Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[C:4](=[O:10])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[CH3:11][CH:12]1[CH2:17][NH:16][CH2:15][CH2:14][NH:13]1>CO>[CH3:11][CH:12]1[NH:13][CH2:14][CH2:15][N:16]([C:3]2[C:4](=[O:10])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:17]1
Reactant: COc1cccccc1=O
Reactant: CC1CNCCN1
Solvent: CO
Product: CC1CN(c2cccccc2=O)CCN1
Yield: 70.6 %

Procedure:
A solution of 2-methoxy-2,4,6-cycloheptatrien-1-one (6.8 g) and 2-methylpiperazine (5 g) in methanol was refluxed for 16 hr and evaporated. The residue (11 g) was chromatographed on silica gel (250 g) using methanol and the eluate was evaporated to give 7.2 g of 2-(3-methyl-1-piperazinyl)-2,4,6-cycloheptatrien-1-one.
Reaction SMILES: [Na].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Br[CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25]>CN(C)C=O>[N:2]1([CH2:12][CH2:13][CH2:14][N:15]2[C:19](=[O:20])[C:18]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]3[C:16]2=[O:25])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[NH2:2][NH2:3]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: c1ccc2[nH]ncc2c1
Agent: [Na]
Solvent: CN(C)C=O
Product: NN
Product: O=C1c2ccccc2C(=O)N1CCCn1ncc2ccccc21

Procedure:
The reaction of the sodium salt of indazole with N-(3-bromopropyl)phthalimide in dimethylformamide solution gives N-(3-(1H-indazol-1-yl)propyl)phthalimide, which upon treatment with hydrazine in refluxing ethanol leads to (3-(1H-indazol-1-yl)propanamine.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1.Cl.[NH2:19][CH2:20][C@H:21]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[C:13]([OH:15])(=[O:14])[CH3:12].[C:25]([O:24][C:22](=[O:23])[C@@H:21]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH2:20][NH:19][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][C:3]2[NH:2][CH:6]=[CH:5][N:4]=2)=[CH:17][CH:16]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Reactant: O=C(O)c1ccc(CCc2ncc[nH]2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(=O)O
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCc2ncc[nH]2)cc1)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acid 23-5 (ca 2 mmol), amine 2-1 (700 mg, 2.0 mmol), HOBT (324 mg, 2.4 mmol), and NMM (0.77 mL, 7.0 mmol) were combined in 10 mL DMF at -15°, then EDC (364 mg, 1.9 mmol) was added The mixture was warmed to RT, stirred overnight, then concentrated. Flash chromatography (silica, 4:1:1 CH2Cl2 /MeOH/HOAc) provided 23-6, Rf 0.22 (silica, 4:1:1 CH2Cl2 :MeOH:HOAc).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:26])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][C:14]=2[CH3:25])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1.C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:28]4[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=4)[CH2:21][CH2:20]3)=[CH:15][C:14]=2[CH3:25])=[O:26])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(N2CCNCC2)ccc1C(=O)Nc1cccc(C(C)(C)C)c1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: Cc1cc(N2CCN(c3ccc(C(=O)O)cc3)CC2)ccc1C(=O)Nc1cccc(C(C)(C)C)c1

