Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][O:10][C:6]=2[C:5](Cl)=[N:4][N:3]=1.[NH2:18][NH2:19]>O1CCOCC1.C(O)C>[Cl:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][O:10][C:6]=2[C:5]([NH:18][NH2:19])=[N:4][N:3]=1
Reactant: NN
Reactant: Clc1nnc(Cl)c2c(-c3ccccc3)noc12
Solvent: CCO
Solvent: C1COCCO1
Product: NNc1nnc(Cl)c2c(-c3ccccc3)noc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 4,7-dichloro-3-phenylisoxazolo[4,5-d]pyridazine (25.5 g, Desimoni, G.; Et al. Tetrahedron 1967, 23, 681) in 1,4-dioxane (200 mL) and ethanol (50 mL) at 0° C. was added hydrazine (7.0 g) slowly. The reaction mixture was allowed to slowly warm to room temperature. After 20 hours, the reaction mixture was concentrated and the solid obtained was washed with water and filtered. The material was purified by column chromatography on silica gel (methanol:dichloromethane=5:95) to afford first the regioisomer of the title compound followed by the later eluting title compound (4.50 g) having the following physical data.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([OH:28])=[O:27].C(N(CC)CC)C>O>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25](=[CH:14][C:13]1[CH:16]=[CH:17][C:10]([S:9][CH3:8])=[CH:11][CH:12]=1)[C:26]([OH:28])=[O:27]
Reactant: CSc1ccc(C=O)cc1
Reactant: O=C(O)Cc1ccccc1F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CSc1ccc(C=C(C(=O)O)c2ccccc2F)cc1
Temperature: 90 °C
Yield: 62.9 %

Procedure:
Acetic anhydride (60 mL), 4-(methylthio)benzaldehyde (7.05 g, 44 mmol), 2-fluorophenylacetic acid (7.79 g, 50.5 mmol), and triethylamine (5.50 g, 54.5 mmol) were placed in a 250 mL round bottom flask and heated to reflux for 1.75 hours. The reaction was cooled to 90° C., and water (100 mL) was added cautiously through an addition funnel. This caused the solution to reflux vigorously and the temperature to rise to 135° C. A yellow precipitate formed and after cooling to room temperature the solid was collected by filtration, washed with water, and recrystallized from toluene to provide 2-(2-fluorophenyl)-3-(4-methylthiophenyl)propenoic acid as yellow needles (7.98 g, 63%): mp 151.5°-156.0° C. 1H NMR (CDCl3) 300 MHz 8.01 (s,1H), 7.41-7.00 (m, 8H), 2.43 (s, 3H). 19F NMR (CDCl3) -113.40 (m). Mass spectrum M+H+ =289.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O.C1(C)C=CC=CC=1>CN(C)C=O>[C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:20])=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Yield: 91 %

Procedure:
4-Benzoylbenzoic acid (BBA), 1.0 kg (4.42 moles), was added to a dry 5 liter Morton flask equipped with reflux condenser and overhead stirrer, followed by the addition of 645 ml (8.84 moles) of thionyl chloride and 725 ml of toluene. Dimethylformamide, 3.5 ml, was then added and the mixture was heated at reflux for 4 hours. After cooling, the solvents were removed under reduced pressure and the residual thionyl chloride was removed by three evaporations using 3×500 ml of toluene. The product was recrystallized from 1:4 toluene:hexane to give 988 g (91% yield) after drying in a vacuum oven. Product melting point was 92-94° C. Nuclear magnetic resonance (NMR) analysis (1H NMR (CDCl3)) was consistent with the desired product: aromatic protons 7.20-8.25 (m, 9H). All chemical shift values are in ppm downfield from a tetramethylsilane internal standard. The final compound was stored for use in the preparation of a monomer used in the synthesis of Compound III.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH:16]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])[CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[OH-].[Na+]>CO>[C:9]1([C@@H:7]2[CH2:8][C@H:6]2[NH:5][CH2:15][CH:16]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)CCN1CCC(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCN1CCC(CN[C@@H]2C[C@H]2c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.6 %

