were combined and concentrated under reduced pressure to give 0.36 gm (55%) of the title compound.
Reaction SMILES: Cl.[C:2]1(/[C:8](/[CH2:38][CH3:39])=[C:9](\[C:25]2[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:27][CH:26]=2)/[C:10]2[CH:24]=[CH:23][C:13]3[N:14](C4CCCCO4)[N:15]=[N:16][C:12]=3[CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.C(OCC)(=O)C>[NH:14]1[C:13]2[CH:23]=[CH:24][C:10](/[C:9](/[C:25]3[CH:26]=[CH:27][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][CH:30]=3)=[C:8](/[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)\[CH2:38][CH3:39])=[CH:11][C:12]=2[N:16]=[N:15]1
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccccc2)c2ccc3c(c2)nnn3C2CCCCO2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccccc2)c2ccc3[nH]nnc3c2)cc1
Temperature: 70 °C

Procedure:
Hydrochloric acid (2.7 mL, 2M in diethyl ether) was added to a solution of (E)-ethyl 3-(4-((E)-2-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d][1,2,3]triazol-5-yl)but-1-en-1-yl)phenyl)acrylate (0.28 g, 0.55 mmol) in ethyl alcohol (27 mL) at room temperature, and the resulting mixture was heated at 70° C. for 2 h. The reaction was monitored by TLC. Upon completion, the mixture was cooled down to room temperature and concentrated to give a pale yellow solid. This solid was dissolved in ethyl acetate (100 mL), washed with saturated NaHCO3 (50 mL), water (100 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give the crude product. This crude material was purified on a silica gel column eluted with 0-50% ethyl acetate in hexanes affording the title compound. LCMS: 424 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][C:12]=2[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:31]([N:33]([CH2:38][CH3:39])[CH2:34][CH2:35][CH2:36]Cl)[CH3:32]>>[CH2:31]([N:33]([CH2:38][CH3:39])[CH2:34][CH2:35][CH2:36][O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][C:12]=2[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1)[CH3:32]
Reactant: CCN(CC)CCCCl
Reactant: O=S(=O)(c1ccc(O)cc1)c1c(Cc2cccc(C(F)(F)F)c2)oc2ccccc12
Product: CCN(CC)CCCOc1ccc(S(=O)(=O)c2c(Cc3cccc(C(F)(F)F)c3)oc3ccccc23)cc1

Procedure:
Reaction of 3-(4-hydroxyphenylsulfonyl)-2-(3-trifluoromethylbenzyl)benzofuran with 3-diethylaminopropyl chloride as described above gives the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13](CC4C=CC(OC)=CC=4)[N:14]=[C:15]([N:16]4[CH2:21][CH2:20][CH:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]4)[C:8]=23)=[C:4]([F:36])[CH:3]=1.[O:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[C:38]1[CH2:46][C:47](O)=[O:48].C([O-])(O)=O.[Na+]>>[O:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[C:38]1[CH2:46][C:47]([NH:1][C:2]1[CH:35]=[CH:34][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][N:14]=[C:15]([N:16]4[CH2:21][CH2:20][CH:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]4)[C:8]=23)=[C:4]([F:36])[CH:3]=1)=[O:48]
Reactant: COc1ccc(Cn2nc(N3CCC(N(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)Cc1nc2ccccc2o1
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C)C1CCN(c2n[nH]c3nccc(Oc4ccc(NC(=O)Cc5nc6ccccc6o5)cc4F)c23)CC1
Yield: 80 %

Procedure:
Prepared by a 2-step process from 1-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N,N-dimethylpiperidin-4-amine (prepared as in Example 93, Step A) and 2-(benzo[d]oxazol-2-yl)acetic acid according to the procedure of Example 21, Steps A and B, except that the crude was treated with aqueous NaHCO3 solution to remove TFA. The crude was rinsed with Et2O to afford 13 mg (80%) of the desired product. LRMS (ESI pos) m/e 530.1 (M+1). 1H-NMR (400 MHz, CD3OD/CDCl3) δ 8.20 (d, 1H), 7.86 (dd, 1H), 7.72 (m, 1H), 7.60 (m, 1H), 7.41 (m, 3H), 7.30 (t, 1H), 6.22 (d, 1H), 4.15 (m, 2H), 2.95 (t, 3H), 2.64 (s, 6H), 2.09 (m, 2H), 1.84 (m, 2H); 19F-NMR (376 MHz, CD3OD/CDCl3) δ −128.7.
Reaction SMILES: C1([C:7](=[N:14]CCCO)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:52][C:53]1[CH:54]=[C:55]([N:60]2[C:64](=[O:65])[O:63][N:62]=[C:61]2[C:66]2[C:67]([NH:71][C:72](=O)[C:73](F)(F)F)=[N:68][O:69][N:70]=2)[CH:56]=[CH:57][C:58]=1[F:59].[F:78][C:79]([F:84])([F:83])[C:80]([OH:82])=[O:81]>O1CCCC1>[F:78][C:79]([F:84])([F:83])[C:80]([OH:82])=[O:81].[NH2:14][CH2:7][CH2:73][CH2:72][NH:71][C:67]1[C:66]([C:61]2[N:60]([C:55]3[CH:56]=[CH:57][C:58]([F:59])=[C:53]([Cl:52])[CH:54]=3)[C:64](=[O:65])[O:63][N:62]=2)=[N:70][O:69][N:68]=1
Reactant: O=C(Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1)C(F)(F)F
Reactant: OCCCN=C(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: NCCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 15 %

