Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[C:19]([F:20])[C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Si:21]([O:28][CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:38]=[CH:39][C:40](Cl)=[N:41][CH:42]=2)[CH2:33][CH2:32]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Si:21]([O:28][CH2:29][CH2:30][CH:31]1[CH2:32][CH2:33][N:34]([C:37]2[CH:38]=[CH:39][C:40]([NH:15][C:12]3[N:13]=[CH:14][C:9]4[C:8]5[CH:16]=[CH:17][N:18]=[C:19]([F:20])[C:7]=5[N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:10]=4[N:11]=3)=[N:41][CH:42]=2)[CH2:35][CH2:36]1)([C:24]([CH3:27])([CH3:25])[CH3:26])([CH3:23])[CH3:22]
Reactant: Nc1ncc2c3ccnc(F)c3n(C3CCCC3)c2n1
Reactant: CC(C)(C)[Si](C)(C)OCCC1CCN(c2ccc(Cl)nc2)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OCCC1CCN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)CC1
Temperature: 120 °C
Yield: 0.1 %

Procedure:
A 10 mL microwave reaction tube was charged with compound 245 (80.0 mg, 295 mmol), 5-(4-(2-(t-butyldimethylsilyloxy)ethyl)piperidin-1-yl)-2-chloropyridine (293) (105 mg, 295 mmol), tris(dibenzylideneacetone)dipalladium (0) (20.3 mg, 22.1 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (25.6 mg, 44.2 mmol), sodium t-butoxide (56.7 mg, 590 mmol), and dioxane (3 mL). The reaction was purged with argon and heated with microwave energy (300 W) for 3.5 hours at 120° C. The reaction was taken up in ethyl acetate (40 mL) and washed with water (30 mL) and brine (30 mL). The organic phase was dried (MgSO4) and evaporated to give an orange oil. Silica gel chromatography (gradient elution hexanes+2.5% TEA/0-100% ethyl acetate+2.5% TEA) afforded compound 294 as a yellow solid (113 mg, 65%).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]2)[CH2:9]1)C1C=CC=CC=1.Cl.N#N>CCO.[Pd]>[NH:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH2:14][CH2:15][S:16](=[O:20])(=[O:19])[CH2:17][CH2:18]2)[CH2:9]1
Reactant: O=S1(=O)CCN([C@@H]2CCN(Cc3ccccc3)C2)CC1
Agent: [Pd]
Agent: Cl
Agent: N#N
Solvent: CCO
Product: O=S1(=O)CCN([C@@H]2CCNC2)CC1
Yield: 96.6 %

Procedure:
Compound Y (88 mg, 0.2989 mmol, 1 eq) was dissolved in EtOH (2.0 ml) and 1N HCl was added (300 μl). Degassed solution 3 times with N2 and the Palladium catalyst (10 mg, 5% mmol) was added. Degassed with H2 (g) 3 times and hydrogenated for 90 minutes. The catalyst was filtered off and 1N HCl was added (300 μl). The solvent was removed in vacuo and taken up in water and lyophilized to obtain the desired compound as a yellow oil (59 mg, 82%). 1H NMR (400 MHz) D2O δ 3.88-3.68 (dm, 2H), 3.57-3.45 (m, 10H), 3.37-3.29 (m, 2H), 2.45 (m, 1H), 2.10 (m, 1H). 205.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]=1)([O-])=O.[Cl-].[NH4+]>[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Temperature: 70 °C