Procedure:
To a solution of tert-butyl 3-(3-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl) acetamido)methyl)pyrrolidin-1-yl)propanoate (65 mg, 0.148 mmol) in methanol (2 mL) was added sodium hydroxide (6M, 0.3 mL, 1.800 mmol), and the mixture was stirred at room temperature for 18 h. The mixture was purified using reverse-phase HPLC. The fractions containing the product were combined, treated with 1N HCl and concentrated. The residue was dried under vacuum to give 28 mg of product (HCl salt) as off-white solid. MS: (M+H)+=289.2. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.43 (q, 1H), 1.58-1.74 (m, 1H), 2.01 (s, 1H), 2.38 (br. s., 1H), 2.62 (m, 1H), 2.87-3.13 (m, 4H) 3.25-3.68 (m, 8H), 7.18-7.44 (m, 5H).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][S:12]([CH2:15][CH2:16][C:17]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:19])[CH3:18])(=[O:14])=[O:13].[CH2:31](I)[CH3:32]>CN(C=O)C.CCOC(C)=O>[CH2:31]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][S:12]([CH2:15][CH2:16][C:17]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([CH3:18])[CH3:19])(=[O:13])=[O:14])[CH3:32]
Reactant: CCI
Reactant: CC(C)(CCS(=O)(=O)CCOCCOCCO)NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOCCOCCOCCS(=O)(=O)CCC(C)(C)NC(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 26.8 %

Procedure:
A solution of 60% sodium hydride (50 mg, 1.3 mmol) in DMF (4 ml) was cooled to 0° C. under N2 and benzyl 4-(2-(2-(2-hydroxyethoxy)ethoxy)ethylsulfonyl)-2-methylbutan-2-ylcarbamate (419.6 mg, 1.005 mmol) in DMF (1 ml) was added dropwise. Ethyl iodide (100 ul, 1.25 mmol) was added dropwise. The solution was stirred for 3 h, diluted with EtOAc (300 ml), washed with 2×100 ml sat. NaCl, dried on MgSO4, and concentrated in vacuo. The resulting residue was purified by flash chromatography (30% to 80% EtOAc in hexanes) to afford the title compound as a clear oil (119.8 mg, 0.2691 mmol, 27%). 1H NMR (CDCl3, 400 MHz) δ 1.18 (t, J=4.4 Hz, 3H), 1.32 (s, 6H), 2.17-2.21 (m, 2H), 3.12-3.17 (m, 2H), 3.48-3.58 (m, 10H), 3.87 (dd, J=5.6, 5.6 Hz, 2H), 5.03-5.06 (m, 3H), 7.3-7.4 (m, 5H). LRMS (ESI/APCI): 446 [M+H]+, 468 [M+Na]+.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:49]([O:50]C(=O)C)[C@H:48]([O:54]C(=O)C)[C@@H:47]([C:58]([O:60]C)=[O:59])[O:46][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:17]([CH2:18][CH2:19][C@H:20]([O:28]C(=O)C)[C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:16](=[O:32])[N:15]2[C:33]2[CH:38]=[CH:37][C:36]([C:39]#[C:40][C:41]([NH:43][CH2:44][CH3:45])=[O:42])=[CH:35][CH:34]=2)=[CH:10][CH:9]=1)(=O)C.[C-]#N.[Na+]>CO>[O:7]([C:8]1[CH:9]=[CH:10][C:11]([C@@H:14]2[C@@H:17]([CH2:18][CH2:19][C@@H:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[OH:28])[C:16](=[O:32])[N:15]2[C:33]2[CH:34]=[CH:35][C:36]([C:39]#[C:40][C:41]([NH:43][CH2:44][CH3:45])=[O:42])=[CH:37][CH:38]=2)=[CH:12][CH:13]=1)[C@@H:6]1[O:46][C@H:47]([C:58]([OH:60])=[O:59])[C@@H:48]([OH:54])[C@H:49]([OH:50])[C@H:5]1[OH:4]
Reactant: CCNC(=O)C#Cc1ccc(N2C(=O)[C@H](CC[C@H](OC(C)=O)c3ccc(F)cc3)[C@H]2c2ccc(O[C@@H]3O[C@H](C(=O)OC)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc2)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: CCNC(=O)C#Cc1ccc(N2C(=O)[C@H](CC[C@H](O)c3ccc(F)cc3)[C@H]2c2ccc(O[C@@H]3O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]3O)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-((2S,3R)-3-[(3S)-3-(acetyloxy)-3-(4-fluorophenyl)propyl]-1-{4-(3-(ethylamino)-3-oxoprop-1-yn-1-yl]phenyl}-4-oxoazetidin-2-yl)phenyl methyl 2,3,4-tri-O-acetyl-β-D-glucopyranosiduronate (11a) (22.0 mg, 0.026 mmol) and sodium cyanide (˜1 mg, 0.020 mmol) in methanol (3 mL) was heated to 45° C. After 18 h, the reaction mixture was concentrated under reduced pressure and dissolved in methanol/water/triethylamine (1:3:1, 2.5 mL). After stirring at room temperature for approximately 1 h, the volatiles were evaporated in vacuo, and the crude residue purified by preparative reversed phase high performance liquid chromatography on YMC Pack Pro C18 phase (gradient elution; 10-60% acetonitrile/water as eluent, 0.1% TFA modifier) to give the title compound (11b) m/z (ES) 663.0 (M+H)+; HRMS (ES) m/z calcd. for C35H36FN2O10 (MH+) 663.2354, found 663.2341.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)([O:12][CH3:13])[O:10][CH3:11])=[CH:4][CH:3]=1.[OH:20]O>ClCCl.C[Re](=O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:14]2[CH:15]=[CH:16][N+:17]([O-:20])=[CH:18][CH:19]=2)([O:10][CH3:11])[O:12][CH3:13])=[CH:4][CH:3]=1
Reactant: COC(Cc1ccc(F)cc1)(OC)c1ccncc1
Reactant: OO
Agent: C[Re](=O)(=O)=O
Solvent: ClCCl
Product: COC(Cc1ccc(F)cc1)(OC)c1cc[n+]([O-])cc1
Temperature: 25 °C

