Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]([OH:24])=O)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[NH:26][C:27]([CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[NH:28].O>CN(C)C=O>[CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]4[O:24][N:28]=[C:27]([CH:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[N:26]=4)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N=C(NO)C1CCCC1
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Solvent: CN(C)C=O
Solvent: O
Product: c1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](Cc4nc(C5CCCC5)no4)CS3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
The compound (140 mg, 0.41 mmol) prepared in Example 42 was dissolved in N,N-dimethylformamide (5 ml). 1,1′-Dicarbonyldiimidazole (73 mg, 0.45 mmol) was added thereto, and the mixture was stirred for 30 min at room temperature. N-hydroxy-cyclopentanecarboxamidine (260 mg, 2.03 mmol) was added thereto, and the mixture was stirred for 5 h at 80° C. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (100 mg, Yield 56%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:42])=[N:4][O:5][C:6]=1[N:7](COCCOC)[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[CH:26]=[C:25]2[O:27][CH2:28][O:29][C:24]2=[CH:23][C:22]=1[CH2:30][CH2:31][O:32]C(=O)C)(=[O:10])=[O:9].Cl>CO>[Cl:1][C:2]1[C:3]([CH3:42])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[CH:26]=[C:25]2[O:27][CH2:28][O:29][C:24]2=[CH:23][C:22]=1[CH2:30][CH2:31][OH:32])(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(Cc2cc3c(cc2CCOC(C)=O)OCO3)sc2ncccc12
Agent: Cl
Solvent: CO
Product: Cc1noc(NS(=O)(=O)c2c(Cc3cc4c(cc3CCO)OCO4)sc3ncccc23)c1Cl
Yield: 83.3 %

Procedure:
The title compound was prepared by the method of Example 4(D) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-{2-[2-(acetoxy)ethyl]-4,5-(methylenedioxy)benzyl}thieno[2,3-b]pyridine-3-sulfonamide (83 mg, 0.13 mmoles), methanol (3 ml) and 4N HCl (1 ml). Recrystallization from CH2Cl2 /hexanes provided 55 mg (84%) of the title compound as a white solid, m.p. 104-106° C.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([C:6]1[CH:15]=[CH:14][C:9]([NH:10][C:11](=S)[CH3:12])=[CH:8][CH:7]=1)#[N:5].[CH2:16]1[CH2:20]OCC1>>[C:4]([C:6]1[CH:15]=[CH:14][C:9]([N:10]2[C:20]([CH3:16])=[N:3][N:2]=[C:11]2[CH3:12])=[CH:8][CH:7]=1)#[N:5]
Reactant: C1CCOC1
Reactant: CC(=S)Nc1ccc(C#N)cc1
Reactant: NN
Solvent: O
Product: Cc1nnc(C)n1-c1ccc(C#N)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Hydrazine hydrate (1.64 ml, 34 mmol) was added dropwise to a solution of p-cyanothioacetanilide prepared according to J. Pharm. Soc. Jpn., 1952, 72, 739 (5.43 gm, 30.9 mmol) in THF (50 ml) at room temperature. After 30 minutes, the solution was concentrated under reduced pressure and the residue treated with triethyl orthoacetate (40 ml). The mixture was heated at 80° C. for 30 minutes, cooled and the excess reagent was removed under reduced pressure. The residue was treated with ice-cold dilute aqueous ammonia (100 ml) and the product was filtered off, washed with water and dried in vacuo. The title triazole (4.85 g) was an off-white solid, m.p. >230° C.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:22]=[C:21]([C:23]#[C:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]>ClCCl>[Cl:12][C:13]1[CH:22]=[C:21]([C:23](=[O:6])[CH:24]=[CH:25][N:26]([CH3:28])[CH3:27])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1ccc(C#CCN(C)C)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)C=CN(C)C)cc1Cl
Temperature: -20 °C
Reaction time: 0.21 h

