Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[C:10]([CH3:22])([CH3:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.[Cl:35][C:36]1[CH:37]=[CH:38][C:39]2[N:40]([CH:42]=[C:43]([CH2:45]Cl)[N:44]=2)[N:41]=1>O>[Cl:35][C:36]1[CH:37]=[CH:38][C:39]2[N:40]([CH:42]=[C:43]([CH2:45][O:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[C:9](=[O:23])[C:10]([CH3:21])([CH3:22])[O:11][C:12]=4[C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[CH:6][CH:7]=3)[N:44]=2)[N:41]=1
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)C(=O)C(C)(C)O2)cc1
Reactant: ClCc1cn2nc(Cl)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2=C(c3ccc(OCc4cn5nc(Cl)ccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 80 °C
Yield: 59.1 %

Procedure:
4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (200 mg, 0.64 mmol) was added to a mixture of cesium carbonate (838 mg, 2.5 mmol) and DMF (5 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 30 min upon which 6-chloro-2-(chloromethyl) imidazo[1,2-b]pyridazine (196 mg, 9.6 mmol) was added. The mixture was heated at 80° C. for 4 h (the reaction was monitored by TLC). The reaction mixture was diluted with water and extracted with EtOAc; the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The organic residue was purified by flash column chromatography using 30% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 4-(4-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (180 mg, 63.0%) as an off-white solid. 1H NMR, 500 MHz, DMSO-d6: δ 8.45 (s, 1H), 8.2 (d, 1H), 7.55 (d, 2H), 7.4 (d, 1H), 7.15 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.25 (s, 2H), 3.8 (s, 3H), 1.25 (s, 6H). MS: [M+H]+: m/z=476.7. HPLC: (96.7%, Condition-A).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:15]3[CH:16]=[C:17]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:14]=3[O:13][C:12]2=[O:28])=[CH:7][CH:6]=1)[CH:2]=C.[CH3:29]S(O)(=O)=O>C(O)(=O)C>[C:24]([C:17]1[CH:18]=[C:19]([C:20]([CH3:22])([CH3:23])[CH3:21])[C:14]2[O:13][C:12](=[O:28])[CH:11]([C:8]3[CH:7]=[CH:6][C:5]4[O:4][CH:1]([CH3:2])[CH2:29][C:10]=4[CH:9]=3)[C:15]=2[CH:16]=1)([CH3:26])([CH3:27])[CH3:25]
Reactant: CS(=O)(=O)O
Reactant: C=CCOc1ccc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc1
Solvent: CC(=O)O
Product: CC1Cc2cc(C3C(=O)Oc4c3cc(C(C)(C)C)cc4C(C)(C)C)ccc2O1
Yield: 28 %

Procedure:
3.80 g (10.0 mmol) of 3-(4-allyloxyphenyl)-5,7-di-tert-butyl-benzofuran-2-one are kept under nitrogen for about 4 hours at 220° C. After cooling, 10 ml of acetic acid and 0.3 ml of methanesulfonic acid are added and the reaction mixture is refluxed for 7 hours. After dilution with 100 ml of water, the product is extracted with dichloromethane. The organic phases are washed with water, combined, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Chromatography of the residue on silica gel with the eluant system dichloromethane/hexane=1:2 and crystallisation of the pure fractions from ligroin gives 1.07 g (28%)of 5,7-di-tert-butyl-3-(2-methyl-dihydrobenzofuran-5-yl)benzofuran-2-one, m.p. 136°-152° C. as a mixture of diastereoisomers (compound (101), Table 1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]([CH2:34][NH:35][C:36]([NH:38][CH3:39])=[O:37])[C:30]([O:32]C)=[O:31])=[CH:25][CH:24]=1)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C1COCC1.CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:24]=[CH:25][C:26]([CH:29]([CH2:34][NH:35][C:36]([NH:38][CH3:39])=[O:37])[C:30]([OH:32])=[O:31])=[CH:27][CH:28]=1)=[O:22])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CNC(=O)NCC(C(=O)OC)c1ccc(C(=O)Nc2cc(-c3ccsc3)ccc2NC(=O)OC(C)(C)C)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)NCC(C(=O)O)c1ccc(C(=O)Nc2cc(-c3ccsc3)ccc2NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-[4-({[2-[(tert-butoxycarbonyl)amino]-5-(3-thienyl)phenyl]amino}carbonyl)phenyl]-3-{[(methylamino)carbonyl]-amino}propanoate (420 mg, 0.76 mmol) in THF (4 mL) and MeOH (1.5 mL) was added KOH (1N, 0.91 mL, 0.91 mmol). After stirring at room temperature for 1 h, the mixture was diluted with 1 M citric acid and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), and concentrated to yield 2-[4-({[2-[(tert-butoxycarbonyl)amino]-5-(3-thienyl)phenyl]amino}carbonyl)-phenyl]-3-{[(methylamino)carbonyl]amino}propanoic acid as an off-white powder. MS (ESI) calcd [M+H]+ 539.2, found 539.1.
Reaction SMILES: [C:1]([S:4]/[CH:5]=[CH:6]\[C:7]([OH:9])=O)(=[O:3])[CH3:2].CN(C)C=O.C(Cl)(=O)C([Cl:18])=O>C1(C)C=CC=CC=1>[C:1]([S:4]/[CH:5]=[CH:6]\[C:7]([Cl:18])=[O:9])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)S/C=C\C(=O)O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)S/C=C\C(=O)Cl