Procedure:
55 g (0.21 mole) of 4-[2-(4-Fluoro-phenyl)-1,1-dimethoxy-ethyl]-pyridine and 445 mg of methyltrioxorhenium are dissolved in 250 mL of dichloromethane. 112 mL of commercial hydrogen peroxide solution is added to the reaction mixture which is further stirred over night at room temperature. The reaction mixture is then decanted and the organic phase is washed with sodium hydrogen sulfate and water and dried over magnesium sulfate. After concentration, 33 g of 4-[2-(4-Fluoro-phenyl)-1,1-dimethoxy-ethyl]-pyridine 1-oxide is obtained as a green oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>CO>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22](/[CH:29]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[CH:21]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CN1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: CN1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ncccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
A solution of 6-hydroxy-7-[(4-methylpiperazin-1-yl)methyl]benzofuran-3(2H)-one (0.100 g, 0.381 mmol) obtained in Example A31, Step 1 in methanol (1.5 mL) was added with 7-aza-1H-indole-3-carboxaldehyde (0.0557 g, 0.381 mmol) and piperidine (0.00324 g, 0.0381 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the precipitated solid was collected by filtration to obtain (Z)-2-((1H-pyrrolo[2,3-b]pyridin-3-yl)methylene)-6-hydroxy-7-[(4-methylpiperazin-1-yl)methyl]benzofuran-3(2H)-one (0.109 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13](C(OC)=O)[CH2:12][CH:11]3[CH3:20])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[OH-].[K+].CC(O)C>O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH:11]3[CH3:20])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: COC(=O)N1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)C(C)C1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC1CNCCC1n1c(=O)[nH]c2cc(Cl)ccc21