Procedure:
4-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-3-methyl-phenyl]-piperazin-1-yl}-benzoic acid was synthesized by the coupling of N-(3-tert-butyl-phenyl)-2-methyl-4-piperazin-1-yl-benzamide and 4-bromo benzoic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C29H33N3O3 (m/e) 471, obsd 472 (M+H).
Reaction SMILES: Cl.[Br:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:24]=1[CH:25]=O.[BH4-].[Na+]>CO.C(OCC)(=O)C>[Br:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][CH2:25][C:24]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:23]=3[Cl:22])[CH2:10]2)[CH:6]=[CH:5][CH:4]=1
Reactant: N[C@H]1CCN(c2cccc(Br)n2)C1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Clc1ccc(CN[C@H]2CCN(c3cccc(Br)n3)C2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve (3S)-1-(6-bromopyridin-2-yl)-pyrrolidin-3-ylamine hydrochloride (131 mg, 0.47 mmol) in methanol. Add triethylamine (200 μL, 1.44 mmol) and 2,4-dichlorobenzaldehyde (116 mg, 0.66 mmol). Stir at room temperature overnight. Add sodium borohydride (100 mg, 2.63 mmol) and stir 2 hours. Pour onto a column of Dowex® 50wx4-200 and wash with methanol. Elute with 10:90 triethylamine:methanol, concentrate to give a residue. Chromatograph the residue on silica gel eluting with 100:0 to 40:60 ethyl acetate:hexanes to give the title compound. Combine the title compound and ethyl acetate and add 1 N hydrochloric acid in methanol (1.5 mL). Concentrate to dryness to give the hydrochloride salt of the title compound (174 mg, 85%). 1H NMR (400 MHz, MeOH-d4) δ 7.67 (d, 1H, J=2.0 Hz), 7.64 (d, 1H, J=8.0 Hz), 7.49 (dd, 1H, J=8.0, 2.0 Hz), 7.40 (t, H, J=8.0 Hz), 6.79 (d, 1H, J=8.0 Hz), 6.49 (d, 1H, J=8.0 Hz), 4.46 (s, 2H), 4.17-4.11 (m, 1H), 3.95-3.91 (m, 1H), 3.79-3.75 (m, 1H), 3.73-3.66 (m, 1H), 3.54-3.48 (m, 1H), 2.65-2.56 (m, 1H), 2.38-2.29 (m, 1H); MS (ES): m/z=400 [M+H].
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1([CH2:11][CH2:12][C:13]([OH:15])=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:16][C@H:17]([NH:26][CH3:27])[C@@H:18]([OH:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[OH:25][CH:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH:17]([N:26]([CH3:27])[C:13](=[O:15])[CH2:12][CH2:11][CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)[CH3:16]
Reactant: CN[C@@H](C)[C@@H](O)c1ccccc1
Reactant: O=C(O)CCC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C(O)c1ccccc1)N(C)C(=O)CCC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (3.5 mL, 48 mmol) was added to a solution of cyclohexanepropionic acid (5.5 mL, 32 mmol) in CH2Cl2 (60 mL). The mixture was heated at reflux for 60 min and then allowed to cool to ambient temperature and the solvent removed. The residue was redissolved in THF (50 mL) and (1R,2R) pseudoephedrine (4.8 g, 29 mmol) in THF (60 mL) was added to the reaction mixture at 0° C. After stirring for 30 min, a solution of saturated NaHCO3 was added to the mixture which was then extracted with EtOAc. The organic phase was dried (MgSO4) and concentrated. The residue was chromatographed (silica gel; EtOAc/hexanes 1:1) to afford an oil which solidified when placed in the refrigerator over night (8.2 g, 94%). MS (CI/NH3) m/z: 304 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(N(CC)CC)C.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[C:14]=1[CH2:21][C:22](=O)[CH3:23]>CO>[CH3:2][O:3][N:4]=[C:22]([CH3:23])[CH2:21][C:14]1[C:15]([Cl:20])=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=1[Cl:12]
Reactant: CC(=O)Cc1c(Cl)cc(Cl)cc1Cl
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CON=C(C)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
A solution of O-methyl-hydroxylamine hydrochloride (0.79 g, 9.4 mmol) in methanol (20 ml) was treated with triethylamine (1.32 ml, 9.4 mmol) followed by 1-(2,4,6-trichlorophenyl)-propan-2-one (1.5 g, 6.31 mmole). The resulting mixture was stirred at 60° C. for 3 hours. The reaction mixture was quenched with water and methanol was evaporated off. The resulting aqueous medium was extracted with ethylacetate (3×50 ml). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure (100 mbar; 45° C.). The resulting crude mass was purified by column chromatography using 60-120μ mesh silica gel and product collected at 2% ethyl acetate in hexane as elution system to give 1-(2,4,6-Trichloro-phenyl)-propan-2-one O-methyl-oxime (1.2 g, 76%), which was taken up for further reduction.
Reaction SMILES: [C:1]([O:4][CH2:5][C@:6]1([OH:24])[CH2:15][C:14]2[C:9](=[C:10]([O:18][CH3:19])[CH:11]=[CH:12][C:13]=2[O:16][CH3:17])[C:8]2(SCCS2)[CH2:7]1)(=[O:3])[CH3:2].O.C([O:28]CC)C>O1CCCC1.CO>[C:1]([O:4][CH2:5][C@:6]1([OH:24])[CH2:15][C:14]2[C:9](=[C:10]([O:18][CH3:19])[CH:11]=[CH:12][C:13]=2[O:16][CH3:17])[C:8](=[O:28])[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CCOCC
Reactant: COc1ccc(OC)c2c1C[C@@](O)(COC(C)=O)CC21SCCS1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(OC)c2c1C[C@@](O)(COC(C)=O)CC2=O
Reaction time: 1 h