Procedure:
To a mixture of 2.8 g (0.0162 mol) of cis-3-(acetylthio)propenoic acid and 0.1 ml of N,N-dimethylformamide in 50 ml of toluene under nitrogen was added 2.84 ml (0.0325 mol) of oxalyl chloride. After 3 h the solvents were removed to give cis-3-(acetylthio)propenoyl chloride. This crude product was used in the next step without any further purification.
Reaction SMILES: O1CCOCC1.O.C([O:10][C:11](=[O:28])[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)C.O.[OH-].[Li+]>O1CCOCC1>[C:22]1([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH2:13][CH2:12][C:11]([OH:28])=[O:10])=[CH:17][CH:18]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)CCCOc1ccc(-c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCCOc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
A suspension in 1:1 dioxane/water (70 mL) of 4-(4-phenylphenoxy)butanoic acid ethyl ester (10.29 g, 36 mmol), prepared as in step 1, and lithium hydroxide hydrate (2.05 g, 49 mmol) was heated at reflux for 18 hours. Dioxane (35 mL) was then added and an additional 2.0 equivalents of lithium hydroxide hydrate was added four hours later. The reaction mixture was heated at reflux for two more hours, then was cooled to ambient temperature and concentrated in vacuo. The resulting white solids were shaken with ethyl ether and aqueous 1M NaOH and the residual solid (4-(4-phenylphenoxy)butyric acid, 3.53 g) was filtered off. The organic phase was discarded and the aqueous phase was acidified with concentrated HCl. The aqueous phase was extracted with ethyl acetate. The ethyl acetate extracts were dried over MgSO4, filtered, and concentrated in vacuo to give an additional 6.25 g of 4-(4-phenylphenoxy)butanoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:10]=1[CH2:11][N:12]1[C:16]([CH3:17])=[CH:15][C:14]([CH:18]=O)=[N:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]([CH:29]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:28]>C1COCC1.CCOC(C)=O>[CH3:25][O:26][C:27](=[O:28])/[CH:29]=[CH:18]/[C:14]1[CH:15]=[C:16]([CH3:17])[N:12]([CH2:11][C:10]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:13]=1
Reactant: Cc1cc(C=O)nn1Cc1cc(Cl)ccc1OCc1ccccc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cc(C)n(Cc2cc(Cl)ccc2OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 70 h
Yield: 99 %

Procedure:
To a stirred solution of aldehyde 13, (1 g, 2.9 mmol) in THF was added (methoxycarbonylmethylene)triphenylphosphorane, 2 g (6 mmol). The mixture was stirred at room temperature for 70 hours. The mixture was diluted with EtOAc and the organic phase was washed with 2M HCl, saturated NaHCO3 and brine, dried over MgSO4 and evaporated in vacuo. The crude unsaturated ester 14 was purified on silica to yield 1.2 g as a white solid (99%).
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][C:20]([SH:22])=[N:19][N:18]=3)=[CH:13][C:12]=12.Cl[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:33][CH3:34])=[C:29]([CH:32]=1)[C:30]#[N:31]>>[CH3:34][O:33][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][S:22][C:20]2[O:21][C:17]([C:14]3[CH:15]=[CH:16][N:11]4[N:10]=[CH:9][N:8]=[C:12]4[CH:13]=3)=[N:18][N:19]=2)=[CH:32][C:29]=1[C:30]#[N:31]
Reactant: COc1ccc(CCl)cc1C#N
Reactant: Sc1nnc(-c2ccn3ncnc3c2)o1
Solvent: CCN(CC)CC
Product: COc1ccc(CSc2nnc(-c3ccn4ncnc4c3)o2)cc1C#N
Yield: 56 %

