Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([SH:10])[NH:9][C:5]=2[CH:4]=1.[H-].[Na+].Cl.[CH3:16][N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[CH2:27]Cl)[CH2:20][CH2:19][CH2:18]1>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([S:10][CH2:27][C:25]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:26]=3[N:17]([CH3:16])[CH2:18][CH2:19][CH2:20]4)[NH:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: CN1CCCc2cccc(CCl)c21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Product: COc1ccc2nc(SCc3cccc4c3N(C)CCC4)[nH]c2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 49.7 %

Procedure:
A solution of 5-methoxy-2-mercaptobenzimidazole(0.9 g), sodium hydride (60% in oil, 0.20 g) and 18-crown-6(i.e. 1,4,7,10,13,16-hexaoxacyclooctadecane) (50 mg) in dimethyl formamide (15 ml) was stirred for 20 minutes at room temperature. To the mixture was added a solution of 1-methyl-8-chloromethyl-1,2,3,4-tetrahydroquinoline hydrochloride (1.1 g) in dimethyl formamide (15 ml) and the solution was stirred for 20 hours at room temperature. Dimethyl formamide was distilled off, and chloroform, 30% aqueous solution of sodium hydroxide and water were added to the resulting residue. The mixture was stirred for 2 hours and extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off. The resultant residue was purified by silica gel column chromatography [eluent:n-hexane-ethyl acetate (4:1)] to give 8-(5-methoxy-2-benzimidazolyl)thiomethyl-1-methyl-1,2,3,4-tetrahydroquinoline (0.80 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([OH:28])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1.[OH-].[Na+]>>[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][S:8]([C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=4)(=[O:10])=[O:9])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(O)cc23)CC1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)Oc2ccc3[nH]cc(C4CCN(C)CC4)c3c2)cc1
Yield: 79.3 %

Procedure:
By a method similar to Example 31, using 4-methylbenzenesulfonyl chloride (228 mg, 1.2 mmol) and 3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (230 mg, 1.0 mmol), 0.2 N sodium hydroxide (5.5 mL, 1.1 mmol) gave 400 mg of crude product. The crude product was recrystallized from ethyl acetate to give 305 mg (79%) of a white powder: mp=186-187° C. MS(m/e): 384 (M+); Calculated for C21H24N2O3S: Calcd: C, 65.60; H, 6.29; N, 7.29. Found: C, 65.50; H, 6.35; N, 7.23.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32]#[N:33])=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>O>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:25]4[CH:30]=[CH:29][C:28]([CH2:31][C:32]#[N:33])=[CH:27][CH:26]=4)[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Reactant: CC1(C)OB(c2ccc(CC#N)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#CCc1ccc(-c2nccc(Nc3cc(C4CC4)[nH]n3)n2)cc1
Temperature: 100 °C
Yield: 10.6 %