Procedure:
Gradually, 3-chloroperoxybenzoic acid (10.76 g) was added to a solution of 2-chloro-4-(3-dimethylamino-propyn-1yl)-benzoic acid, methyl ester (15.07 g in dichloromethane (40 ml), at a rate to maintain the reaction temperature at −20° C. The mixture was stirred for 10-15 minutes. The resulting N-oxide was purified by chromatography on Activity Grade I basic alumina (215 g), eluting with 10% methanol/dichloromethane. The solvent was evaporated in vacuo between 12 to 18° C. The resulting residue was dissolved in methanol (100 ml) and heated at 60-65° C. with stirring for 18 hours. After removing the solvent in vacuo, and the product was purified by column chromatography on silica gel (190 g), eluting with 70% ethyl acetate/hexane. Trituration with diethyl ether containing some hexane afforded the title compound as a solid (5.68 g), m.p. 92-96° C.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][C:14]([C:16]3([CH3:22])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.Cl[C:26]1[C:27]2[CH:34]=[CH:33][NH:32][C:28]=2[N:29]=[CH:30][N:31]=1.C(N(CC)CC)C>C(O)(C)C>[F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][C:14]([C:16]3([CH3:22])[CH2:17][CH2:18][N:19]([C:26]4[C:27]5[CH:34]=[CH:33][NH:32][C:28]=5[N:29]=[CH:30][N:31]=4)[CH2:20][CH2:21]3)=[O:15])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC1(C(=O)Nc2cccc(Oc3ccc(F)cc3)c2)CCNCC1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC1(C(=O)Nc2cccc(Oc3ccc(F)cc3)c2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 180 °C

Procedure:
To a solution of N-(3-(4-fluorophenoxy)phenyl)-4-methylpiperidine-4-carboxamide from example 1, step B, (20 mg, 0.05 mmol) in isopropanol (1 mL), was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (15 mg, 0.1 mmol) and triethylamine (0.04 mL, 0.3 mmol). The reaction mixture was heated at 180° C. for 30 minutes under microwave conditions, and then concentrated under vacuum. The product was isolated by prep HPLC to give the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)=[CH:5][CH:4]=1.Cl.[NH+]1C=CC=CC=1>>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=1
Reactant: COc1ccc(-c2ccc3ccccc3c2)cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: Oc1ccc(-c2ccc3ccccc3c2)cc1

Procedure:
The title compound was prepared by reacting 2-(4-methoxyphenyl)naphthalene (1.01 g, 4.31 mmol) with 10 g of pyridinium HCl at 190° C. according to method B to yield 0.84 g (89%) of a white solid: mp 148° C.; 1H NMR (DMSO-d6): δ 6.92 (2H, d, J=8.71 Hz), 7.46-7.53 (2H, m), 7.66 (2H, d, J=8.71 Hz), 7.79 (1H, dd, J=1.78 Hz, J=8.51 Hz), 7.90 (1H, d, J=8.31 Hz), 7.95 (2H, d, J=8.31 Hz), 8.11 (1H, d, J=1.19 Hz), 9.65 (1H, s); MS (ESI) m/z 219 (M−H)−.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[N:12]=[C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][OH:22])[CH2:15][CH2:14]2)[CH:10]=[C:9]([CH:23]2[CH2:26][CH2:25][CH2:24]2)[N:8]=1)([CH3:6])([CH3:5])[CH3:4].[Cl:27][C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1>CCCCC.O1CCOCC1>[ClH:27].[C:3]([C:7]1[N:8]=[C:9]([CH:23]2[CH2:26][CH2:25][CH2:24]2)[CH:10]=[C:11]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH2:21][O:22][C:28]3[N:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[CH2:17][CH2:18]2)[N:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: Clc1ncccn1
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCO)CC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCCCC
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCOc3ncccn3)CC2)n1
Product: Cl
Yield: 91.5 %