Procedure:
In the same manner as in Example 1 and using 5-(1,2,4-triazolo[1,5-a]pyridin-7-yl)-1,3,4-oxadiazole-2-thiol triethylamine salt instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 5-(chloromethyl)-2-methoxybenzonitrile instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 56%) was obtained as pale-brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24](F)(F)F)[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.F[B-](F)(F)F.[CH3:33][O+](C)C>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:24])[O:13][N:12]([CH3:33])[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[C:16]([CH3:23])[CH:15]=3)=[CH:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C[O+](C)C
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Agent: F[B-](F)(F)F
Solvent: ClCCCl
Product: Cc1cc(C2=CC(C)(c3cc(Cl)cc(Cl)c3)ON2C)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 29.9 %

Procedure:
To a solution of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzamide (200 mg) in 1,2-dichloroethane (3 ml) was added trimethyloxonium tetrafluoroborate (85 mg) and the reaction mixture was stirred at room temperature for 19 hours then more trimethyloxonium tetrafluoroborate (210 mg). After 4 hours 30 minutes, more trimethyloxonium tetrafluoroborate (0.5 ml) was added and after 2 hours, the reaction mixture was heated at (85° C.) for 18 hours. The solution was then concentrated under vacuo to give a crude residue (210 mg). Part of this residue (100 mg) of the crude was extracted between AcOEt and saturated NaHCO3. The organic phases were gathered, dried over anhydrous MgSO4, filtered and evaporated to give the desired compound (54 mg). 1H-NMR (CDCl3, δ in ppm): 7.50-7.31 (m, 6H), 5.75 (bs, 2H), 5.41 (s, 1H), 2.99 (s, 3H), 2.52 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:5](=[C:7]([S:11](Cl)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[NH3:15]>O1CCCC1>[CH3:1][C:2]1[S:3][C:4]2[C:5](=[C:7]([S:11]([NH2:15])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1
Reactant: N
Reactant: Cc1nc2c(S(=O)(=O)Cl)cccc2s1
Solvent: C1CCOC1
Product: Cc1nc2c(S(N)(=O)=O)cccc2s1
Temperature: 25 °C

Procedure:
A solution of 18 g of the product from Example 1 in 170 mL of tetrahydrofuran was cooled to 0° C. under an atmosphere of nitrogen and treated with 5 mL of anhydrous ammonia. The mixture was stirred at room temperature for about an hour, filtered to remove the ammonium chloride, and the filtrate concentrated in vacuo to give an off-white solid. This crude product was purified by silica gel chromatography; elution with ethyl acetate-hexanes (3:1) gave 1.9 g of 2-methyl-4-benzothiazolesulfonamide as a white powder, m.p. 236°-239° C.; NMR (DMSO-d6 /CDCl3): δ 2.95 (3H, s), 7.0 (2H, br s, SO2NH2), 7.55 (1H, t, J=8 Hz), 8.0 (1H, dd, J=2, 8 Hz), 8.2 (1H, dd, J=2, 8 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([C:20]2[C:29]([OH:30])=[C:28]3[C:23]([CH:24]=[CH:25][CH:26]=[N:27]3)=[C:22]([Cl:31])[CH:21]=2)[NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[Cl:41][CH2:42][C:43](Cl)=[O:44]>C(Cl)Cl>[Cl:41][CH2:42][C:43]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([C:20]2[C:29]([OH:30])=[C:28]3[C:23]([CH:24]=[CH:25][CH:26]=[N:27]3)=[C:22]([Cl:31])[CH:21]=2)[NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:3]=1)=[O:44]
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc(C(NC(=O)COc2ccccc2)c2cc(Cl)c3cccnc3c2O)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)Nc1cccc(C(NC(=O)COc2ccccc2)c2cc(Cl)c3cccnc3c2O)c1
Yield: 53.2 %