Procedure:
A mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (200 mg, 0.85 mmol, 1.0 equiv.), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile (250 mg, 1.0 mmol, 1.2 equiv.), Pd(dippf)Cl2 (69.5 mg, 0.085 mmol, 0.1 equiv.), Na2CO3 (360.4 mg, 3.4 mmol, 4.0 equiv.), dioxane (5 ml) and water (1 ml) was added to the filtrate. The reaction mixture was heated to 100° C. for 15 h under nitrogen atmosphere. The residue was purified by silica gel chromatography (CH2Cl2/methanol 500:1 to 60:1) to afford title compound 2-(4-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)phenyl)acetonitrile (Compound 17) (28.6 mg, 10%) as solid. LC-MS (m/z)=317.1 [M+H]+;
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]2[CH2:5][C:6]3[C:10]([C@H:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12](=[O:14])[CH3:13].[CH2:16]([C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([CH2:27][CH3:28])[C:25]=1[OH:26])[CH:21]=O)[CH3:17].COC([C@@H](NC([C@@H](N)CC(O)=O)=O)CC1C=CC=CC=1)=O.Cl.Cl>C(O)C.C(O)(C)C.CC(=O)OCC>[CH2:16]([C:18]1[CH:19]=[C:20]([CH2:21][CH2:13][C:12]([C:7]2[S:8][C:9]([CH3:11])=[C:10]3[C:6]=2[CH2:5][C@H:4]2[C:2]([CH3:15])([CH3:1])[C@H:3]23)=[O:14])[CH:23]=[C:24]([CH2:27][CH3:28])[C:25]=1[OH:26])[CH3:17]
Reactant: CCc1cc(C=O)cc(CC)c1O
Reactant: CC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Agent: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(C)O
Product: CCc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(CC)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (1aS,5aR)-1-(1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pen-talen-4-yl)-ethanone (890 mg, 4.04 mmol) and 3,5-diethyl-4-hydroxy-benzaldehyde (900 mg, 5.05 mmol, Lit: G. Trapani, A. Latrofa, M. Franco, C. Altomare, E. Sanna, M. Usal, G. Biggio, G. Liso J. Med. Chem. 41 (1998) 1846-1854; G. G. Ecke, J. P. Napolitano, A. H. Bilbey, A. J. Kolka, J. Org. Chem. 22 (1957) 639-642) in ethanol (7.5 mL) and 5 N HCl in isopropanol (2.5 mL) is stirred at rt for 72 h. The mixture is diluted with EA and is washed with water. The sovent of the organic layer is evaporated, the residue is dissolved in ethanol, treated with Pd/C (200 mg, 10% Pd) and stirred at rt for 18 h under 1.8 bar H2. The mixture is filtered, the filtrate is concentrated and the crude product is purified by CC on silica gel eluting with heptane:EA 8:2 to give 3-(3,5-diethyl-4-hydroxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (1.05 g) as a yellow oil; LC-MS: tR=1.15 min, [M+1]+=383.25.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][C:7](=[O:16])[NH:6][C:5]=2[N:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>C(#N)C>[Si:27]([O:26][CH2:25][CH2:24][N:6]1[C:5]2[N:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8][C:7]1=[O:16])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: O=C1Cc2ccccc2-c2cccnc2N1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCCN1C(=O)Cc2ccccc2-c2cccnc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Add 5,7-dihydropyrido[2,3-d][3]benzazepin-6-one (33.8 g, 0.16 mol) in acetonitrile (340.0 mL) and stir at 20-30° C. for 0.5-1 hour. Add cesium carbonate (104.6 g, 0.32 mol) and (2-bromoethoxy)-tert-butyldimethylsilane (42.2 g, 0.18 mol) and heat the reaction mixture to 70-80° C. for 18-20 hours. Cool the reaction mixture to 20-25° C. and filter through diatomaceous earth (50.6 g). Wash the filter cake with acetonitrile (2×50.6 mL) and concentrate the filtrate under reduced pressure to arrive at a total volume of approximately 67.5 mL. Add toluene (152 mL), active carbon (2.53 g) and heat the mixture to 60-70° C. for 1-2 hours. Cool the mixture to 25-35° C. and filter the reaction mixture over diatomaceous earth (50.6 g). Rinse the filter cake with toluene (17.0 mL) and concentrate under reduced pressure to obtain the title compound as a light brown oil that crystallizes on standing (56.8 g, 92.2%).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH2:6][CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]#[N:9])[CH3:4].C[O-].[Na+].CO[CH:21](OC)[CH2:22][NH2:23]>ClCCl.CO>[CH3:2][N:3]([CH3:4])[CH2:5][CH2:6][CH:7]([C:8]1[NH:9][CH:21]=[CH:22][N:23]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN(C)CCC(C#N)c1ccccc1
Reactant: COC(CN)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCC(c1ccccc1)c1ncc[nH]1
Reaction time: 8 h

Procedure:
Hydrogen chloride was passed into a solution of α-(N,N-dimethylaminoethyl)benzeneacetonitrile (18.8 g) and dry methanol (6.3 ml) in dry dichloromethane (200 ml) for 8 h at 5°-15°. Solvent was removed to give a colourless oil which was taken up in dry methanol (150 ml) and treated with 2 M sodium methoxide solution (65 ml). Aminoacetaldehyde dimethyl acetal (10.6 g) was added and the mixture left to stand overnight. Methanol was then removed and the residue dissolved in 2 N hydrochloric acid (200 ml) and heated at 80° for 30 min. The mixture was cooled, adjusted to pH 9.5 with potassium carbonate and extracted with ethyl acetate (3×200 ml). The extracts were washed with brine (200 ml), concentrated and dried in vacuo to give the title compound, m.p. 135°-136° (16.3 g).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11]3[CH2:17][CH2:16][CH2:15][CH:12]32)=[CH:7][CH:6]=1)([O-])=O.Cl.[H][H]>CO.[Pd]>[NH2:2][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11]3[CH2:17][CH2:16][CH2:15][CH:12]32)=[CH:7][CH:6]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)C1CCCN1CC2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc2c(c1)C1CCCN1CC2
Yield: 104.9 %