Procedure:
0.31 g of sodium hydride (7.8 mmol; 60% in paraffin) was washed oil-free with pentane before 1.3 g of 3-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-propan-1-ol (3.91 mmol) dissolved in 20 ml of dioxane were added. The reaction was heated to reflux for 1 h. After cooling, 0.7 g of 2-chloro-pyrimidine (6.11 mmol) dissolved in 10 ml of dioxane were added. The reaction mixture was heated under reflux for 2 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, the solvent evaporated, and the residue re-dissolved in isopropanol and treated with hydrochloric acid in diethyl ether. After removing most of the organic phase, the residue was treated with isopranol/diisopropyl ether, which, after cautious evaporation, yielded 1.6 g of the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=2)[O:10][CH2:11][CH2:12][C:13](O)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[OH-:23].[Na+].Cl.[NH2:26]O>O>[C:1]1([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=2)[O:10][CH2:11][CH2:12][C:13]([NH:26][OH:23])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCOc1cccc(-c2ccccc2)c1
Reactant: NO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Product: O=C(CCOc1cccc(-c2ccccc2)c1)NO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 3-(3-phenylphenoxy)propionic acid (0.27 g, 1.1 mmol) and excess thionyl chloride was heated at reflux for 30 minutes. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was azeotroped three times with ethyl ether, and then was taken up in THF (30 mL). To the acid chloride solution was added aqueous hydroxylamine (3.34 mmol; prepared by adding 2.8 mL of aqueous 50% NaOH to a solution in 5 mL water of hydroxylamine hydrochloride) and the reaction mixture was stirred for 4 hours. The reaction mixture was quenched with 1:1 dichloromethane-saturated aqueous NH4Cl. The aqueous phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was taken up in ethyl ether and left standing at -30° C. for 3 days. The resulting crystals were collected to give 3-(3-phenylphenoxy)propanohydroxamic acid. mp 113°-116° C. 1H NMR (DMSO-d6) δ 10.58 (s, 1H), 8.68-8.63 (d, 1H, J=1.5 Hz), 7.67-7.65 (d, 2H, J=7 Hz), 7.48-7.43 (t, 2H, J=7.7 Hz), 7.38-7.34 (t, 2H, J=7.7 Hz), 7.24-7.21 (d, 1H, J=7.4 Hz), 7.15 (m, 1H), 6.94-6.90 (dd, 1H, J=3, 7 Hz), 4.28-4.24 (t, 2H, J=6 Hz), 2.47-2.43 (t, 2H, J=6 Hz). MS (DCI/NH3) 275 (M+NH4)+. Anal. Calcd for C15H15NO3 ·0.25H2O: C, 68.82; H, 55.96; N, 5.35. Found: C, 68.92; H, 5.87; N, 5.33.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:16](=[O:25])[CH:17]=[C:18]([C:21]([O:23][CH3:24])=[O:22])[O:19][CH:20]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]>C(O)C.[H][H].[Pd]>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][O:19][CH:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH:16]2[OH:25])=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCCCOc2coc(C(=O)OC)cc2=O)ccc(C(C)=O)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(OCCCCCOC2COC(C(=O)OC)CC2O)ccc(C(C)=O)c1O
Yield: 16.9 %

Procedure:
The title product of Example 2 (840 mg, 1.96 mmole) was dissolved in 110 ml ethanol, and then hydrogenated at room temperature using 2 psi of hydrogen and 5% palladium on carbon as catalyst. Insolubles were removed by filtration and the filtrate was concentrated in vacuo, and the incompletely reduced residue (as determined by nmr in (CD3)2SO) was again hydrogenated. Purification by high performance chromatography on silica gel (using 30% by volume acetone-hexane) afforded 145 mg of the title compound as an oil. Spectral data indicate complete reduction of the pyranone moiety to the hydroxy-substituted cyclic ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[C:19](OC(=O)CC)(=O)[CH2:20][CH3:21].Cl>C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:11])[C:12]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:18][C:19]=2[CH2:20][CH3:21])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(Cc1cc(F)cc(F)c1)c1ccccc1O
Reactant: CCC(=O)OC(=O)CC
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1oc2ccccc2c(=O)c1-c1cc(F)cc(F)c1
Temperature: 25 °C
Yield: 71.3 %