Procedure:
To a suspension of N-[(3-aminophenyl)(5-chloro-8-hydroxyquinolin-7-yl)methyl]-2-phenoxyacetamide (800 mg, 1.84 mmol) in methylenechloride (30 ml) cooled to 0 C was added DIEA (300 mg, 2.32 mmol) followed by chloroacetyl chloride (300 mg, 2.65 mmol). Purification by flush chromatography (eluent 30% acetone/DCM) afforded 500 mg (53%) of 2-chloro-N-(3-{(5-chloro-8-hydroxyquinolin-7-yl)[(phenoxyacetyl)amino]methyl}phenyl)acetamide an off-white solid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH:15]=[CH:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:2].[H][H]>N.C1(C)C=CC=CC=1.[Rh]>[NH2:2][CH2:1][CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CCC(CC=Cc1cccnc1)CCCC#N
Reactant: [H][H]
Agent: [Rh]
Agent: N
Solvent: Cc1ccccc1
Product: CCOC(=O)CCC(CCCCN)CCCc1cccnc1

Procedure:
A solution of 125 g of ethyl 4-(3-cyanopropyl)-7-(3-pyridyl)-6-heptenoate in 825 ml of 9.53% ethanolic ammonia is added to a slurry of 62.5 g of 5% rhodium on carbon (50% water wet) in 300 ml of 9.53% ethanolic ammonia. The mixture is hydrogenated at about 3 atmospheres pressure (50 psi=3.45 bar) until theoretical uptake of hydrogen (4 moles) for saturation of the nitrile and double bond is obtained (about 12 h). The catalyst is then filtered off, washed with methylene chloride and ethanol, and the filtrate is evaporated to dryness to yield a residue which is redissolved in toluene. Evaporation to dryness yields ethyl 8-amino-4-[3-(3-pyridyl)propyl]-octanoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.Cl[C:23]1[N:28]=[N:27][C:26]([N:29]([CH3:40])[CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]2)=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[C:23]1[N:28]=[N:27][C:26]([N:29]([CH3:40])[CH:30]2[CH2:35][C:34]([CH3:36])([CH3:37])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]2)=[CH:25][CH:24]=1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: COc1cc2c(cc1B1OC(C)(C)C(C)(C)O1)CCC2=O
Product: COc1cc2c(cc1-c1ccc(N(C)C3CC(C)(C)NC(C)(C)C3)nn1)CCC2=O
Yield: 100 %

Procedure:
Following standard GENERAL METHOD 1-4 for Suzuki coupling using 6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (300 mg, 1.06 mmol) and 6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (Intermediate 1-1, 611 mg, 2.12 mmol) afforded 6-methoxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-1-one (433 mg) MS [M+H+]=409.7.
Reaction SMILES: [ClH:1].[C:2]([CH:10]1[C:15](=O)[N:14]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[S:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:26][Mg+].[Br-]>CCOCC>[ClH:1].[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][N:14]1[C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[S:11][CH:10]([C:2]([CH3:26])([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[OH:9])[CH2:15]1
Reactant: CN(C)CCN1C(=O)C(C(=O)c2ccccc2)Sc2ccccc21
Reactant: C[Mg+]
Agent: Cl
Agent: [Br-]
Solvent: CCOCC
Product: CN(C)CCN1CC(C(C)(O)c2ccccc2)Sc2ccccc21
Temperature: 0 °C

Procedure:
Interaction of the free base of the product of example 1 with 1 equivalent of CH3MgBr in ether at room temperature forms a Grignard complex which is decomposed with ice water and the ethereal solution dried over anhydrous MgSO4, filtered and the filtrate treated with anhydrous HCl to yield the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.Cl.Cl[CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18]>>[CH3:18][N:17]([CH3:19])[CH2:16][CH2:15][CH2:14][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:10]#[N:11]
Reactant: CN(C)CCCCl
Reactant: COc1cccc(CC#N)c1
Agent: Cl
Product: COc1cccc(C(C#N)CCCN(C)C)c1