Procedure:
To a solution of 7.4 mL dioxane, 5.5 mL ethanol and 3.7 mL distilled water was added tert-butyl 4-(5-nitro-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (184 mg, 0.54 mmol). To the mixture was added powdered iron (0) (0.15 g, 5.0 eq) and ammonium chloride (0.885 g, 4.0 eq). The reaction was heated to 70° C. under argon for 3 h. The reaction was cooled and filtered and washed with MeOH. The solvent was removed to obtain the crude which was purified by silica gel chromatography to afford the desired compound tert-butyl 4-(5-amino-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate.
Reaction SMILES: O.NN.[CH3:4][C:5]1[NH:6][C:7]([CH3:40])=[C:8]([C:24]([O:26][CH2:27][CH2:28][N:29]2C(=O)C3=CC=CC=C3C2=O)=[O:25])[CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]>C(O)C>[CH3:4][C:5]1[NH:6][C:7]([CH3:40])=[C:8]([C:24]([O:26][CH2:27][CH2:28][NH2:29])=[O:25])[CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2C(=O)c3ccccc3C2=O)C1c1ccccc1[N+](=O)[O-]
Agent: NN
Solvent: CCO
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN)C1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
1.5 ml (30 mmol) of hydrazine hydrate in 7.5 ml of ethanol are added dropwise to a boiling solution of 5.05 g (10 mmol) of 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(2-nitrophenyl)-5-(2-phthalimidoethoxy)carbonylpyridine in 50 ml of ethanol. Boiling is continued for 2 hours and the reaction mixture is then cooled and concentrated by evaporation under vacuum. The residue is stirred up with 25 ml of 2N-hydrochloric acid for 30 minutes at room temperature and the precipitated solid is removed by suction filtration and the filtrate is adjusted to pH 10 with conc. ammonia. The product is extracted three times with 30 ml portions of methylene chloride and the organic phases obtained are then dried and concentrated by evaporation. 2.91 g (77%) of a yellow amorphous solid is obtained as residue which is used without further purification.
Reaction SMILES: O[CH2:2][C:3]1[CH:22]=[CH:21][C:6](/[CH:7]=[CH:8]/[C@@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:43]>C1COCC1>[Br:43][CH2:2][C:3]1[CH:22]=[CH:21][C:6](/[CH:7]=[CH:8]/[C@@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:5][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1/C=C/c1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1/C=C/c1ccc(CBr)cc1

Procedure:
To a solution of the product of Example 149C (0.9 g, 2.97 mmol) dissolved in THF (50 mL) was added resin bound triphenylphosphine (5.93 mmol) and carbon tetrabromide (1.48 g, 4.45 mmol) and the resultant solution stirred at room temperature for 2 hours. The resin was then filtered off, washed with THF and the combined filtrate was then dried, filtered, and concentrated to afford the title compound. m/z 368 (M+H)+.
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])[CH3:3].[N:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=1.Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH3:3][C:2]1[CH2:1][CH:16]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]2[C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]=1
Reactant: C=C(C)C1CCCCC1=O
Reactant: C1=NCCCC1
Agent: C/C1=C\CCCCC(=O)N2CCCCC2C1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CC1=CCCCCC(=O)N2CCCCC2C1

Procedure:
Following the general procedure as described in Example 17, 2-(prop-1-en-2-yl)cyclohexanone (0.88 g, 6.38 mmol), 2,3,4,5-tetrahydropyridine (0.64 g, 7.65 mmol), and SnCl4 (1.66 g, 6.38 mmol) in 1,2-dichloroethane (65 ml) were reacted to give the title product as a colorless liquid (0.97 g, 69% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:40][S:41]([CH2:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)(=[O:43])=[O:42]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:50]3[CH2:49][CH2:48][N:47]([CH2:46][CH2:45][CH2:44][S:41]([CH3:40])(=[O:42])=[O:43])[CH2:52][CH2:51]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:31])[CH3:32])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)O)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% of 1:1 ethanol/acetonitrile in carbon dioxide). HR-MS (ES, m/z) calculated for C37H47N4O5SCl2 [(M+H)+] 729.2639, observed 729.2634.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:5]1)(=O)[NH2:2].B.C1COCC1.Cl.[OH-].[Na+]>C1COCC1>[NH2:2][CH2:1][CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH2:5]1
Reactant: NC(=O)C1CCCN(Cc2ccc(Cl)cc2)C1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: NCC1CCCN(Cc2ccc(Cl)cc2)C1
Temperature: 70 °C
Reaction time: 15 h
Yield: 57.2 %