Procedure:
Intermediate 70 (2.0 g, 8.08 mmoles) was taken in a RB flask and to this triethylamine (20 ml) and propionic anhydride (3.26 g, 25.2 mmoles) were added and the mixture was refluxed for 24 h. After cooling to RT, the reaction mixture was acidified by the addition of 1N HCl solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried with sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as off-colourless liquid (1.65 g, 72% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.05(dd, J=7.9,1.2 Hz, 1H), 7.84(dt, J=8.5,1.4 Hz, 1H), 7.68(d, J=8.4 Hz, 1H), 7.51(t, J=7.8 Hz, 1H), 7.30(tt, J=7.2,2.2 Hz, 1H), 7.07(d, J=6.1 Hz, 2H), 2.58(q, J=7.5 Hz, 1H), 1.21(t, J=7.6 Hz, 3H).
Reaction SMILES: N[C@H](C(O)=O)C[SeH].[Li]CCCC.CN(C)CCN(C)C.[CH2:21]([N:23]([CH2:34][CH3:35])[C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[CH3:22].[CH3:36][S:37]C>C1COCC1>[CH2:34]([N:23]([CH2:21][CH3:22])[C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[S:37][CH3:36])[CH3:35]
Reactant: CSC
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1
Agent: CN(C)CCN(C)C
Agent: N[C@@H](C[SeH])C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(OC)cc1SC
Reaction time: 0.25 h

Procedure:
Sec-BuLi (1.4 M in cyclohexane, 11.34 mL, 15 mmol) was carefully added to a mixture of N,N,N′,N′-tetramethylethane-1,2-diamine (2.2 mL, 15 mmol) in anhydrous THF at −78° C. N,N-Diethyl-4-methoxybenzamide (3 g, 14.4 mmol) dissolved in 5 mL of anhydrous THF was added dropwise to the reaction mixture which was allowed to stir for 1 h Dimethyl sulfide (2.5 mL, 28.8 mmol) was then added to the reaction. After stirring for 15 min, the cooling bath was removed and the mixture was stirred overnight. The reaction was diluted with ethyl acetate and washed with a solution of saturated sodium bicarbonate, water and then brine. The organic layer was then dried with sodium sulfate, concentrated and purified by flash chromatography using a gradient of 20 to 80% ethyl acetate in hexanes to obtain the product as a light yellow oil. Yield=2.51 g. MS (M+H)+ 254.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9](O)=[N:8][C:6]=2[N:7]=1.ClCCl.S(Cl)([Cl:26])=O.[CH3:28][N:29]([CH3:32])[CH:30]=O>>[Cl:26][C:9]1[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:11][C:5]2[CH:4]=[N:3][C:2]([N:1]=[CH:28][N:29]([CH3:32])[CH3:30])=[N:7][C:6]=2[N:8]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2cc3cnc(N)nc3nc2O)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(-c2cc3cnc(N=CN(C)C)nc3nc2Cl)cc1
Reaction time: 6 h

Procedure:
To a mixture of 67.0 g of 2-amino-6-(4-methoxy-phenyl)-pyrido[2,3-d]pyrimidin-7-ol from Example 10, 1 L of dichloromethane, and 155 mL of dimethylformamide was added dropwise with cooling 72 mL of thionyl chloride keeping the temperature below 15° C. The suspension was heated to reflux with stirring for 6 hours. The reaction mixture was filtered and the filtrate evaporated in vacuo maintaining the temperature below 60° C. The resulting residue was dissolved in ice water and aqueous sodium hydroxide added with ice. The product was taken up in chloroform, washed with water, dried over anhydrous potassium carbonate, and evaporated. The residue was slurried with acetonitrile and the insoluble product collected by filtration to afford 31 g of the title compound N'-(7-chloro-6-(4-methoxyphenyl)-pyrido[2,3-d]pyrimidin-2-yl)-N,N-dimethyl-formamidine. The product was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[C:8]2[CH2:9][C:10]3[S:14][C:13]([SH:15])=[N:12][C:11]=3[C:16]=2[CH:17]=[CH:18][CH:19]=1)C.Br[CH2:22][CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([CH:24]=[CH:23][CH2:22][S:15][C:13]2[S:14][C:10]3[CH2:9][C:8]4[C:7]([O:6][CH2:5][C:4]([OH:3])=[O:20])=[CH:19][CH:18]=[CH:17][C:16]=4[C:11]=3[N:12]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCC=Cc1ccccc1
Reactant: CCOC(=O)COc1cccc2c1Cc1sc(S)nc1-2
Product: O=C(O)COc1cccc2c1Cc1sc(SCC=Cc3ccccc3)nc1-2
Yield: 50 %