Procedure:
1.9 g of (S)-3'-acetoxymethyl-1',2',3',4'-tetrahydro-3'-hydroxy-5',8'-dimethoxyspiro[1,3-dithiolane-2,1'-naphthalene] in 40 ml of tetrahydrofuran were added to a stirred suspension of 6.4 g of mercuric chloride and 6.4 g of mercuric oxide in 200 ml of methanol containing 18 ml of water. After standing at room temperature for 1 hour, ca 150 ml of solvent were removed by evaporation under reduced pressure, 200 ml of dichloromethane were added and the resulting suspension was filtered to remove insoluble material. The filtrate was washed with three 200 ml portions of water, dried over magnesium sulphate and evaporated to give a solid residue. Trituration with diethyl ether gave (S)-3-acetoxymethyl-1,2,3,4-tetrahydro-3-hydroxy-5,8-dimethoxy-1-oxo-naphthalene in the form of an off-white powder which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)=[N:11][C:10]=2[C:25]([NH2:27])=[O:26])=[O:7])=[CH:4][CH:3]=1.CCN(CC)CC.[C:37]([O:40][CH2:41][C:42](Cl)=[O:43])(=[O:39])[CH3:38]>C1COCC1>[C:37]([O:40][CH2:41][C:42]([NH:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)=[N:11][C:10]=2[C:25]([NH2:27])=[O:26])=[O:7])=[CH:4][CH:3]=1)=[O:43])(=[O:39])[CH3:38]
Reactant: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)c1ccc(N)cc1
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)Nc1ccc(C(=O)Nc2sc(Nc3ccc4ccccc4c3)nc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a mixture of 5-(4-aminobenzamido)-2-(naphthalen-2-ylamino)thiazole-4-carboxamide (0.15 g, 0.37 mmol) and Et3N (0.3 mL, 2.33 mmol) in THF (20 mL) was added acetoxyacetyl chloride (0.12 mL, 1.11 mmol) at 0° C. The mixture was stirred overnight at rt. The solvent was evaporated, and the residue was purified by silica gel column chromatography eluted with 50% EtOAc in hexane to give 0.15 g (80% yield) of the titled compound.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[S:8][C:7]([CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:6][C:5]=1[C:16]([OH:18])=O)[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:43]1[C:51]2[C:46](=[C:47]([C:52]3[CH:53]=[C:54]([NH2:61])[C:55]4[CH:56]=[N:57][NH:58][C:59]=4[CH:60]=3)[CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44]1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:43]1[C:51]2[C:46](=[C:47]([C:52]3[CH:60]=[C:59]4[C:55]([CH:56]=[N:57][NH:58]4)=[C:54]([NH:61][C:16]([C:5]4[N:6]=[C:7]([CH2:9][N:10]5[CH2:11][CH2:12][O:13][CH2:14][CH2:15]5)[S:8][C:4]=4[CH:2]([CH3:1])[CH3:3])=[O:18])[CH:53]=3)[CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44]1
Reactant: CC(C)c1sc(CN2CCOCC2)nc1C(=O)O
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1sc(CN2CCOCC2)nc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 30.5 %