Procedure:
A solution of 3-[(diphenylmethylene)amino]propan-1-ol (80 mg, 0.33 mmol) and triphenylphosphine (93 mg, 0.36 mmol) in tetrahydrofuran (1 mL) at 0° C. was treated with diisopropyl azodicarboxylate (75 μL, 0.38 mmol) dropwise. The reaction mixture was stirred at 0° C. for 15 min, treated with a solution of N-{4-[4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-2,2,2-trifluoroacetamide (100 mg, 0.25 mmol) in tetrahydrofuran (0.5 mL), and stirred at 25° C. for 16 h. The reaction mixture was treated with trifluoroacetic acid (1 mL), stirred at 25° C. for 3 h, and concentrated to a crude residue. This material was purified by preparative LCMS to give the desired product (18 mg, 15%). LCMS for C13H13ClFN6O3 (M+H)+: m/z=355.1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=[O:14])[O:12][CH:13]=2)=[CH:5][CH:4]=1.[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:10][C:11](=[O:14])[O:12][C:13]=2[CH:16]([CH3:17])[C:15]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2coc(=O)[nH]2)cc1
Reactant: C=CC(=O)OC
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)C(C)c1oc(=O)[nH]c1-c1ccc(OC)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 20.7 %

Procedure:
4-(4-Methoxyphenyl)-2-oxo-4-oxazoline (1.00 g), methyl acrylate (0.94 mL) was dissolved in toluene (20 mL) and boron trifluoride etherate (1.31 mL) was added. The obtained mixture was heated to 90° C., and after stirring for 2 h, the solvent was concentrated under reduced pressure to give an oily substance. The obtained oily substance was subjected to silica gel column chromatography and eluted with n-hexane-ethyl acetate (1:1). The solvent was evaporated and the obtained oil was crystallized from ethanol. Isopropyl ether (10 mL) was added and the mixture was stirred at not higher than 5° C. for 1 h. The crystals were collected by filtration and washed with isopropyl ether to give the title compound (0.30 g; yield 20.7%) as gray-white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:25])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[C:26]([O:30][C:31]([NH:33][CH2:34][C:35](O)=[O:36])=[O:32])([CH3:29])([CH3:28])[CH3:27]>C(OCC)C>[C:26]([O:30][C:31](=[O:32])[NH:33][CH2:34][C:35](=[O:36])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9](=[O:25])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[O:11])[CH:3]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: Nc1cccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)c1

Procedure:
The title compound is prepared from N-(3-aminophenyl)-2-(4-benzyl-piperidin-1-yl)-2-oxo-acetamide (Example 11) and N-(tert-butoxycarbonyl)glycine (Aldrich) according to the method described in Example 1c. Melting Point: 81-85° C. (diethylether)
Reaction SMILES: Cl.[Cl:2][C:3]1[S:7][C:6]([C:8]([NH2:10])=[NH:9])=[CH:5][CH:4]=1.[CH2:11]([CH:13]([C:19](=O)[CH3:20])[C:14](OCC)=[O:15])[CH3:12].C[O-].[Na+]>C(O)C>[Cl:2][C:3]1[S:7][C:6]([C:8]2[NH:10][C:14](=[O:15])[C:13]([CH2:19][CH3:20])=[C:11]([CH3:12])[N:9]=2)=[CH:5][CH:4]=1
Reactant: N=C(N)c1ccc(Cl)s1
Reactant: CCOC(=O)C(CC)C(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCc1c(C)nc(-c2ccc(Cl)s2)[nH]c1=O
Temperature: 25 °C
Yield: 47 %

