Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH2:9]([O:13][C:14](=[O:17])[CH:15]=[CH2:16])[CH2:10][CH2:11][CH3:12]>>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1/[CH:16]=[CH:15]/[C:14]([O:13][CH2:9][CH2:10][CH2:11][CH3:12])=[O:17]
Reactant: C=CC(=O)OCCCC
Reactant: Cc1ccccc1I
Product: CCCCOC(=O)/C=C/c1ccccc1C

Procedure:
2-Iodotoluene (32 μL, 0.25 mmol) and n-butylacrylate (54 μL, 0.375 mmol) were coupled using the procedure described above to give 83% conversion to (E)-n-butyl 3-(2-methylphenyl)acrylate by GC analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([F:21])[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(O)C>[F:21][C:15]1[CH:14]=[C:13]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: N#Cc1ccc(Br)cc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2ccc(Cl)cc2Cl)cc1F
Yield: 94 %

Procedure:
1.0 g (5.2 mmol) of 2,4-dichlorophenylboronic acid, 1.1 g (5.5 mmol) of 4-bromo-2-fluorobenzonitrile, 1.6 g (15.0 mmol) of sodium carbonate and 0.8 g (0.7 mmol) of tetrakis(triphenylphosphine) palladium were added to a solvent mixture of 50 ml of toluene, 25 ml of ethanol and 25 ml of water, and the reaction was carried out under reflux with heating for 2 hours. The reaction mixture was poured into ice-cold water and extracted with toluene. The toluene layer was washed with water twice and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.3 g of 2-fluoro-4-(2,4-dichlorophenyl)benzonitrile (yield 93.0%), which was used in Example 8 (1) as the starting material.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3](Cl)=[O:4].CN1CCOCC1.[N:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[NH2:25]>O1CCCC1>[Br:1][CH:2]([CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([NH:25][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][N:19]=1)=[O:4]
Reactant: O=C(Cl)C(Br)CC1CCCC1
Reactant: Nc1cnccn1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C(Nc1cnccn1)C(Br)CC1CCCC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 23.7 %

Procedure:
A solution of 2-bromo-3-cyclopentyl-propionyl chloride (1.46 g, 6.09 mmol) in tetrahydrofuran (32.1 mL, 0.19M) cooled to 0° C. was treated with N-methylmorpholine (0.66 mL, 6.09 mmol). The reaction mixture was stirred at 0° C. for 5 min. After this time, the reaction was treated with pyrazin-2-ylamine (0.58 g, 6.09 mmol) and allowed to warm to 25° C. The reaction stirred at 25° C. for 2 d. After this time, the reaction mixture was partitioned between water (100 mL) and ethyl acetate (2×150 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 115 g, 10-50% ethyl acetate/hexanes gradient) afforded 2-bromo-3-cyclopentyl-N-pyrazin-2-yl-propionamide (0.43 g, 24%) as a light brown solid; ES+-HRMS m/e calcd for C12H16N3OBr [M+H+] 298.0550, found 298.0550.
Reaction SMILES: C[O-:2].[Na+].Cl.Cl.[CH3:6][N+:7]1([O-:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C>CO.C(#N)C>[OH2:13].[OH2:2].[CH3:6][N+:7]1([O-:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: C[O-]
Agent: C[N+]1([O-])CCNCC1
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 3.16N solution (6.7 cc.) of sodium methoxide in methanol is added to a suspension of 1-methylpiperazine-1-oxide dihydrochloride (2.0 g.) in anhydrous methanol (10 cc.). After stirring for 10 minutes at 25° C., the suspension is treated with decolourising charcoal (0.1 g.) and then filtered. The methanolic filtrate is evaporated under reduced pressure (20 mm.Hg) at 40° C. maximum. The oily residue (2.0 g.) is dissolved in anhydrous acetonitrile (50 cc.) and 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-1-one (2.15 g.) is added. The reaction mixture is heated for 4 hours at 50° C. and then stirred for 48 hours at a temperature of about 25° C., filtered and concentrated under reduced pressure. The residue (3.8 g.) is dissolved in methylene chloride (50 cc.). The solution is passed through a column of Merck silica (0.02 -0.05) (60 g.). Elution is carried out successively with methylene chloride (50 cc.), ethyl acetate (50 cc.), a mixture (50 cc.) of ethyl acetate and methanol (80-20 volume), a mixture (50 cc.) of ethyl acetate and methanol (50--50 by volume), and finally with the same mixture of solvents (100 cc.). This last fraction is evaporated under reduced pressure. The residue obtained (0.9 g., m.p. about 200° C.) is dissolved in acetonitrile (10 cc.) and distilled water (1 cc.), near the boiling point. After cooling to 2° C., the crystals which have appeared are filtered off, washed with ice-cold acetonitrile (0.5 cc.) and dried under reduced pressure (20 mm.Hg). 4-{[2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-isoindolin-1-yl]oxycarbonyl{-1-methyl-piperazine-1-oxide dihydrate (0.62 g.), melting at about 200° C. (decomposition), is obtained.
Reaction SMILES: [C:1]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:18])[CH2:15][C:16]#[N:17])[CH:8]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]=[C:30](Cl)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:18])[C:15](=[C:30]([NH:29][S:26]([C:23]2[CH:22]=[CH:21][C:20]([CH3:19])=[CH:25][CH:24]=2)(=[O:28])=[O:27])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:16]#[N:17])[CH:8]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: Cc1ccc(S(=O)(=O)N=C(Cl)c2ccccc2)cc1
Reactant: C=C(C)C(=O)Oc1cccc(NC(=O)CC#N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)Oc1cccc(NC(=O)C(C#N)=C(NS(=O)(=O)c2ccc(C)cc2)c2ccccc2)c1
Reaction time: 1 h