Procedure:
3-Carbamoyl-1-(4-chlorobenzyl)piperidine (3.80 g, 15 mmol) was dissolved in THF (30 mL) and 1 M BH3-THF (9.4 mL) was added to the solution. The reaction mixture was stirred at 70° C. for 15 h. After the mixture was cooled to 0° C., 2 N aqueous HCl solution (50 mL) was added and the mixture was stirred at room temperature for additional 3 h, basicified with 4 N aqueous NaOH solution, and extracted with ethyl acetate (100 mL×3). The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. Column chromatography (SiO2, ethyl acetate/EtOH/Et3N=80/15/5) afforded 3-(aminomethyl)-1-(4-chlorobenzyl)piperidine (2.05 g, 55%): 1H NMR (CDCl3, 400 MHz) δ1.00-1.09 (m, 1H), 1.50-1.87 (m, 7H), 1.97-2.06 (m, 1H), 2.65-2.77 (m, 2H), 3.16-3.26 (m, 2H), 3.32 (s, 2H), 3.40. (d, J=13.3 Hz, 1H), 3.49 (d, J=13.3 Hz, 1H), 7.22-7.33 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([S:14]C#N)=[CH:11][CH:12]=2)[CH2:7][CH2:6]1.O.SCC(O)=O>CO>[CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([SH:14])=[CH:11][CH:12]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)CN1CCc2cc(SC#N)ccc21
Agent: O=C(O)CS
Solvent: CO
Solvent: O
Product: COC(=O)CN1CCc2cc(S)ccc21
Yield: 95 %

Procedure:
Compound 25B (1.05 g, 4.2 mmol) was refluxed in a solution of water (2 ml), methanol (20 ml) and mercaptoacetic acid (1.2 g, 13 mmol) for 3 h. The solvent was removed under the vacuo, and the crude product was passed a short silica gel chromatography to give 25C in 95% yield.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][NH:25][CH2:26]2>CN(C=O)C>[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][N:25]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=1[F:16])[CH2:26]2
Reactant: Clc1cccc2c1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4cccc(Cl)c4C3)c(F)cc2c1=O
Yield: 50 %

Procedure:
136 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 230 mg of 4-chloroisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 100 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21]CC)=[O:20]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[O:10][CH2:18][C:19]([OH:21])=[O:20]
Reactant: Oc1c(Cl)cc(F)cc1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)COc1c(Cl)cc(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
The mixture of 2,6-dichloro-4-fluorophenol (362 mg, 2.0 mmol), potassium carbonate (910 mg, 6.6 mmol), ethyl bromoacetate (500 mg, 3.0 mmol) and acetone (25 ml) was refluxed for 12 h. After cooling, the mixture was filtered to remove potassium carbonate. The filtrate was concentrated under reduced pressure. To this residue, 10 ml dioxane and 14 ml 5% sodium hydroxide solution were added. After the mixture was stirred at room temperature overnight, it was acidified with concentrated hydrochloric acid to pH 2, and then extracted three times with ethyl acetate (15 ml each). Organic phases were combined, washed with water and brine, dried over magnesium sulfate, filtered, and then evaporated in vacuo. The residue was recrystallized from ethyl acetate and petroleum ether to give 348 mg 2,6-dichloro-4-fluorophenoxyacetic acid as white crystals, mp 155-158° C., yield: 72.8%.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH:12]([C:16]([O:18]C)=[O:17])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH:12]([C:16]([OH:18])=[O:17])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
A 1 mol/L aqueous potassium hydroxide solution (3 mL) was added to methyl 4-(tert-butoxycarbonyl)morpholine-2-carboxylate (251 mg, 1.02 mmol) in methanol (15 mL). The mixture was stirred at room temperature for 8 hours. Subsequently, water was added to the mixture, followed by addition of a 5% aqueous citric acid solution to make the mixture acidic. The mixture was then extracted with ethyl acetate. The extract was washed with brine and was dried over magnesium sulfate. Evaporation of the solvent gave 219 mg (93%) of the desired compound as a colorless powder.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]1([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:41]=[C:40]4[C:36]([C:37]([NH:50][C:51](=[O:55])[CH2:52][CH2:53][CH3:54])=[N:38][N:39]4COCC[Si](C)(C)C)=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C>O1CCCC1>[C:19]1([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:41]=[C:40]4[C:36]([C:37]([NH:50][C:51](=[O:55])[CH2:52][CH2:53][CH3:54])=[N:38][NH:39]4)=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OCc4ccccc4)cc3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(OCc4ccccc4)cc3)ccc12
Temperature: 66 °C