Procedure:
To a solution of 5-(1-methylethyl)-2-(4-morpholinylmethyl)-1,3-thiazole-4-carboxylic acid (31 mg) in DMF (3 ml) was added HATU (44 mg) and the mixture stirred at 20° C. for 10 min, then 6-(1H-indol-4-yl)-1H-indazol-4-amine (13 mg) and DIPEA (0.037 ml) were added and the mixture allowed to stand for 18 h. The mixture was blown to dryness under a stream of nitrogen and the residue purified by mass directed preparative HPLC (Method A) to give the title compound (8 mg) as a pale brown solid.
Reaction SMILES: [O-]CC.[Na+].[C:5]([NH:8][CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:7])[CH3:6].Cl[CH2:21][C:22]1[C:23]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:24]([O:28][CH3:29])[CH:25]=[CH:26][CH:27]=1.O>C(O)C.C(O)(=O)C>[C:5]([NH:8][C:9]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:7])[CH3:6]
Reactant: COc1cccc(CCl)c1OCc1ccccc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(Cc1cccc(OC)c1OCc1ccccc1)(NC(C)=O)C(=O)OCC
Temperature: 0 °C
Yield: 66.4 %

Procedure:
A quantity of 136.20 g (0.42 mole) of 21 wt.% sodium ethoxide in ethanol is added to a stirred solution of 90.14 g (0.415 mole) of diethyl acetamidomalonate (Aldrich) in 800 mL of absolute ethanol. A solution of the benzyl chloride derivative of Example 38 in 500 mL of absolute ethanol is added and the mixture is heated at reflux for 2 hours. The cooled mixture is poured into 4 L of ice and water containing 20.0 g of glacial acetic acid. The supernatant is decanted from the separated gum. The gum is dissolved in 2 L of ether, the solution dried (magnesium sulfate), and concentrated to ca 300 mL volume. Petroleum ether (100 mL) is added to precipitate 107.1 g (66.4% yield) of pure crystalline product; mp 94°-96° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:40][N:41]([CH3:56])[CH2:42][CH2:43][N:44]([CH3:55])[C:45]1[S:46][C:47]2[CH:53]=[C:52]([NH2:54])[CH:51]=[CH:50][C:48]=2[N:49]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[CH3:40][N:41]([CH3:56])[CH2:42][CH2:43][N:44]([CH3:55])[C:45]1[S:46][C:47]2[CH:53]=[C:52]([NH:54][C:9](=[O:11])[CH:8]=[CH:7][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:14])=[CH:13][CH:12]=3)[CH:51]=[CH:50][C:48]=2[N:49]=1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)C=Cc3ccc(C(F)(F)F)cc3)cc2s1
Yield: 21.2 %

Procedure:
Prepare according to Method A, using trans-4-trifluoromethylcinnamic acid (130 mg, 0.60 mmol), HATU (229 mg, 0.602 mmol), N2-(2-dimethylamino-ethyl)-N2-methyl-benzothiazole-2,6-diamine (100 mg, 0.400 mmol), DIEA (260 μL, 1.49 mmol), and a chromatography gradient of MeOH in CH2Cl2 (8-20%) to afford the title compound (38 mg, 21%). mass spectrum (m/e): 449.0 [M+H], 447.0 [M−H]. 1H NMR (400 MHz, DMSO-d6): δ 10.50 (s, 1H), 8.31 (d, 1H, J=2.2 Hz), 7.87-7.78 (m, 4H), 7.64 (d, 1H, J=15.8 Hz), 7.52 (dd, 1H, J=8.8, 2.2 Hz), 7.44 (d, 1H, J=8.8 Hz), 7.03 (d, 1H, J=15.8 Hz), 3.97 (dd, 2H, J=6.4, 6.4 Hz), 3.39 (dd, 2H, J=6.2, 6.2 Hz), 3.13 (s, 3H), 2.85 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:13]=1[NH2:14]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[NH:14][C:13]3[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:12]=3[N:11]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: O=C(O)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2nc(-c3ccc(Cl)cc3)[nH]c2c1
Yield: 87 %