Procedure:
To 9-nitro-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline hydrochloride (Example 31(b), 2.0 g) in methanol (100 ml) was added concentrated hydrochloric acid (0.67 ml) and 5% palladium on carbon (200 mg). The mixture was hydrogenated at 50 psi on a Parr Hydrogenator. Hydrogen uptake was complete in 1.0 h. The catalyst was filtered off and the solvent removed under reduced pressure. The residue was dissolved in water, the solution basified with 2.5M sodium hydroxide and the product extracted into dichloromethane. The extracts were dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure to yield the title compound as a thick oil (1.55 g).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25])[CH3:20]>>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([NH:25][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:26]=[CH:27][CH:28]=1)[CH3:20]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CCOc1cccc(N)c1
Agent: [Na+]
Product: CCOc1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1
Yield: 68.5 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 540 mg of 3-ethoxyaniline in place of the 2,4-difluoroaniline. 235 mg of N-(3-ethoxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:7][CH2:1][CH2:2][O:3][CH2:4][CH2:5][O:6][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][Br:8])=[O:16]
Reactant: OCCOCCO
Reactant: O=C(O)CCCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(CCCCCBr)OCCOCCOC(=O)CCCCCBr
Temperature: 25 °C
Yield: 92.2 %

Procedure:
Into a 3-liter 4-neck round bottom flask equipped with a mechanical stirrer was added a solution of diethylene glycol (100 g), 6-bromo hexanoic acid (386 g) and para-toluene sulphonic acid (5 g) in toluene (1000 ml). The solution was refluxed for 3 hours using a Dean-Stark apparatus with azeotropic removal of water. The solution was cooled to room temperature. The toluene layer was washed with 5% sodium bicarbonate solution (1500 ml) and water (1000 ml). The solution was dried over anhydrous sodium sulphate and distilled to obtain 6-bromohexanoic acid 2-[2-(6-bromohexanoyloxy)-ethoxy]-ethyl ester (400 g) as light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[N:6]2[N:15]=[CH:16][CH:17]=[C:5]2[N:4]=1.[C:18](Cl)(=[O:23])/[CH:19]=[CH:20]/[CH2:21][CH3:22]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:10][CH2:11][N:12]([C:18](=[O:23])/[CH:19]=[CH:20]/[CH2:21][CH3:22])[CH2:13][CH2:14]2)[N:6]2[N:15]=[CH:16][CH:17]=[C:5]2[N:4]=1
Reactant: COc1cc(N2CCNCC2)n2nccc2n1
Reactant: CC/C=C/C(=O)Cl
Solvent: ClCCl
Product: CC/C=C/C(=O)N1CCN(c2cc(OC)nc3ccnn23)CC1
Reaction time: 0.17 h
Yield: 50 %

Procedure:
5-Methoxy-7-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine (23.3 mg, 0.1 mmol) was dissolved in anhydrous dichloromethane (1 ml), TEA (17.4 μl, 1.25 mmol) followed by (E)-pent-2-enoyl chloride (14.8 mg, 0.125 mmol) were added, the mixture was shaken for 10 minutes, diluted with dichloromethane, washed with 10% sodium bicarbonate solution, water and the organic phase was evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 16.1 mg of a solid (0.05 mmol, 51%).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C-]#N.[K+].[CH2:21]([OH:24])[CH:22]=[CH2:23]>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:24][CH2:21][CH:22]=[CH2:23])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: C=CCO
Agent: [C-]#N
Agent: [K+]
Product: C=CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 1.99 g of 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile, 0.59 g of potassium cyanide and 20 ml of allyl alcohol is stirred at room temperature for 20 hours and thereafter the allyl alcohol is distilled off. The residue is poured onto ice/water and extracted with methylene chloride, and the combined extracts are washed with water, dried over anhydrous sodium sulphate and evaporated. After flash chromatography on silica gel (elutent: ethyl acetate) there is obtained pure allyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17](F)=[CH:18][CH:19]=2)[C:3]=1[CH3:21].[CH3:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17]([N:26]3[CH2:27][CH2:28][CH:23]([CH3:22])[CH2:24][CH2:25]3)=[CH:18][CH:19]=2)[C:3]=1[CH3:21]
Reactant: Cc1c(-c2ccc(F)nc2)nc2cc(F)cc(F)c2c1Cl
Reactant: CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccc(N3CCC(C)CC3)nc2)nc2cc(F)cc(F)c2c1Cl
Temperature: 80 °C
Reaction time: 19.5 h