Procedure:
reacting 3-methoxybenzeneacetonitrile with 3-chloro-N,N-dimethylpropanamine, monohydrochloride in the presence of a base to obtain α-[3-(dimethylamino)propyl]-3-methoxybenzeneacetonitrile
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:15](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:16]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:3][C:2]=1[N:1]=[C:15]=[S:16]
Reactant: CC(=O)NC(C)c1ccc(Cl)c(N)c1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC(C)c1ccc(Cl)c(N=C=S)c1

Procedure:
N-[1-(3-Amino-4-chlorophenyl)ethyl]acetamide (90 mg, 0.2 mmol) was added to a mixture of 1,1′-thiocarbonyldi-2-pyridone (69 mg, 0.2 mmol), DMAP (7 mg, 0.05 mmol) and DCM (2 mL) at rt. The mixture was concentrated and used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH:13]([CH3:15])[CH3:14])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:4].C(=O)([O-])[O-:17].[Na+].[Na+]>>[OH:17][CH2:2][C:3]([N:5]([CH:13]([CH3:15])[CH3:14])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CC(C)N(C(=O)CCl)c1ccc(F)cc1
Agent: [Na+]
Product: CC(C)N(C(=O)CO)c1ccc(F)cc1
Temperature: 100 °C

Procedure:
In a 500 ml flask, 23.0 g (0.1 mol) of N-chloroacetyl-N-isopropyl-4-fluoroaniline and 11.7 g (0.11 mol) of sodium carbonate in 340 ml of solvent or solvent mixture are heated with stirring to reflux temperature (100° C.). The reaction is monitored by gas chromatography (sampling after in each case 1 hour). The results are compiled in the table which follows.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:11]=[C:10]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:18]=3)=[CH:15][CH:16]=2)[N:9]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[N:8]=1)=[O:6]>CO>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N:9]1[C:10]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:18]=3)=[CH:15][CH:16]=2)=[CH:11][C:7]([C:5]([OH:6])=[O:4])=[N:8]1
Reactant: COC(=O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(=O)O)nn3-c3ccccc3Cl)s2)c1
Yield: 84.5 %

Procedure:
Aqueous NaOH solution (2N, 80 mL) was added to a suspension of 1-(2-chloro-phenyl)-5-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-1H-pyrazole-3-carboxylic acid methyl ester (5 g, 10.57 mmol) in MeOH (80 mL), and the resulting mixture was stirred at reflux for 10 h. The volatiles was removed in vacuo, the residual solution was acidified with aqueous HCl (6N) to pH 2, extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4, and evaporated in vacuo. The crude product was recrystallized from DCM/hexane to give the title compound as a white solid (4.1 g, 86%). 1H-NMR (DMSO-d6): δ 12.73 (s, 1H), 7.98 (m, 1H), 7.83 (m, 2H), 7.77 (m, 2H), 7.71 (m, 1H), 7.67 (d, 1H), 7.62 (m, 2H), 7.34 (s, 1H), 7.19 (s, 1H), 3.26 (s, 3H). MS(ES): 459 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([N:10]2[C:14]([CH3:15])=[C:13]([C:16]#[N:17])[CH:12]=[N:11]2)[CH:5]=1.S(Cl)([Cl:22])(=O)=O>C(Cl)Cl>[Cl:22][C:5]1[C:6]([N:10]2[C:14]([CH3:15])=[C:13]([C:16]#[N:17])[CH:12]=[N:11]2)=[N:7][N:8]([CH3:9])[C:4]=1[O:3][CH:2]([F:1])[F:18]
Reactant: Cc1c(C#N)cnn1-c1cc(OC(F)F)n(C)n1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: Cc1c(C#N)cnn1-c1nn(C)c(OC(F)F)c1Cl
Reaction time: 1 h

Procedure:
0.57 g (2.25 mmol) 1-(5-Difluoromethoxy-1-methyl-3-pyrazolyl)-5-methyl-4-pyrazolecarbonitrile was dissolved in 30 ml methylene chloride and at room temperature was treated with 0.30 g (2.25 mmol) sulfuryl chloride. The mixture was stirred for one hour and then concentrated.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([CH:9]([CH2:15][C:16]([OH:18])=O)[C@@H:10]([C:12]([OH:14])=O)N)[CH3:8].[CH2:19]1COCC1>>[CH2:7]([CH:9]([CH2:15][CH2:16][OH:18])[CH:10]([CH3:19])[CH2:12][OH:14])[CH3:8]
Reactant: C1CCOC1
Reactant: CCC(CC(=O)O)[C@H](N)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCC(CCO)C(C)CO
Temperature: 36 °C
Reaction time: 6 h