Procedure:
A mixture of 26 parts of methyl 4-(5-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-3-methyl-1-piperidinecarboxylate, 36 parts of potassium hydroxide, 200 parts of 2-propanol and 6 parts of water is stirred and refluxed for 18 hours. The reaction mixture is evaporated and water is added to the residue. The whole is acidified with a concentrated hydrochloric acid solution, while cooling. The free base is liberated in the conventional manner and stirred with trichloromethane for 30 minutes. The layers are separated and the aqueous layer is extracted with trichloromethane. The combined organic phases are dried, filtered and evaporated. The oily residue solidifies on triturating in a mixture of 2,2'-oxybispropane and a small amount of 2-propanol. The product is filtered off and crystallized from 4-methyl-2-pentanone, yielding 5-chloro-1,3-dihydro-1-(3-methyl-4-piperidinyl)-2H-benzimidazol-2-one; mp. 198.9° C.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[CH2:8][C:9](=[O:31])[NH:10][C:11]1[CH:12]=[C:13]2[C:29](=[O:30])[NH:28][N:27]=[CH:26][C:15]3=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[NH:17][C:18]([CH:19]=1)=[C:14]23)(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>C(Cl)Cl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[CH3:6][NH:7][CH:8]([CH3:35])[C:9]([NH:10][C:11]1[CH:12]=[C:13]2[C:29](=[O:30])[NH:28][N:27]=[CH:26][C:15]3=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[NH:17][C:18]([CH:19]=1)=[C:14]23)=[O:31]
Reactant: CN(CC(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(C)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reaction time: 0.5 h
Yield: 98 %

Procedure:
The title compound of Example 19 (19 mg, 0.042 mmol) in CH2Cl2 (0.65 mL) was treated with trifluoroacetic acid (0.45 mL) and allowed to stir for 0.5 hours. The volatile components were removed under vacuum, and diethyl ether was added and evaporated three times to give the title compound (19 mg, 0.041 mmol) as a yellow, orange powder in 98% yield.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[C:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[S:15])=[CH:9][CH:8]=1)#[N:6]>C(O)C>[C:2]([NH:3][C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]#[N:6])=[CH:8][CH:9]=1)=[S:15])#[N:1]
Reactant: N#Cc1ccc(N=C=S)cc1
Reactant: N#CN
Agent: [Na]
Solvent: CCO
Product: N#CNC(=S)Nc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
The suspension of monosodium cyanamide (4.3 g, 67.2 mmol) in absolute ethanol (170 mL) was slowly treated with 4-cyanophenylisothiocyanate (10.75 g, 67.2 mmol). The reaction was allowed to stir at room temperature for 1 hour and then heated at 75° C. for 4 hours. The reaction was cooled to room temperature and the colorless solid was filtered and washed with ethanol to give the title A compound (10.0 g), m.p. >250° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl[CH2:12][C:13]#[C:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:12][C:13]#[C:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CC(C)(C)OC(=O)NCC#CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC#CCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.51 g), tert-butyl (4-chlorobut-2-yn-1-yl)carbamate (2.60 g), cesium carbonate (4.80 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 2 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→33:67) to give the title compound (2.61 g) as an orange oil.
Reaction SMILES: NC1N=C2C=CC(C3C=C(NS(C)(=O)=[O:19])C(Cl)=NC=3)=NN2C=1C1C=CC=C(F)C=1.[Cl:30][C:31]1[N:36]=[CH:35][C:34]([C:37]2[CH:38]=[CH:39][C:40]3[N:41]([C:43]([C:50]4[CH:55]=[CH:54][C:53]([F:56])=[C:52]([C:57](N5CCOCC5)=[O:58])[CH:51]=4)=[C:44]([NH:46]C(=O)C)[N:45]=3)[N:42]=2)=[CH:33][C:32]=1[NH:65][S:66]([CH3:69])(=[O:68])=[O:67].[OH-].[Na+]>>[NH2:46][C:44]1[N:45]=[C:40]2[CH:39]=[CH:38][C:37]([C:34]3[CH:35]=[N:36][C:31]([Cl:30])=[C:32]([NH:65][S:66]([CH3:69])(=[O:68])=[O:67])[CH:33]=3)=[N:42][N:41]2[C:43]=1[C:50]1[CH:55]=[CH:54][C:53]([F:56])=[C:52]([CH:51]=1)[C:57]([OH:58])=[O:19]
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)nn2c1-c1ccc(F)c(C(=O)N2CCOCC2)c1
Reactant: CS(=O)(=O)Nc1cc(-c2ccc3nc(N)c(-c4cccc(F)c4)n3n2)cnc1Cl
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)Nc1cc(-c2ccc3nc(N)c(-c4ccc(F)c(C(=O)O)c4)n3n2)cnc1Cl
Reaction time: 0.33 h
Yield: 27 %

