Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:9](Cl)([N:10]=1)[N:8]=[CH:7][N:6]=2.[CH3:12][C:13]1[NH:17][N:16]=[C:15]([NH2:18])[CH:14]=1>C(O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:9]([NH:18][C:15]3[CH:14]=[C:13]([CH3:12])[NH:17][N:16]=3)([N:10]=1)[N:8]=[CH:7][N:6]=2
Reactant: Cc1cc(N)n[nH]1
Reactant: ClC1=NC2(Cl)N=CN=C2C=N1
Solvent: CCO
Product: Cc1cc(NC23N=CN=C2C=NC(Cl)=N3)n[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 57.6 %

Procedure:
To a suspension of 2,4-dichloro-purine (2.0 g, 10.6 mmol) in anhydrous ethanol (10 mL) was added 5-methyl-1H-pyrazol-3-yl amine (2.05 g, 21.2 mmol). The resulting mixture was stirred at room temperature for 48 h. The resulting precipitate was collected by filtration, washed with ethanol, and dried under vacuum to afford 1.524 g (58% yield) of (2-chloro-purin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine which was used in the next step without further purification. To a solution of (2-chloro-purin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (200 mg, 0.80 mmol) was added 4-methylpiperidine (4 mL, 8.01 mmol) and the reaction mixture heated at reflux overnight. The solvent was evaporated and the residue dissolved in a mixture EtOH:water (1:3, 4 mL). Potassium carbonate (57 mg, 0.41 mmol) was added and the mixture was stirred at room temperature for 2 hours. The resulting suspension was filtered, washed with water (×2) and rinsed with Et2O (×2) to afford IV-33 as a white solid (225 mg, 90%): mp>300° C.; 1H NMR (DMSO) δ 0.91 (3H, d), 1.10 (2H, m), 1.65 (3H, m), 2.24 (3H, s), 2.84 (2H, m), 4.60 (2H, m), 6.40 (1H, s), 7.87 (1H, m), 9.37-9.59 (1H, m), 12.03-12.39 (2H, m); IR (solid) 1651, 1612, 1574, 1484, 1446, 1327, 1317, 1255, 1203; MS 313.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[O:7])=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[NH:28]1[CH2:38][CH2:37][CH:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:30][CH2:29]1>O1CCOCC1.CN(C1C=CN=CC=1)C>[CH2:35]([O:34][C:32]([CH:31]1[CH2:37][CH2:38][N:28]([C:2]2[CH:18]=[CH:17][C:5]([C:6](=[O:7])[NH:8][C:9]3[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=3[F:16])=[CH:4][N:3]=2)[CH2:29][CH2:30]1)=[O:33])[CH3:36]
Reactant: O=C(Nc1ccc(I)cc1F)c1ccc(Cl)nc1
Reactant: CCOC(=O)C1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(I)cc3F)cn2)CC1
Temperature: 95 °C
Yield: 55 %

Procedure:
6-Chloro-N-(2-fluoro-4-iodo-phenyl)-nicotinamide (80 mg, 0.22 mmol) was dissolved in dioxane (6 mL) and the mixture was treated with diisopropyl ethyl amine (0.11 mL, 0.66 mmol), ethyl isonipecotate (100 mg, 0.66 mmol) and a catalytic amount of DMAP. This solution was then heated in a sealed tube at 95° C. for 21 h. The mixture was then cooled and the solvent was evaporated. The residue was chromatographed with a silica gel column and 20-40% EtOAc in hexanes gradient to afford the product. (60 mg, Yield: 55%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](=[NH:7])[NH2:6].O=[C:12]1[CH2:17][CH2:16][CH2:15][S:14][CH:13]1[C:18](OC)=[O:19].C[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:18]([OH:19])[C:13]3[S:14][CH2:15][CH2:16][CH2:17][C:12]=3[N:7]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: N=C(N)c1cccc(Cl)c1
Reactant: COC(=O)C1SCCCC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Oc1nc(-c2cccc(Cl)c2)nc2c1SCCC2
Temperature: 85 °C
Reaction time: 16 h
Yield: 67.3 %