Procedure:
Using ethyl[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate and 3-bromo-1-phenyl-1-propene, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 50%.
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH2:12][C:13]([CH2:15][CH3:16])=[O:14])=[C:9]([Br:17])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:18]1(=O)[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[CH2:19]1.Cl.CN(C)CCCN=C=NCC.CN(C1C=CC=CN=1)C>C(Cl)Cl>[Br:1][C:2]1[C:10]([O:11][CH2:12][C:13]([CH2:15][CH3:16])=[O:14])=[C:9]([Br:17])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:18]1[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[CH:19]=1)=[O:5]
Reactant: CCC(=O)COc1c(Br)ccc(C(=O)O)c1Br
Reactant: O=C1CCCC(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CCC(=O)COc1c(Br)ccc(C(=O)OC2=CC(=O)CCC2)c1Br

Procedure:
0.415 g (1.10 mmol) of 2,4-dibromo-3-(ethylcarbonylmethoxy)benzoic acid, 0.140 g (1.20 mmol) of cyclohexane-1,3-dione, 0.222 g (1.10 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 0.001 g of dimethylaminopyridine were stirred in 30 ml of CH2Cl2 at room temperature for 3 h. The mixture was then diluted with CH2Cl2 and washed with 0.5 N HCl, with water, with saturated NaHCO3 solution and again with water. The combined organic phases were dried over Na2SO4 and evaporated to dryness, giving 3-oxo-1-cyclohexenyl 2,4-dibromo-3-(ethylcarbonylmethoxy)benzoate in the form of a yellow resin which was sufficiently pure for the subsequent reaction.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[S:20][CH3:21])[CH3:11])=[O:9])[C:4](=[O:22])O1.[CH2:24]=O.[N:26]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:10]([CH3:11])[C:8]([C:7]2[CH2:24][N:34]([CH2:33][CH2:32][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[C:4](=[O:22])[C:5]=2[OH:6])=[O:9])=[C:14]([S:20][CH3:21])[CH:15]=1
Reactant: NCCN1CCOCC1
Reactant: CSc1cc(F)ccc1CN(C)C(=O)C=C1OC(C)(C)OC1=O
Reactant: C=O
Product: CSc1cc(F)ccc1CN(C)C(=O)C1=C(O)C(=O)N(CCN2CCOCC2)C1
Yield: 76 %

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methylsulfanyl-benzyl)-N-methyl-acetamide was reacted with paraformaldehyde and 2-morpholin-4-yl-ethylamine as described in Method 44B to give the title compound as a white solid (0.032 g, 76% yield). 1HNMR (300 MHz, CDCl3) δ: 7.07 (1H, dd, J=9.52, 6.23 Hz), 6.92 (1H, dd, J=9.52, 2.56 Hz), 6.82 (1H, td, J=8.06, 2.57 Hz), 4.61 (2H, s), 4.27 (2H, s), 3.95–3.90 (8H, m), 3.76–3.72 (2H, m), 3.39 (2H, t, J=5.85 Hz), 2.97 (3H, s), 2.47 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:33][CH2:32][C:19]5([CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:21][CH2:20]5)[CH2:18][CH2:17]4)=[N:12][N:11]3[C:34]=2[C:35]2[CH:40]=[CH:39][N:38]=[C:37]3[N:41](S(C4C=CC(C)=CC=4)(=O)=O)[CH:42]=[CH:43][C:36]=23)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:17][CH2:18][C:19]5([CH2:24][N:23]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:22][CH2:21][CH2:20]5)[CH2:32][CH2:33]4)=[N:12][N:11]3[C:34]=2[C:35]2[CH:40]=[CH:39][N:38]=[C:37]3[NH:41][CH:42]=[CH:43][C:36]=23)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(-c5ccc(F)cc5)nc5ccc(N6CCC7(CCCN(C(=O)OC(C)(C)C)C7)CC6)nn45)ccnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC2(CCN(c3ccc4nc(-c5ccc(F)cc5)c(-c5ccnc6[nH]ccc56)n4n3)CC2)C1