Procedure:
Prepared from 4-chlorobenzoic acid (17.83 g, 0.114 mol) and 2-amino-5-nitroaniline (18 g, 0.114 mol), in a manner similar to that of Example 9b. Yield: 87%; Rf (6/4 toluene/ethyl acetate): 0.61; m.p.: 302.5-305° C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:24](=[O:25])[N:11]3[N:12]=[C:13](Cl)[C:14]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)=[CH:15][C:10]3=[N:9]2)=[CH:5][CH:4]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>O.C1(C)C=CC=CC=1.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>[F:28][C:2]([F:29])([F:1])[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:24](=[O:25])[N:11]3[N:12]=[C:13]([C:34]4[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=4)[C:14]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)=[CH:15][C:10]3=[N:9]2)=[CH:5][CH:4]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2cc(-c3ccc(Cl)cc3)c(Cl)nn12
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: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nn12
Temperature: 125 °C
Reaction time: 10 h
Yield: 12.6 %

Procedure:
To a suspension of 2-(4-(trifluoromethyl)benzyl)-6-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (150 mg, 0.34 mmol), 4-chlorophenylboronic acid (60 mg, 0.38 mmol), Na2CO3 (90 mg, 0.85 mmol) dissolved in water (0.2 mL) in toluene (3 mL) was added Pd(PPh3)4 (25 mg, 0.02 mmol). The resulting reaction mixture was bubbled with argon for 10 min before the flask was placed in an oil bath preheated at 125° C. After stirring at 125° C. for 10 h, the reaction was then allowed to cool to room temperature. To the reaction was added water (10 mL), the aqueous mixture extracted with EtOAc (10 mL×3). The combined EtOAc extracts were washed with water (10 mL×2), followed by saturated aqueous NaCl (10 mL×2) and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (Conditions: Phenomenex Luna 5μ C18 21.2×100 mm; Eluted with 17% to 100% B, 25 min gradient, hold at 100% B for 5 min (A=90% H2O, 10% acetonitrile and B=10% H2O, 90% acetonitrile); Flow rate at 20 mL/min, UV detection at 220 nm) to obtain 22 mg (13%) the title compound as a yellow solid. LC/MS (Method C): retention time=4.26 min; (M+H)+=515. 1H NMR (CDCl3, 500 MHz): δ 7.61 (d,J=5.0 Hz, 2H), 7.56 (d,J=5.0 Hz, 2H), 7.41(s, 1H), 7.24-7.30 (m, 4H), 7.21 (d,J=5.0 Hz, 2H,), 7.01 (d,J=5.0 Hz, 2H), 5.29 (s, 2H).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][SH:5].[Na].Br[CH2:8][C:9]1[CH:13]=[CH:12][S:11][N:10]=1>C(O)C>[ClH:1].[NH2:2][CH2:3][CH2:4][S:5][CH2:8][C:9]1[CH:13]=[CH:12][S:11][N:10]=1
Reactant: NCCS
Reactant: BrCc1ccsn1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: NCCSCc1ccsn1
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A solution was prepared by the gradual addition of cysteamine hydrochloride (2.03 g.) to sodium (0.83 g.) dissolved in ethanol (50 ml.) with stirring at 0° under a nitrogen atmosphere. After stirring for 2 hours at 0°, 3-bromomethylisothiazole (3.2 g.) was added dropwise over 15 minutes at 0°, the reaction mixture subsequently being set aside overnight at room temperature. Following acidification to pH 3.5 with hydrochloric acid, concentration and re-evaporation with ethanol, the residue was dissolved in ethanol, filtered and concentrated to yield 3-[(2-aminoethyl)thiomethyl]isothiazole hydrochloride (3.5 g.). This was converted directly to the free base by treatment with aqueous potassium carbonate and extraction with ether. The extracts were dried over magnesium sulphate, filtered and concentrated to yield the amine base as an oil (1.56 g.). The amine was dissolved in ethanol (10 ml.), methyl isothiocyanate (0.66 g.) added, and the solution heated under reflux for 30 minutes. Concentration, followed by purification of the crude product by chromatography on a column of silica gel with ethyl acetate as eluant followed by chromatography on a column of alumina with benzene-ethyl acetate as eluant gave N-methyl-N'-[2-(3-isothiazolylmethylthio)ethyl]thiourea. (Found: C, 38.9; H, 5.4; N, 16.5; S, 38.3. C8H13N3S3 requires: C, 38.8; H, 5.3; N, 17.0; S, 38.9).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][OH:10])[C:5]([CH:11]([O:19]C(=O)C)[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][N:3]=1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][O:10][S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=2)(=[O:31])=[O:30])[C:5]([CH:11]([OH:19])[C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[CH:4][N:3]=1
Reactant: CC(=O)OC(c1ccc(Cl)cc1)c1cnc(C)c(O)c1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCc2c(C(O)c3ccc(Cl)cc3)cnc(C)c2O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.4 %