Procedure:
To a solution of 3-chlorobenzimidamide (4.3 g, 27.7 mmol) in ethanol (120 mL) was added methyl 3-oxotetrahydro-2H-thiopyran-2-carboxylate (4.82 g, 27.7 mmol) and sodium methoxide (1.8 g, 33.2 mmol). The mixture was stirred at 85° C. for 16 h. After this time, the mixture was concentrated after which ethanol (10 mL) was added and the suspension was chilled to 0° C. HCl (2 M, 50 mL) was added and the suspension was filtered and washed with water. The solid was dried under heat and vacuum to afford the title compound (5.2 g, 67%) as a light yellow solid. MW=278.75. 1H NMR (DMSO-d6, 500 MHz) δ 12.81 (s, 1H), 8.12 (s, 1H), 8.03 (d, J=7.5 Hz, 1H), 7.63-7.58 (m, 1H), 7.56-7.51 (m, 1H), 3.01-2.95 (m, 2H), 2.74 (t, J=6.0 Hz, 2H), 2.12-2.04 (m, 2H); APCI MS m/z 279 [M+H]+.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4][CH2:5][CH3:6])=O.O[CH2:12][C:13]([C:15]1C=C[CH:18]=[CH:17][CH:16]=1)=[O:14].CC[O-].[Na+].S(=O)(=O)(O)O>C(O)C.O.C1(C)C=CC=CC=1>[O:14]=[C:13]1[C:15]2[C:5](=[CH:6][CH:18]=[CH:17][CH:16]=2)[O:4][C:2]([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[CH:12]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=C(CO)c1ccccc1
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cc(=O)c2ccccc2o1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 189.8 %

Procedure:
In a mixture containing 180 g of toluene and 12.0 g of diethyl oxalate was dissolved 30 g of 2-hydroxyacetophenone, to which 65.0 g of a 20% solution of sodium ethylate in ethanol was added dropwise. After completion of the reaction 13 g of 98% sulfuric acid was subsequently added, and the mixture was stirred at 60° C. for about 30 minutes. Then 140 g of water was added, and the mixture was subjected to separation of the organic layer. The resultant organic layer was concentrated, after which 55.0 g of hexane was added and the mixture was filtered below 10° C. which yields about 34.0 g of ethyl 4-oxochromene-2-carboxylate. (Approximately 95% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:51][NH:52][CH2:53][C:54]1[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=1>>[CH3:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:50][CH:49]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([N:52]([CH3:51])[CH2:53][C:54]6[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=6)=[O:36])=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:46][CH:45]=1
Reactant: CNCc1cccnc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3F)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N(C)Cc4cccnc4)cc3F)cn2)cc1
Yield: 100.6 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-benzoic acid (80.0 mg, 0.118 mmol) obtained in Step A in Example 1-D-21 and N-methyl-N-(3-pyridylmethyl)amine (21.6 mg, 0.177 mmol) instead of 1-pyridine-3-yl-piperazine, the amidation was carried out in the same manner as Step B in Example 1-D-21, to obtain a crude product of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-N-methyl-N-pyridin-3-ylmethyl-benzamide as a yellow solid (92.8 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-318) as a yellow powder (38.0 mg, 59%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][C:10]=2[O:12][CH3:13])[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:24]=[C:23]([OH:25])[C:22]([CH3:26])=[CH:21][CH:20]=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:25][C:23]1[CH:24]=[C:19]([NH:18][C:2]2[C:11]3[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][C:10]=3[O:12][CH3:13])[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:20]=[CH:21][C:22]=1[CH3:26]
Reactant: Cc1ccc(N)cc1O
Reactant: COc1ccc(OC)c2c(Cl)c(C#N)cnc12
Agent: CCOC(C)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(OC)c2c(Nc3ccc(C)c(O)c3)c(C#N)cnc12
Yield: 84.2 %

Procedure:
A mixture of 0.148 g of 4-chloro-5,8-dimethoxy-3-quinolinecarbonitrile, 0.087 g of 5-amino-o-cresol, and 5 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 30 minutes. The mixture was cooled and added to 50 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, dried, and washed with 10 ml of hexanes-ethyl acetate (4:1) to give 0.168 g of 4-(3-hydroxy-4-methyl-phenylamino)-5,8-dimethoxy-quinoline-3-carbonitrile as a solid, mp 240-242° C.; mass spectrum (EI, m/e): M 335.1260.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28]CN)=[CH:26][CH:25]=1.C1CCN2[C:36](=[N:37]CCC2)CC1.O>CN1C(=O)CCC1>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:37]([CH3:36])[C:13]2[CH:12]=[C:11]3[C:16]([CH:17]=[C:8]([C:6]4[CH:7]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=4[Cl:21])[C:9](=[O:20])[N:10]3[CH3:19])=[CH:15][N:14]=2)=[CH:31][CH:32]=1
Reactant: Cn1c(=O)c(-c2cc(N)ccc2Cl)cc2cnc(Cl)cc21
Reactant: COc1ccc(CCN)cc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2cc(N)ccc2Cl)c(=O)n3C)cc1
Temperature: 180 °C
Yield: 95.4 %