Procedure:
A 100-mL round bottomed flask was charged with 5-chlorothiophene-2-carboxamidine HCl salt (394 mg, 2 mmol, 1 eq.), ethyl 2-ethyl-3-oxo-butanoate (950 mg, 6 mmol, 3 eq.), and ethanol (10 ml). To the mixture was added sodium methoxide (25 w % in methanol, 1.73 g, 8 mmol, 3 eq.). The resulting mixture was stirred under reflux for 7 hr. After cooling to room temperature, the mixture was evaporated under reduced pressure to dryness and the residue was treated with 2N HCl (4.5 ml). Solid was collected by filtration and washed with water followed by hexane. The product thus obtained was forwarded to the next step without any further purification (240 mg, 47% yield).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([CH3:15])[NH:5][C:4](=[O:16])[CH:3]=1.[Br:17]Br.N#N>C(O)(=O)C>[CH3:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([CH3:15])[NH:5][C:4](=[O:16])[C:3]=1[Br:17]
Reactant: Cc1cc(=O)[nH]c(C)c1Cc1ccccc1
Reactant: BrBr
Agent: N#N
Solvent: CC(=O)O
Product: Cc1[nH]c(=O)c(Br)c(C)c1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.3 %

Procedure:
To a solution of 4,6-dimethyl-5-benzyl-1H-pyridin-2-one (2.21 g, 10.4 mmol) in anhydrous acetic acid (10 mL) was added bromine (3.3 g, 1.06 mL, 20.7 mL). It was stirred at room temperature for one hour. Then the reaction vessel was blew N2 to remove bromine and evaporation removed volatiles. The residue was partitioned between CH2Cl2/sat. NaHCO3/saline (100/50/50 mL). The organic layer was dried over Na2SO4 and evaporation gave the brominated compound as a yellow solid (3.17 g, 100%). 1H NMR (CDCl3) δ 2.07 (s, 3H), 2.37 (s, 3H), 3.81 (s, 2H), 7.00–7.40 (m, 5H); MS (CI) m/z 293, 295 (MH+).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@@H:21](O)[CH2:22][C@@H:23]([OH:28])[CH2:24][C:25]([OH:27])=[O:26])[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@@H:10]([OH:30])[CH2:9]1)=[O:6])[CH3:4].C1(N=C=NC2CCCCC2)CCCCC1.ON1C(=O)CCC1=O>CN(C)C=O>[CH3:4][CH:3]([CH2:2][CH3:1])[C:5]([O:7][CH:8]1[CH:13]2[C:12]([CH:17]=[CH:16][CH:15]([CH3:18])[CH:14]2[CH2:19][CH2:20][CH:21]2[CH2:22][CH:23]([OH:28])[CH2:24][C:25](=[O:26])[O:27]2)=[CH:11][CH:10]([OH:30])[CH2:9]1)=[O:6]
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)O)[C@H]21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: CCC(C)C(=O)OC1CC(O)C=C2C=CC(C)C(CCC3CC(O)CC(=O)O3)C21
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
To a dry 100 ml round-bottomed flask equipped with a stir bar and CaSO4 drying tube was added 3.32 g (7.44 mmol) of pravastatin, 3.47 g (16.8 mmol) of dicyclohexylcarbodiimide (DCC), 1.93 g (16.8 mmol) of N-hydroxysuccinimide and 50 ml of dry dimethylformamide (DMF) (distilled from CaO) and the mixture stirred at room temperature for 16 hours. The resulting suspension was filtered and the filtrate evaporated at 30° C. under reduced pressure. The residue was taken up in 50 ml of 20:1 CHCl3 :MeOH, filtered and evaporated. The resulting yellow oil was applied to 300 g of silica gel and eluted in a stepwise manner (1 liter of 40:1 CHCl3 :MeOH; 1 liter of 30:1 CHCl3 :MeOH, 1 liter of 20:1 CHCl3 :MeOH). The product was eluted with the 20:1 eluant. The good fractions (TLC, 8:1 CHCl3 :isopropyl alcohol (IPA) were combined and evaporated and the resulting oil triturated with ether to yield 2.15 g (71%) of the title compound as a white powder.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.[CH:26]1([S:29](Cl)(=[O:31])=[O:30])[CH2:28][CH2:27]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][S:29]([CH:26]2[CH2:28][CH2:27]2)(=[O:31])=[O:30])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2cc(CNS(=O)(=O)C3CC3)ccc2Cl)nn1-c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example-100 by using 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.070 g, 0.189 mmol), cyclopropanesulfonyl chloride (0.2 mL), DIPEA (3 mL), and dry THF (5 mL) to afford 0.029 g of pure product. 1H NMR (400 MHz, DMSO d6): δ 0.86-0.92 (m, 4H), 1.14-1.24 (m, 1H), 4.26-4.28 (d, J=6.4 Hz, 2H), 7.57-7.60 (d, J=8.4 Hz, 1H), 7.63-7.68 (d, J=8.4 Hz, 1H), 7.58-7.81 (m, 1H), 7.86-7.88 (d, J=8.8 Hz, 2H), 8.19-8.21 (d, J=8.4 Hz, 2H), 12.89 (br s, 1H); MS (m/z): 471.30 (M−H−).
Reaction SMILES: [CH2:1]([NH2:19])[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:20]1(=[O:25])[O:24][CH2:23][CH2:22][CH2:21]1>>[OH:25][CH2:20][CH2:21][CH2:22][C:23]([NH:19][CH2:1][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])=[O:24]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: O=C1CCCO1
Product: CCCCCCCCCCCCCCCCCCNC(=O)CCCO
Temperature: 150 °C
Reaction time: 2 h