Procedure:
Following the procedure described for N-(5-(2-amino-3-(3-fluorophenyl)imidazo[1,2-b]pyridazin-6-yl)-2-chloropyridin-3-yl)methanesulfonamide (Example 23), N-(6-(6-chloro-5-(methylsulfonamido)pyridin-3-yl)-3-(4-fluoro-3-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-2-yl)acetamide (TFA salt) (Example 24) (0.016 g, 0.023 mmol) was treated with sodium hydroxide (0.100 mL, 1.0 mmol, 10 M) and purified by preparative HPLC (Phenomenex Gemini 5 micron (Phenomenex, Torrance, Calif.), C18, 100×30 mm, 5 to 85% CH3CN(0.1% TFA)/H2O(0.1% TFA) over 20 min then 100% CH3CN(0.1% TFA) for 3 minutes at 20 mL/min) with the fractions containing suspected product concentrated to afford the title compound as a yellow solid (3.6 mg, 27%). MS (ESI, positive ion) m/z: 477 (M−TFA+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.19 (s, 3H), 6.00 (br s, 2H), 7.40-7.45 (m, 1H), 7.77 (d, J=9.2 Hz, 1H), 7.91 (d, J=9.2 Hz, 1H), 8.23-8.28 (m, 1H), 8.45 (d, J=2.0 Hz, 1H), 8.47-8.50 (m, 1H), 8.93 (d, J=2.0 Hz, 1H), 9.85 (s, 1H), 13.28 (br s, 1H).
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:13]=[CH:14][C:15](=O)C.[C:23]([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1>[CH3:23][C:14](=[CH:13][C:12]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:10]([O:9][CH3:8])[CH:11]=1)[CH:15]=[C:7]1[S:1][C:2](=[S:3])[NH:4][C:5]1=[O:6]
Reactant: CC(=O)[O-]
Reactant: O=C1CSC(=S)N1
Reactant: COc1ccc(C=CC(C)=O)cc1OC
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: COc1ccc(C=C(C)C=C2SC(=S)NC2=O)cc1OC

Procedure:
A mixture of 1.73 g (0.013 mol) of rhodanine, 2.06 g (0.01 mol) of 3,4-dimethoxybenzalacetone, 0.31 g (0.004 mol) of ammonium acetate and 5 ml of toluene was heated under reflux for 2 hours. After cooling, precipitates were recovered by filtration and washed with methanol. The residue was purified by silica gel column chromatography (eluent, chloroform) to obtain 0.5 g of the isomer A of the desired 5-(α-methyl-3,4-dimethoxycinnamylidene)-4-oxo-2-thioxothiazolidine from the first eluate and 0.2 g of the isomer B from the subsequent eluate.
Reaction SMILES: [Na].[CH:2]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[N:11]=[CH:12][N:13]4[C:22]5[C:17](=[C:18](Cl)[CH:19]=[CH:20][CH:21]=5)[C:16](=[O:24])[N:15]([CH3:25])[C:14]=34)[N:6]=2)[CH2:4][CH2:3]1.[CH2:26]([OH:28])[CH3:27]>>[CH:2]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[N:11]=[CH:12][N:13]4[C:22]5[C:17](=[C:18]([O:28][CH2:26][CH3:27])[CH:19]=[CH:20][CH:21]=5)[C:16](=[O:24])[N:15]([CH3:25])[C:14]=34)[N:6]=2)[CH2:4][CH2:3]1
Reactant: Cn1c(=O)c2c(Cl)cccc2n2cnc(-c3noc(C4CC4)n3)c12
Reactant: CCO
Agent: [Na]
Product: CCOc1cccc2c1c(=O)n(C)c1c(-c3noc(C4CC4)n3)ncn21