Procedure:
A mixture of 3-(5-amino-2-chlorophenyl)-7-chloro-1-methyl-1,6-naphthyridin-2(1H)-one (5 g, 15.67 mmol), 4-methoxybenzylmethylamine (3.6 g, 23.5 mmol) and DBU (3.7 g, 23.5 mmol) in NMP (80 mL) was heated at 180° C. under N2 for 4 h. The reaction was cooled to RT and poured into water (600 mL). The precipitate was collected by filtration and dried in vacuo to give 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2-chlorophenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (6.5 g, 95% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.46 (s, 1H), 7.68 (s, 1H), 7.16 (d, J=8.8 Hz, 2H), 7.06 (d, J=8.4 Hz, 1H), 6.85 (d, J=8.8 Hz, 2H), 6.54-6.51 (m, 2H), 6.29 (s, 1H), 5.23 (s, 2H), 4.85 (s, 2H), 3.69 (s, 3H), 3.51 (s, 3H), 3.07 (s, 3H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[C@H:14]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH2:13][C@H:12]([OH:22])[C@@H:11]1[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:32]1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.CI>C(#N)C>[Si:1]([O:8][CH2:9][C@H:10]1[C@H:14]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH2:13][C@H:12]([OH:22])[C@@H:11]1[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1OC1CCCCO1
Reactant: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CC#N
Solvent: CI
Product: COC(=O)CCC/C=C\C[C@@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](OC2CCCCO2)C[C@@H]1O
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.5 %

Procedure:
A solution of (Z)-7-[(1R,2S,3R,5S)-2-(t-butyldimethylsilyloxymethyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptenoic acid (24) (261 mmol) in acetonitrile (1000 ml) was cooled on ice. Diazabicycloundecene (156.0 ml, 1044 mmol) was added thereto and methyl iodide (65.0 ml, 1044 mmol) was added drop wise to the solution. The reaction mixture was warmed to room temperature, and stirred for 14 hours. The reaction mixture was cooled on ice, diazabicycloundecene (39.0 ml, 261 mmol) and methyl iodide (16.3 ml, 261 mmol) were added, then, the mixture was stirred at room temperature for 1.25 hours. The reaction mixture was again cooled on ice, and diazabicycloundecene (39.0 ml, 261 mmol) and methyl iodide (16.3 ml, 261 mmol) were added. After stirring at room temperature for one hour, the reaction mixture was concentrated under reduced pressure. Ethyl acetate (400 ml) and water (400 ml) were added to the residue and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate (400 ml), the organic layers were combined and sequentially washed with 1N-hydrochloric acid (600 ml), saturated sodium bicarbonate water (800 ml) and saturated aqueous sodium chloride (800 ml). After drying with anhydrous magnesium sulfate, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 2000 g; ethyl acetate:hexane =1:3), the fractions containing impurities were re-purified by silica gel column chromatography (Fuji Silysia BW-300: 190 g; ethyl acetate:hexane =1:3) to give methyl (Z)-7-[(1R,2S,3R,5S)-2-(t-butyldimethylsilyloxymethyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptenate (25) (110.4 g, 233.5 mmol, 89.5%) as colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:5][CH:4]=1)#[N:2].CO.[CH3:19]CN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:19][O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: N#Cc1ccc(CCCCCC(=O)O)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
To a solution of 6-(p-cyanophenyl)hexanoic acid (1.0 g), which is disclosed in J. Med. Chem., 36, 1811 (1993), in methylene chloride (10 ml) are added methanol (0.2 ml), WSC.HCl (883 mg) and 4-dimethylaminopyridine (561 mg), and the mixture is stirred at room temperature for 30 minutes. The mixture is diluted with ethyl acetate, and washed with 1N hydrochloric acid and a saturated aqueous sodium hydrogen carbonate solution, and purified by silica gel column chromatography (n-hexane/ethyl acetate=5:1) to give the title compound (600 mg).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[CH:29]=[C:28](Cl)[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O.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>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[CH:29]=[C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2cc(Cl)ncn2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)ncn2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 76.3 %