Procedure:
In a glass reaction vessel, 13.5 grams of octadecylamine were admixed with 4.3 grams of butyrolactone. The mixture was then heated to 150° C. by means of an oil bath until the reaction was complete in a period of 2 hours. A conversion of greater than 95% based on butyrolactone was achieved. Upon cooling to room temperature, the product formed a white to pale yellow, hard, waxy solid. Substantially all of the butyrolactone was reacted indicating greater than 95% conversion.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1>>[F:28][C:26]([F:27])([F:29])[C:23]1[N:21]2[N:22]=[C:17]([N:4]3[CH2:5][CH2:6][N:1]([C:7]4[CH:8]=[CH:9][C:10]([C:13](=[O:15])[CH3:14])=[CH:11][CH:12]=4)[CH2:2][CH2:3]3)[CH:18]=[CH:19][C:20]2=[N:25][N:24]=1
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: CC(=O)c1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
A mixture of 1-(4-piperazin-1-ylphenyl)ethanone and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 1-[4-[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]phenyl]ethanone.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[H-].[Na+].[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22]Cl.[Cl-]>CN(C)C=O>[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Reactant: CN(C)CCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCNc1c2c(nc3ccccc13)CCCC2=O
Temperature: 60 °C

Procedure:
To a suspension of 9-amino-3,4-dihydroacridin-1(2H)-one (10.0 g) in 100 ml of dimethylformamide was added a 50% suspension of sodium hydride in oil (2.9 g). To this was added 2-dimethylaminoethyl chloride (6.5 g). The mixture was heated to 60° C. pot temperature for 2.5 hours, an additional 2.7 g of the chloride was added and this was heated for an additional 1 hour.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:24]([CH:34]=O)=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[N:26]=2)[CH:23]=1.O>COCCOC>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:24](/[CH:34]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[N:26]=2)[CH:23]=1
Reactant: O=Cc1c(-c2ccc(Cl)cc2)nc2ccc(Cl)cn12
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)/C=C/c1c(-c2ccc(Cl)cc2)nc2ccc(Cl)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
Ethyl (diethoxyphosphinyl)acetate (0.44 mL, 0.50 g, 2.2 mmol) was added dropwise to a suspension of sodium hydride (60% in mineral oil, 98 mg, 2.5 mmol) in 1,2-dimethoxyethane (10 mL) and the mixture was stirred at room temperature for 1 h. A suspension of 6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3-carboxaldehyde (Description 18, 650 mg, 2.2 mmol) in 1,2-dimethoxyethane (10 mL) was added and the mixture was stirred at room temperature for 1 h. Further sodium hydride (60% in mineral oil, 98 mg, 2.5 mmol) was added and the mixture was stirred at room temperature for 2 h. Water (100 mL) was added and the solid was collected. Toluene was added and evaporated under reduced pressure and the residue was dried in vacuo to give the title compound as a pale brown solid (380 mg, 47%). 1H NMR (360 MHz, CDCl3) δ 8.47 (1H, d, J 1.8 Hz), 7.94 (1H, d, J 16.4 Hz), 7.68 (3H, m), 7.48 (2H, d, J 8.4 Hz), 7.34 (1H, dd, J 9.4, 1.8 Hz), 6.37 (1H, d, J 16.4 Hz), 4.30 (2H, q, J 7.1 Hz), and 1.36 (3H, t, J 7.1 Hz).
Reaction SMILES: C(Cl)(Cl)Cl.[CH2:5]([O:12][C@@H:13]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:17]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:16]([CH2:35][O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:15][C@H:14]1[C:44]1[CH:49]=[C:48]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([CH2:57][CH2:58][NH:59]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:53][CH:52]=2)[C:47]([CH3:79])=[CH:46][C:45]=1[O:80][CH2:81][C:82]1[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.FC(F)(F)C([O-])=O>C(O)C>[CH2:5]([O:12][C@@H:13]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@H:17]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:16]([CH2:35][O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:15][C@H:14]1[C:44]1[CH:49]=[C:48]([CH2:50][C:51]2[CH:52]=[CH:53][C:54]([CH2:57][CH2:58][NH2:59])=[CH:55][CH:56]=2)[C:47]([CH3:79])=[CH:46][C:45]=1[O:80][CH2:81][C:82]1[CH:83]=[CH:84][CH:85]=[CH:86][CH:87]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(CCNC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(CCN)cc1
Reaction time: 3 h
Yield: 103.1 %