Procedure:
0.24 g (0.66 mmole) of (+)-2-methyl-3-hydroxy-4- hydroxymethyl-5-[4-chloro-α-acetoxybenzyl]pyridine are poured into a 25 ml round bottomed flask and dissolved in 10 ml of methylene chloride. 190 mg (1 mmole) of p-toluene sulphonyl chloride and 75 mg (1 mmole) of pyridine are then added. The reaction mixture is stirred at room temperature for 18 hours the solvent is then removed under reduced pressure. 5 ml of methanolic ammonia are added and the mixture is stirred at room temperature for 2 hours. The solvent is removed under vacuum, dissolved again in 1 ml of methanol and purified by silica TLC. 170 mg of the title compound were obtained as an off-white solid.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH:14]([C:23]([F:26])([F:25])[F:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH3:22])=[O:12])=[CH:7][CH:6]=1)(=O)C.C(N)C1C=CC=CC=1>C(O)C.C(Cl)(Cl)Cl>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH:14]([C:23]([F:24])([F:25])[F:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH3:22])=[O:12])=[CH:7][CH:6]=1
Reactant: CCOCCCCCC(OC(=O)c1ccc(OC(C)=O)cc1)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: NCc1ccccc1
Solvent: CCO
Product: CCOCCCCCC(OC(=O)c1ccc(O)cc1)C(F)(F)F
Reaction time: 4 h

Procedure:
The crude product (1.9 g) of the above compound (2) was dissolved in 50 ml of ethanol, and 4 g of benzylamine was added dropwise. Further, after stirring was conducted at room temperature for 4 hours, the mixture was diluted with 500 ml of chloroform, washed with dilute hydrochloric acid and water in this sequence, and dried over magnesium sulfate. After the solvent was evaporated, the residue was isolated and purified by silica gel column chromatography to obtain 1.2 g of a final product (3).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([CH:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][O:17]2)=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:25]CCCl>ClC(OC(Cl)C)=O>[ClH:25].[CH:16]1([C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][O:17]1
Reactant: O=C(C1CCN(Cc2ccccc2)CC1)C1OCc2ccccc21
Reactant: ClCCCl
Agent: CC(Cl)OC(=O)Cl
Product: Cl
Product: O=C(C1CCNCC1)C1OCc2ccccc21
Reaction time: 1 h

Procedure:
After dissolving 517 mg of (1-benzylpiperidin-4-yl)-(1,3-dihydroisobenzofuran-1-yl)methanone in 5 ml of 1,2-dichloroethane, 0.49 ml of 1-chloroethyl chloroformate was added and the mixture was heated to reflux for 1 hour. The reaction solution was distilled off under reduced pressure, 5 ml of methanol was added to the residue and heating to reflux was continued for 1 hour. The reaction solution was distilled off under reduced pressure, saturated aqueous sodium bicarbonate solution was added and extraction was performed with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure to obtain 104 mg of (1,3-dihydroisobenzofuran-1-yl)-(piperidin-4-yl)methanone hydrochloride.