Procedure:
14 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1.2 g of N-[6-[4-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 30 cm3 of tetrahydrofuran. The reaction medium is heated at about 66° C. for 17 hours. The heating is then stopped and 75 cm3 of ethyl acetate are added. This mixture is washed with 50 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered through a sinter funnel and evaporated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with cyclohexane/ethyl acetate (80/20 by volume) and collecting 30 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 2×2 cm3 of diisopropyl ether. This mixture is filtered through a sinter funnel to give, after drying (90 Pa; 50° C.), 220 mg of N-[6-[4-(phenylmethoxy)phenyl]-1H-indazol-3-yl]butanamide in the form of a white solid melting at 220° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[S:8][C:4]=2[CH:3]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:24](O)=[O:25]>>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[S:8][C:4]=2[C:3]=1[CH:24]=[O:25]
Reactant: Cc1nc2ccc(O)cc2s1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: Cc1nc2ccc(O)c(C=O)c2s1

Procedure:
To a 3-necked flask equipped with a thermometer and an addition funnel were added 6-hydroxy-2-methyl-benzothiazole (1.0 gm, 6.05 mmol) and hexamethylenetetramine (3.4 gm, 24.3 mmol). After cooling in an ice-bath, trifluoroacetic acid (10 mL) was added dropwise with stirring while maintaining the temperature below 60° C. The reaction mixture was stirred overnight at 70°-75° C., cooled, and evaporated. The residue was taken up in ethyl acetate and neutralized with saturated NaHCO3 solution. The organic layer was washed with saturated brine solution and dried (Na2SO4). The solution was filtered, and the filtrate evaporated. The residue was triturated with a mixture of methylene chloride/methanol and filtered. The filtrate was evaporated, and the residue dissolved in a small volume of methylene chloride and chromatographed on a column of silica gel that was eluted with 25% acetone in hexane affording pure title compound.
Reaction SMILES: Br[C:2]1[C:3]([CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][S:5][CH:6]=1.[CH2:18]([O:20][C:21]([C:23]1([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35](B4OC(C)(C)C(C)(C)O4)=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)[CH2:25][CH2:24]1)=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([C:23]1([C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH:33]=[CH:34][C:35]([C:2]4[C:3]([CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)=[CH:4][S:5][CH:6]=4)=[CH:36][CH:37]=3)=[CH:30][CH:31]=2)[CH2:25][CH2:24]1)=[O:22])[CH3:19]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Reactant: OC(CCCc1ccccc1)c1cscc1Br
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4cscc4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 2, using the following starting materials: 1-(4-bromo-thiophen-3-yl)-4-phenyl-butan-1-ol and 1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([C:28]1[N:33]=[C:32]([CH3:34])[C:31]([NH2:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26].CC(C)([O-])C.[Na+].C(OCC)(=O)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2)C(C)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH:35][C:31]4[C:32]([CH3:34])=[N:33][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:29][CH:30]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(S(C)(=O)=O)ccc1N
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(S(C)(=O)=O)ccc1Nc1ncnc2c1cnn2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 160 °C
Yield: 46.5 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol), 6-methanesulfonyl-2-methyl-pyridin-3-ylamine (Intermediate 4; 28 mg, 0.15 mmol), palladium acetate (0.33 mg, 0.01 equivalent), sodium tert-butoxide (34 mg, 0.36 mmol), and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (Aldrich, 1 mg, 0.02 equivalents) in dimethylformamide (2 mL) was heated in the microwave oven at 160° C. for 10 min. Ethyl acetate and water were added, and the aqueous layer was extracted three times with ethyl acetate. The ethyl acetate layers were combined, evaporated, and purified by preparative C18 HPLC, eluting with 10-100% acetonitrile/water. Samples containing the product were extracted twice with dichloromethane and the solvent was evaporated under high vacuum to give 4-[4-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (34 mg, 46%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 1.41 (s, 9H), 1.92-2.00 (m, 4H), 2.55 (s, 3H), 2.90-3.04 (m, 2H), 3.30 (water peak and SO2CH3 peak), 4.00-4.12 (m, 2H), 4.84-4.96 (m, 1H), 7.92 (d, 1H, J=8.5 Hz), 8.22-8.36 (m, 3H), 10.06 (br s, 1H). HRMS Calcd. for C22H30N7O4S (MH+): 488.2075. Found: 488.2073.
Reaction SMILES: C(OC([N:8]([C:28]1[C:33]([O:34][CH3:35])=[N:32][C:31]([CH3:36])=[CH:30][N:29]=1)[S:9]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=2)=[N:14][CH:15]=[CH:16][CH:17]=1)(=[O:11])=[O:10])=O)C(C)C.C[O-].[Na+]>CO>[CH3:27][O:26][C:24]([C:21]1[CH:20]=[CH:19][C:18]([C:13]2[C:12]([S:9]([NH:8][C:28]3[C:33]([O:34][CH3:35])=[N:32][C:31]([CH3:36])=[CH:30][N:29]=3)(=[O:10])=[O:11])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:23][CH:22]=1)=[O:25]
Reactant: COC(=O)c1ccc(-c2ncccc2S(=O)(=O)N(C(=O)OCC(C)C)c2ncc(C)nc2OC)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(-c2ncccc2S(=O)(=O)Nc2ncc(C)nc2OC)cc1
Yield: 28.4 %