Procedure:
To a slurry of LAH (2.06 g, 54.29 mmol) in THF (60 mL) was added 3-ethylglutamic acid (3.5 g, 21.71 mmol) dropwise at 0° C. over 20 min. The reaction was heated to 36° C. for 18 h. The reaction slurry (gray) was cooled to 0° C. and quenched with H2O (3 mL) then washed with 1N NaOH (9 mL) and H2O (3 mL). It was then stirred for 6 h at 25° C. to obtain an off-white slurry. The slurry was filtered and the mother liquor was further dried over MgSO4, filtered and concentrated in vacuo to obtain 3-ethyl-2-methylpentane-1,5-diol as a crude yellow oil (2.85 g, 89.17%). Mass Spectrum (+EST): 170 (M+Na)+.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[N:26](S(C5C=CC=CC=5)(=O)=O)[CH:27]=[CH:28][C:21]=34)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][N:15]3S(C2C=CC=CC=2)(=O)=O)=[O:9])[N:7]=1.[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.C(O)(C)C.[OH-].[Na+]>CS(C)=O>[N:47]1([CH2:2][C:3]2[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]5[NH:26][CH:27]=[CH:28][C:21]=45)[CH:17]=[C:16]4[C:12]=3[CH:13]=[N:14][NH:15]4)=[O:9])[N:7]=2)[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1
Reactant: O=C(Nc1cc(-c2ccnc3c2ccn3S(=O)(=O)c2ccccc2)cc2c1cnn2S(=O)(=O)c1ccccc1)c1csc(CCl)n1
Reactant: C1COCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CS(C)=O
Product: O=C(Nc1cc(-c2ccnc3[nH]ccc23)cc2[nH]ncc12)c1csc(CN2CCOCC2)n1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 19.8 %

Procedure:
2-(Chloromethyl)-N-{1-(phenylsulfonyl)-6-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-indazol-4-yl}-1,3-thiazole-4-carboxamide (30 mg, 0.044 mmol) and morpholine (0.5 ml, 5.74 mmol) were mixed then heated in the microwave for 15 min at 90° C. The solvent was blown off under nitrogen. Isopropanol (1.5 mL) and 2M NaOH (1.500 ml) were added. The reaction mixture was stirred for 1.5 h. Further Isopropanol (1.5 mL) and 2M NaOH (1.5 mL) were added to the mixture which was stirred for 26 hours. The solvent was blown off under nitrogen. The resultant solid was dissolved in DMSO (2 mL). The salts were removed by filtration and the mixture was purified by MDAP to afford the title compound (4 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[CH:14]1([CH2:17][NH2:18])[CH2:16][CH2:15]1>C(O)C>[CH:14]1([CH2:17][NH:18][CH2:2][C:3]2[NH:4][C:5](=[O:13])[C:6]3[CH2:12][O:11][CH2:10][CH2:9][C:7]=3[N:8]=2)[CH2:16][CH2:15]1
Reactant: O=c1[nH]c(CCl)nc2c1COCC2
Reactant: NCC1CC1
Solvent: CCO
Product: O=c1[nH]c(CNCC2CC2)nc2c1COCC2
Temperature: 45 °C
Yield: 46.2 %

Procedure:
To a solution of 2-chloromethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (1.0 g, 4.98 mmol) in ethanol (30 mL) was added cyclopropylmethylamine (2.13 g, 29.9 mmol). The mixture was then heated at 45° C. for 60 hours. The reaction was then stopped and the mixture was concentrated under high vacuum for 24 h. The remaining semi-solid was subjected to column chromatography (Silica gel, 0-10% methanol in dichloromethane) to give 2-[(cyclopropylmethyl-amino)-methyl]-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one as a light brown solid (540 mg, 2.30 mmol, 46% yield) that was directly used in the next step. m/z=236.4 (M+H).