Procedure:
A flask containing 4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-6-chloropyrimidine (0.300 g, 0.634 mmol), phenylboronic acid (0.0696 g, 0.570 mmol), a 2.00 M solution of K2CO3 in H2O (0.317 mL), EtOH (0.0944 mL) and toluene (1.417 mL) was purged with argon for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.0264 g, 0.0229 mmol) was added and the mixture was refluxed overnight. The reaction was cooled and diluted with H2O. The aqueous layer was extracted with CH2Cl2 (3×). The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (0 to 10% EtOAc/hexanes) to afford the title compound (0.224 g, 76%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[Cl:8][S:9]([C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]([CH3:22])=[CH:15][N:16]=[CH:17]2)(=[O:11])=[O:10]>>[ClH:8].[ClH:8].[CH3:1][CH:2]1[NH:3][CH2:4][CH2:5][N:6]([S:9]([C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[C:14]([CH3:22])=[CH:15][N:16]=[CH:17]3)(=[O:10])=[O:11])[CH2:7]1
Reactant: CC1CNCCN1
Reactant: Cc1cncc2cccc(S(=O)(=O)Cl)c12
Product: Cc1cncc2cccc(S(=O)(=O)N3CCNC(C)C3)c12
Product: Cl
Yield: 122.6 %

Procedure:
Using 0.60 g of 2-methylpiperazine and 0.49 g of 5-chlorosulfonyl-4-methylisoquinoline, the procedure of Example 1 was otherwise repeated to provide 0.47 g of the objective compound (white crystals).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([NH2:13])=[C:11]([C:14](=O)[NH2:15])[CH:10]=[N:9]2)=[CH:6][CH:7]=1.O.[NH2:18][NH2:19]>CN(C)C=O>[NH:18]([C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([NH2:13])=[C:11]([C:14]#[N:15])[CH:10]=[N:9]2)=[CH:6][CH:7]=1)[NH2:19]
Reactant: NN
Reactant: NC(=O)c1cnn(-c2ccc(Cl)nn2)c1N
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cnn(-c2ccc(NN)nn2)c1N

Procedure:
A mixture of 10 g. of 3-chloro-6-(4-cyano-5-amino-1-pyrazolyl)-pyridazine (prepared according to Example 24), 20 ml. dimethylformamide and 40 ml. of 98% hydrazine hydrate is heated at 90°-95° C. for 5 hours. After cooling the precipitated product is filtered, washed with water and ethanol, triturated with 50 ml. of hot ethanol, filtered and dried. Yield: 9.1 g. (93%); m.p.: 264°-266° C. The hydrochloride melts at 253°-256° C.
Reaction SMILES: [CH:1]1([C:4]2(O)[C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[O:8][C:7]3[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=3[CH2:5]2)[CH2:3][CH2:2]1.C(O)(=O)C.[BrH:24]>O>[Br:24][CH2:3][CH2:2][CH:1]=[C:4]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[O:8][C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[CH2:5]1
Reactant: OC1(C2CC2)Cc2ccccc2Oc2ncccc21
Reactant: Br
Solvent: O
Solvent: CC(=O)O
Product: BrCCC=C1Cc2ccccc2Oc2ncccc21
Temperature: 60 °C

Procedure:
To a 2 L eggplant flask with a magnetic stirring bar was added 75.0 g. of 5-Cyclopropyl-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ol (0.30 mole) and 75 mL of acetic acid. The solution was cooled with water (ca. 10° C.), 120 ml of 47% aqueous hydrobromic acid was added over a period of 5 minutes. The reaction mixture was warmed to 60° C., stirred for an hour, and evaporated (aspirator vacuum, ca. 50° C.) to ca. 200 mL. The reaction mixture was poured to 1500 mL of saturated aqueous sodium bicarbonate, the mixture is extracted with two 800 mL portions of ethyl acetate, and the combined organic extracts are washed with 500 mL of saturated aqueous sodium chloride. The organic solution was dried with anhydrous magnesium sulfate, filtered, and evaporated (aspirator vacuum, ca. 30° C.). The oily residue was chromatographed on 500 g. of Silica gel 60 by eluting with 5:1-4:1 (v/v) hexane-ethyl acetate mixture. The elution was evaporated, giving the titled compound as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:10]=[C:9]([O:11][CH3:12])[C:7](=[S:8])[CH2:6][CH:5]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][Cl:23].C1CCCCC1>CC(C)=O>[Cl:23][CH2:22][CH2:21][CH2:20][S:8][C:7]1[CH:6]=[CH:5][C:4]([C:2](=[O:3])[CH3:1])=[CH:10][C:9]=1[O:11][CH3:12]
Reactant: COC1=CC(C(C)=O)=CCC1=S
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1CCCCC1
Product: COc1cc(C(C)=O)ccc1SCCCCl
Temperature: 25 °C