Procedure:
30 mg of sodium was dissolved in 10 ml of dry ethanol. Then 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4,5-dihydro-4-methyl-5-oxo-6- chloro-imidazo(1,5-a)quinazoline (0.2 g, 0.5 mmol) was added and the resulting mixture was refluxed for 7 hours. The reaction mixture was evaporated. Glacial acetic acid and water was added to the residue whereupon the title compound was isolated by filtration. M.p. 195°-205° C.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[F:29][C:30]1[CH:40]=[CH:39][CH:38]=[CH:37][C:31]=1/[CH:32]=[CH:33]/[C:34](O)=[O:35]>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:34](=[O:35])/[CH:33]=[CH:32]/[C:31]4[CH:37]=[CH:38][CH:39]=[CH:40][C:30]=4[F:29])[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Reactant: O=C(O)/C=C/c1ccccc1F
Agent: Cl
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2ccccc2F)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J, and trans-2-fluoro-cinnamic acid, by the method of Example 1, step K, giving a solid that was a mixture of cyclohexyl diastereomers by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C30H35FN4O2: 502 (M+H). Found: 503
Reaction SMILES: [CH:1]1([PH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([O:11][CH:12]=[CH2:13])(=[O:10])[CH3:9].N(C(C)(C)C#N)=NC(C)(C)C#N.[C:26]([O:30][CH3:31])(=[O:29])[CH:27]=[CH2:28]>C1C=CC=CC=1>[CH:1]1([P:7]([CH2:13][CH2:12][O:11][C:8](=[O:10])[CH3:9])[CH2:28][CH2:27][C:26]([O:30][CH3:31])=[O:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CC(=O)OC
Reactant: PC1CCCCC1
Reactant: C=COC(C)=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COC(=O)CCP(CCOC(C)=O)C1CCCCC1
Reaction time: 2 h

Procedure:
A stirred solution of 23 g. (0.2 mol) of cyclohexylphoshine, 17 g. (0.2 mol) of vinyl acetate and 0.1 g. of azobis-isobutyronitrile in 100 ml. of benzene is prepared and irradiated with ultraviolet light as in Example 1. The temperature is maintained at 25°-30°C. The course of the reaction is followed by observation of the disappearance of the infrared absorption for the vinyl group at 1650 cm.-1After three hours this absorption has disappeared completely and the P-H absorption has shifted from 2450 to 2425 cm.-1 indicating conversion of the primary ##EQU7## absorption to the secondary >P--H. Thus: ##EQU8## To this secondary phosphine intermediate product there is added 18 g. (0.21 mol) of methyl acrylate plus an additional 0.1 g. of azo-bis-isobutyronitrile and irradiation continued under the above conditions for another two hours at which point a scan of the infrared absorption spectrum of the reaction mixture shows the disappearance of the P-H absorption. Removal of the benzene by distillation leaves behind the cyclohexyl-2-acetoxyethyl-2-carbomethoxy ethylphosphine as a colorless, viscous oil.
Reaction SMILES: [CH:1]1([OH:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[H-].[Na+].Cl[C:14]1[C:15]2[CH:24]=[CH:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=3[CH3:32])[C:16]=2[C:17](=[O:21])[N:18]([CH3:20])[N:19]=1>CN(C=O)C.O>[CH:1]1([O:10][C:14]2[C:15]3[CH:24]=[CH:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=4[CH3:32])[C:16]=3[C:17](=[O:21])[N:18]([CH3:20])[N:19]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: OC1CCc2ccccc21
Reactant: Cc1ccc(-n2ccc3c(Cl)nn(C)c(=O)c32)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-n2ccc3c(OC4CCc5ccccc54)nn(C)c(=O)c32)c(C)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 48.4 %

Procedure:
To a solution of 1-indanol (60 mg, 0.45 mmol) in DMF (1 ml) was added sodium hydride (60% in oil, 18 mg, 0.45 mmol). The mixture was stirred for 10 min before addition of 4-chloro-1-(2,4-dimethylphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (43.2 mg, 0.15 mmol). The mixture was stirred at 60° C. for 3 hours, then diluted with water (30 ml) and extracted with ethyl acetate (30 ml×2). The extract were combined, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (10:1) to give 28 mg (48%) of the title compounds as an oil.