Procedure:
To a chloroform solution of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-(benzyloxy)-4-methyl-5-[4-[2-(tritylamino)ethyl]benzyl]phenyl]-D-glucitol (0.402 g, 0.336 mmol) was added at room temperature trifluoroacetate (0.5 mL), and the mixture was stirred for 3 hours at the same temperature. To the reaction solution was added ethanol and then the solvent was evaporated under reduced pressure. Thus obtained residue was purified with NH type silica gel column chromatography (hexane:ethyl acetate=4:6, chloroform:methanol=20:1) to obtain the title compound (0.296 g, quant.) as a colorless oily compound.
Reaction SMILES: C(#N)C.[CH2:4]([C:6]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[C:17]([CH2:19][O:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]([NH:31]C(=O)OC(C)(C)C)=[CH:23][CH:22]=3)[CH:16]=[CH:15][N:14]=2)[CH:9]=[N:8][CH:7]=1)[CH3:5].S(=O)(=O)(O)O.N>O>[NH2:31][C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([O:20][CH2:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:10]3[CH:9]=[N:8][CH:7]=[C:6]([CH2:4][CH3:5])[N:11]=3)[CH:18]=2)=[CH:22][CH:23]=1
Reactant: CCc1cncc(Nc2cc(COc3ccc(NC(=O)OC(C)(C)C)c4ccccc34)ccn2)n1
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Product: CCc1cncc(Nc2cc(COc3ccc(N)c4ccccc34)ccn2)n1
Temperature: 20 °C
Yield: 75 %

Procedure:
Acetonitrile (200 mL) was added to tert-butyl (4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)carbamate (Intermediate D (protected)) (10.5 g) and the heterogeneous mixture was stirred at 20° C. Sulfuric acid (4.5 eq, 5.5 mL) was added over 2 h at 20° C. The heterogeneous mixture was stirred for an additional 2 h at 20° C. Aqueous ammonia (10 eq, 17 mL) was added to the reaction mixture over 15 min and the temperature was kept at 20° C. by cooling. Water (33.4 mL) was added to the heterogeneous mixture over 5 min at 20° C. After stirring for 30 min at 20° C., the mixture was cooled to 5° C. and stirred for an additional 2 h at 5° C. The precipitate was filtered and washed with water (33.4 mL) and 2-propanol (18 mL). The product was dried at 50° C. in vacuo for 24 h to give N-(4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)-6-ethylpyrazin-2-amine (6.2 g, 75%).
Reaction SMILES: [OH-].[Na+].[CH:3]([NH:5][C:6]1[N:11]=[C:10]([C:12](=O)[C:13]([O:15]CC)=[O:14])[CH:9]=[CH:8][CH:7]=1)=[O:4].Cl.[CH3:20][O:21][NH2:22]>C(O)C>[CH:3]([NH:5][C:6]1[N:11]=[C:10]([C:12](=[N:22][O:21][CH3:20])[C:13]([OH:15])=[O:14])[CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: CCOC(=O)C(=O)c1cccc(NC=O)n1
Reactant: CON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CON=C(C(=O)O)c1cccc(NC=O)n1
Reaction time: 0.33 h
Yield: 60.2 %

Procedure:
2N Sodium hydroxide solution [solvent:water (1 part)+ethanol (4 parts)] (14.87 ml.) was added to a solution of ethyl 2-(6-formamidopyridin-2-yl)glyoxylate (6.00 g.) in ethanol (180 ml.) at room temperature and stirred at the same temperature for 20 minutes. Methoxyamine hydrochloride (2.71 g.) was added to the resultant solution, stirred at room temperature for 1.5 hours and then concentrated to a small volume under reduced pressure. The precipitates were collected by filteration washed with ethyl acetate and water, dissolved in methanol and then treated with activated charcoal. The solution was concentrated under reduced pressure and then the precipitates were collected by filtration to give 2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid (3.63 g.), mp 170° to 171° C. (dec.).