Procedure:
A mixture of 1-(4-thio-3-methoxyphenyl)ethanone (10.0 g, 54.9 mmol), potassium carbonate (9.0 g, 65.1 mmol), and acetone (100 ml) was stirred at reflux under nitrogen for 30 minutes. The reaction was cooled to ambient temperature and a solution of 1-bromo-3-chloropropane (6.5 ml, 9.5 g, 60.4 mmol) dissolved in acetone (25 ml) was dripped into the reaction. After complete addition, the reaction was heated to reflux and stirred under nitrogen for 17 hours. After the reaction was carried to substantial completion, the reaction mixture was filtered and the resulting filter cake was washed with acetone. The filtrate was concentrated to provide an amber oil. A small sample was solidified by trituration with hot cyclohexane to provide 1-[4-[(3-chloropropyl)thio]-3-methoxyphenyl]ethanone as a yellow solid, 11.7 g, m.p.=53°-55° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=1.[O-:23][S:24]([O-:26])=[O:25].[Na+:27].[Na+].CCO>O>[Na+:27].[CH2:16]([O:15][C:11]1[CH:10]=[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:24]([O-:26])(=[O:25])=[O:23])[CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S([O-])[O-]
Reactant: BrCCCCCCCc1cccc(OCc2ccccc2)c1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])CCCCCCCc1cccc(OCc2ccccc2)c1

Procedure:
Following the procedure described for 11.1 using 10.2 (0.4 g, 1.1 mmol), Na2SO3 (0.19 g, 1.5 mmol) and EtOH (8 mL)/H2O (4 ml) mixture, the crude 11.2 was obtained and used in the next step without further purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]#[N:9])[CH2:4][CH2:3]1.[OH:10][NH:11][C:12](=N)[CH:13]([CH3:15])[CH3:14]>C(OCC)(=O)C.CCOCC.[Cl-].[Cl-].[Zn+2]>[CH3:14][CH:13]([C:12]1[N:9]=[C:8]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[O:10][N:11]=1)[CH3:15]
Reactant: N#CN1CCC(O)CC1
Reactant: CC(C)C(=N)NO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)c1noc(N2CCC(O)CC2)n1
Temperature: 100 °C

Procedure:
4-Hydroxypiperidine-1-carbonitrile (3.0 g) and N-hydroxy-2-methylpropanimidamide (2.9 g) are dissolved in ethyl acetate (20 ml) and 1 M ZnCl2 in Et2O (29 ml) is added. A precipitate forms and the solvent is decanted off. Additional Et2O (20 ml) is added to wash the precipitate and is decanted off. EtOH (20 ml) is added followed by conc. HCl (7.5 ml) and the mixture is heated to 100° C. for 3.5 h. The mixture is concentrated, redissolved in H2O (5 ml) and made basic by addition of concentrated NaHCO3. The aqueous layer is extracted with dichloromethane (2×50 mL) and the organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by silica gel chromatography (0% to 100% ethyl acetate/hexanes) to afford the title compound. LC (method 20): tR=1.56 min; Mass spectrum (APCI): m/z=212 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[CH3:12][S:13]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([CH:25]=1)[C:21]([NH:23][NH2:24])=[O:22])(=[O:15])=[O:14]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](/[C:8](=[N:24]/[NH:23][C:21](=[O:22])[C:20]2[CH:25]=[C:16]([S:13]([CH3:12])(=[O:15])=[O:14])[CH:17]=[N:18][CH:19]=2)/[CH3:9])[CH:7]=1
Reactant: CS(=O)(=O)c1cncc(C(=O)NN)c1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cncc(S(C)(=O)=O)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 65 %

Procedure:
1-(5-Chloro-2-hydroxyphenyl)ethanone (50 mg, 0.293 mmol) and 5-(methylsulfonyl) nicotinohydrazide (63.1 mg, 0.293 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (3% CH3OH/CH2Cl2) affording the title compound (70 mg, 63.0% yield) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 11.86 (s, 1H), 9.37 (s, 1H), 9.27 (s, 1H), 8.76 (s, 1H), 7.68 (s, 1H), 7.36 (d, 1H, J=8.8 Hz), 6.97 (d, 1H, J=8.8 Hz), 3.42 (s, 3H), 2.53 (s, 3H). ESI-MS: 368.8 [M+H]+.