Procedure:
A solution of N-(isobutoxycarbonyl)-2-(4-methoxycarbonylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (830 mg) and sodium methoxide (433 mg) in methanol (25 ml) was heated under reflux for 1 hour. Volatile material was removed by evaporation and saturated ammonium chloride solution (20 ml) was added to the residue. The mixture was extracted with ethyl acetate (2×20 ml) and the extracts were washed with water (2×15 ml) and dried (MgSO4). The solvent was removed by evaporation and the residue was purified by flash chromatography, eluting with 25-50% ethyl acetate/hexane, to give 2-(4-methoxycarbonylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (190 mg), m.p. 144-146° C.; microanalysis found: C, 55.2; H, 4.3; N, 13.3%; C23H24BrN4O4S requires: C, 55.1; H, 4.4; N, 13.5%.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=O)=[N:14][CH:15]=1>O.CO>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[N:7][OH:8])=[N:14][CH:15]=1
Reactant: O=C(Cc1ccc(Cl)cn1)c1ccc(F)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ON=C(Cc1ccc(Cl)cn1)c1ccc(F)cc1
Yield: 98.9 %

Procedure:
Sodium acetate (6.47 g) and hydroxylamine hydrochloride (5.74 g) were dissolved in water (45 ml) and added to a solution of 2-(5-chloropyridin-2-yl)-1-(4-fluorophenyl)ethanone (3.39 g, 13.6 mmol) in methanol (200 ml). After heating at reflux for 2 h, the cooled reaction mixture was partitioned between water and ethyl acetate and the organic phase dried and concentrated to give the title compound as a yellow solid (3.56 g, 98%). NMR (CDCl3) δ 4.35 (2H, s, CH2); 7.02 (2H, t, 8 Hz, arom); 7.25 (1H, d, J 9 Hz, arom); 7.53 (1H, dd, J 9 & 2 Hz, arom); 7.71 (2H, m, arom); 8.12 (1 H, br s, OH); 8.48 (1H, s, 2 Hz, arom); Tlc SiO2 cyclohexane:ethyl acetate (3:1) Rf 0.42 detection uv254.