Procedure:
To a stirred solution of 4-chloro-5,7-difluoro-2-(6-fluoropyridin-3-yl)-3-methylquinoline (0.1 g, 0.32 mmol) in DMF (3.0 mL) was added 4-methylpiperidine (0.035 g, 0.36 mmol) followed by potassium carbonate (0.090 g, 0.65 mmol). The reaction was stirred at 80° C. and stirring continued for 19.5 h. After which, the reaction mixture was cooled to rt and water was added. The crude reaction mixture was extracted with EtOAc, dried over magnesium sulfate and concd in vacuo. The crude material was purified on silica gel, eluting with 0-30% EtOAc in hexanes to provide 4-chloro-5,7-difluoro-3-methyl-2-(6-(4-methylpiperidin-1-yl)-pyridin-3-yl)quinoline as a tan solid. Mass Spectrum (ESI) m/e=388.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:28]([OH:30])=O)=[CH:5][C:6]2[N:10]=[C:9]([NH:11][C:12]3[S:13][C:14]4[CH:20]=[C:19]([O:21][C:22]([F:25])([F:24])[F:23])[CH:18]=[CH:17][C:15]=4[N:16]=3)[N:8]([CH3:26])[C:7]=2[CH:27]=1.C(O)(=O)C.[CH3:35][N:36]([CH3:41])[C:37](=[O:40])[CH2:38][NH2:39].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:35][N:36]([CH3:41])[C:37]([CH2:38][NH:39][C:28]([C:4]1[C:3]([O:2][CH3:1])=[CH:27][C:7]2[N:8]([CH3:26])[C:9]([NH:11][C:12]3[S:13][C:14]4[CH:20]=[C:19]([O:21][C:22]([F:25])([F:23])[F:24])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[N:10][C:6]=2[CH:5]=1)=[O:30])=[O:40]
Reactant: COc1cc2c(cc1C(=O)O)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Reactant: CN(C)C(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1C(=O)NCC(=O)N(C)C)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 51.7 %