Procedure:
The tert-butyl 9-{2-(4-fluorophenyl)-3-[1-(4-methylphenylsulphonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]imidazo[1,2-b]pyridazin-6-yl}-2,9-diazaspiro[5.5]undecane-2-carboxylate obtained in step 5.1 is dissolved in 3 ml of a mixture of methanol and tetrahydrofuran (2/1) and is treated using 0.09 ml (0.54 mmol) of a 6N aqueous solution of sodium hydroxide at 60° C. for 1 and a half hours. The solvent is evaporated under reduced pressure and the residue taken up in 3 ml of water. The product is extracted 2 times with 3 ml of dichloromethane. The organic phase is dried over sodium sulphate and the solvent is removed by evaporation under reduced pressure. The residue obtained is then purified by chromatography on a silica gel column (4 g) by eluting with a gradient of dichloromethane, methanol and aqueous ammonia (of 95/5/05 to 90/10/1) in order to give 0.06 g of tert-butyl 9-[2-(4-fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]-2,9-diazaspiro[5.5]undecane-2-carboxylate after crystallization in 10 ml of acetonitrile, filtration and drying.
Reaction SMILES: CO[C:3]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[C:8]([O:15][CH3:16])=[C:7]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:6]=1)=[O:4].C(O)CO.[CH2:25]([N:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[CH2:32][NH2:33])[CH3:26].O>C(O)(=O)C>[CH2:25]([N:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[CH2:32][NH:33][C:3]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[C:8]([O:15][CH3:16])=[C:7]([S:17](=[O:19])(=[O:20])[NH2:18])[CH:6]=1)=[O:4])[CH3:26]
Reactant: COC(=O)c1cc(S(N)(=O)=O)c(OC)c2c1OCCO2
Reactant: CCN1CCCC1CN
Solvent: O
Solvent: OCCO
Solvent: CC(=O)O
Product: CCN1CCCC1CNC(=O)c1cc(S(N)(=O)=O)c(OC)c2c1OCCO2
Temperature: 50 °C
Yield: 72.9 %

Procedure:
150 g of methyl-8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylate and 750 cm3 of ethylene glycol were introduced into a balloon flask. After dissolution, 127 g of 1-ethyl-2-aminomethylpyrrolidine was added and the mixture was heated at 50° C. The resulting solution was dissolved with 2 liters of water and acidified by means of 120 cm3 of acetic acid. The precipitate formed was dried off, washed with water and then dried. The precipitate was then redissolved in 915 cm3 of hot water. The solution was filtered and then the base was precipitated with ammonia. The precipitate was dried off, washed with water and then dried. 144 g of N-(1-ethyl-2-pyrrolidyl-methyl)-8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxamide was produced (M.P.: 110°-115° C.; yield: 73%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH:11]([C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1)([CH3:13])[CH3:12].O>CN(C)C=O>[CH:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:22])[NH:1][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([OH:7])=[O:6])=[CH:16][CH:15]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1ccc(N=C=O)cc1
Reactant: Nc1cccc(C(=O)O)c1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccc(NC(=O)Nc2cccc(C(=O)O)c2)cc1
Reaction time: 20 h
Yield: 85.3 %

Procedure:
A solution of 3-aminobenzoic acid (0.46 g, 3.4 mmol) in dimethylformamide (20 mL) at 0° C. was treated with 4-isopropylphenyl isocyanate (0.59 mL, 3.7 mmol). After stirring for 20 h, the solution was poured into 200 mL water, and the resulting precipitate was collected by filtration, washed with water and tetrahydrofuran, and dried under vacuum to afford the title product (0.85 g, 2.9 mmol, 85%) as a powder (m.p. 295-300° C.). TLC Rf 0.20 (ethyl acetate). 1H NMR (d6-DMSO, 300 MHz): δ 8.82 (1H, s), 8.57 (1H, s), 8.09 (1H, t, J=1.8 Hz), 7.58 (1H, dd, J=8.1, 1.1 Hz), 7.51 (1H, d, J=7.8 Hz), 7.36 (1H, t, J=8.0 Hz), 7.34 (2H, d, J=8.4 Hz), 7.12 (2H, d, J=8.4 Hz), 2.82 (1H, heptet, J=6.9 Hz), 1.17 (6H, d, J=6.9 Hz). MS (ES+): 299