Procedure:
6-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide (37 mg) was prepared by following General Procedure F starting from 6-methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (60 mg), glycine dimethylamide acetate (25 mg), HBTU (63 mg), and DIEA (36 uL). LC/MS: m/z 523.7. 1H NMR (DMSO-d6, 400 MHz): δ 12.29 (bs, 1H), 8.84 (t, 1H), 8.26 (s, 1H), 7.90 (s, 1H), 7.72 (d, 1H), 7.35 (d, 1H), 7.30 (s, 1H), 4.21 (d, 2H), 4.04 (s, 3H), 3.65 (s, 3H), 3.00 (s, 3H), 2.91 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([S:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)=[C:5]([C:20]([O:22]C)=O)[N:6]2[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].CC(C)([O-])C.[K+].Cl>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([S:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)=[C:5]1[C:20](=[O:22])[CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:12][N:6]12
Reactant: CCOC(=O)CCCn1c(C(=O)OC)c(Sc2ccc(Cl)cc2)c2c(Br)cc(F)cc21
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CCn2c(c(Sc3ccc(Cl)cc3)c3c(Br)cc(F)cc32)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
To a solution of the indole of Step 2 (460 mg, 0.9 mmol) in THF (100 mL) at 0° C. was added potassium t-butoxide (1.2 mL of a 1M solution in THF The reaction mixture was stirred for 2 hours at 0° C. and 1N HCl was added. The phases were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to give 400 mg of a pale yellow solid used as such.
Reaction SMILES: Cl.[CH2:2]([CH2:4][NH2:5])[OH:3].[C:6]([Cl:11])(=[O:10])[C:7]([CH3:9])=[CH2:8]>C1(C)C=CC=CC=1>[ClH:11].[CH3:9][C:7](=[CH2:8])[C:6]([O:3][CH2:2][CH2:4][NH2:5])=[O:10]
Reactant: C=C(C)C(=O)Cl
Reactant: NCCO
Agent: Cl
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OCCN
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
In a 500 mL three-neck flask equipped with a thermometer and a reflux condenser were placed 300 g of toluene and 60.0 g (0.62 mol) of ethanolamine hydrochloride, followed by heating to 110° C. with stirring. After the inner temperature reached 110° C., 77.1 g (0.74 mol) of methacryloyl chloride was added dropwise thereto over a period of 30 minutes. After completion of the dropwise addition, the mixture was continued to stir for further 3 hours and then cooled to 0° C. with stirring. The precipitated solid was collected by filtration and then the resulting solid was washed with 300 g of diisopropyl ether. The solid was collected by filtration and then dried under reduced pressure to obtain 85.2 g of 2-aminoethyl 2-methylacrylate hydrochloride.
Reaction SMILES: C[C:2]1[CH:6]=C(C)[N:4]([C:8](=[NH:20])[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1.CS(O)(=O)=O.NN1CC[O:30][CH2:29][CH2:28]1>>[NH2:20][C:8]([NH:4][N:3]1[CH2:2][CH2:6][O:30][CH2:29][CH2:28]1)=[N:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)n2nc(C)cc2C)cc1
Reactant: NN1CCOCC1
Agent: CS(=O)(=O)O
Product: Cc1ccc(S(=O)(=O)N=C(N)NN2CCOCC2)cc1

Procedure:
The compound of Example 20 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of N-aminomorpholine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 298.11; found mol. wt. (M+H) 299.3; 597.1 (Dimer)
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[SnH3][C:13]1[O:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1>C1COCC1.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:13]3[O:21][C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=3)=[CH:3][N:4]=2)[N:7]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: [SnH3]c1cc2ncccc2o1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc2ncc(-c3cc4ncccc4o3)n2n1
Yield: 57.3 %

Procedure:
In an inert atmosphere, 3.0 g (12.9 mmol) of 3-bromo-6-chloroimidazo[1,2-b]-pyridazine, 6.85 g (16.8 mmol) of the crude 2-stannylfuro[3,2-b]pyridine, 246 mg (1.29 mmol) copper (I) iodide and 453 mg (0.645 mmol) bis(triphenylphosphine) palladium(II)chloride in 100 mL of THF was stirred over night at 85° C. in a sealed pressure tube. The solvent was evaporated, the obtained solid was digested in dichloromethane/methanol and filtered off. The solid was washed with methanol and hexane to give 2 g of the title compound as solid material.
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]([NH2:11])[CH:7]([C:8]([OH:10])=[O:9])[CH:2]1[CH:3]=[CH:4]2.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>O.O1CCOCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:11][CH:6]2[CH:5]3[CH2:1][CH:2]([CH:3]=[CH:4]3)[CH:7]2[C:8]([OH:10])=[O:9])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NC1C2C=CC(C2)C1C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)C1C2C=CC(C2)C1NS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 12 h
Yield: 98 %

Procedure:
To a solution of 3-exo-aminobicyclo[2.2.1]hept-5-ene-2-exo-carboxylic acid (4.60 g, 0.03 mol) and 4-benzyloxy-benzenesulfonyl chloride (8.49 g, 0.03 mol) in water-dioxane (30 mL−30 mL) was added triethylamine (8.38 mL, 0.06 mol) at room temperature. The mixture was stirred for 12 h. The solution was concentrated and the residue was dissolved in water (30 mL). The aqueous solution was extracted with ether (50 mL) and the aqueous layer was acidified with 1 N HCI. The white precipitate was collected and dried to give 3-(4-benzyloxy-benzenesulfonylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (98% yield). Mp=201-203° C. (white solid).