Procedure:
To a mixture of 4.89 g (20 mmol) of 3-(2-cyanoacetamido)phenyl methacrylate, 5.88 g (20 mmol) of N-(4-methylphenylsulfonyl)benzenecarboximidoyl chloride and 200 ml of methylene chloride was added dropwise 4.05 g (40 mmol) of triethylamine with 10 ml of methylene chloride rinse. The resultant solution was stirred for 1 hr and washed twice with 10% HCl and once with water. The solution was dried over magnesium sulfate and concentrated after adding t-butylpyrocatechol inhibitor. The solid residue was treated with ligroine, collected and recrystallized from ethanol.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=C[CH:7]=[C:8]([Br:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[Cl-].[NH4+:15]>C1COCC1.[Zn]>[Br:11][C:8]1[CH:9]=[C:10]2[C:5](=[N:15][CH:7]=1)[NH:4][C:3](=[O:12])[CH2:2]2
Reactant: [NH4+]
Reactant: O=C1Nc2ccc(Br)cc2C1(Br)Br
Agent: [Cl-]
Agent: [Zn]
Solvent: C1CCOC1
Product: O=C1Cc2cc(Br)cnc2N1
Reaction time: 0.33 h

Procedure:
A solution of 3,3,5-tribromooxindole (5.0 g, 13.4 mmol) in fresh THF (100 mL) is stirred at room temperature and a saturated aqueous solution of ammonium chloride (100 mL) is added. The flask is placed in a water bath and activated zinc dust (15.0 g, 230 mmol) is added. The mixture is stirred for 20 min and the zinc is removed by filtration through a pad of diatomaceous earth. The organic layer is separated and the aqueous layer is extracted with THF (20 mL). The combined organic layers were washed with saturated brine solution, dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. The brown residue is triturated with water (20 mL) and the tan solid is collected by filtration and dried under vacuum to give 5-bromo-7-azaoxindole as a tan solid, 2.02 g (71%). 1H NMR (DMSO-d6) δ11.13 (s,1H), 8.15 (s,1H), 8.76 (s,1H), 3.57 (s, 2H). MS (AP−ve) 211 (100) (M−H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[C:19]1([CH2:25][C:26](O)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>>[N:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:26](=[O:27])[CH2:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:11]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
To a 4 mL vial was added the product from Example 1B (20 mg in dimethyl acetamide), phenylacetic acid [1.5 equivalents in dimethyl acetamide], O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 2 equivalents in dimethyl acetamide) and triethylamine (3 equivalents, neat). The vial was capped and microwaved at 150° C. for 30 minutes. The reaction was checked by LC/MS and concentrated to dryness upon completion. The residue was dissolved in 1:1 MeOH:DMSO and purified by reverse phase HPLC (conditions from Example 10C): 1H NMR (500 MHz, DMSO-d6/D2O) δ 8.33-8.28 (m, 1H), 8.03 (d, J=7.5, 1H), 8.01-7.96 (m, 1H), 7.94-7.87 (m, 1H), 7.40-7.33 (m, 4H), 7.33-7.25 (m, 1H), 3.86-3.78 (m, 4H), 3.67 (s, 2H), 3.11-3.06 (m, 4H); MS (ESI+) M/Z 365 (M+H)+.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]#[N:12].C(O)(=[O:19])C.S(=O)(=O)(O)O.[OH-].[Na+]>O>[CH:13]1[C:10]2[C:11](=[O:19])[NH:12][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8][C:9]=2[CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccccc1Sc1ccccc1N
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1Nc2ccccc2Sc2ccccc21
Temperature: 0 °C

Procedure:
2-(2-Aminophenylthio)benzonitrile (3.72 g, 16 mmol) was dissolved in water (35 ml), acetic acid (35 ml) and concentrated sulphuric acid (35 ml) and stirred and heated under reflux for 3 hr. The mixture was allowed to cool and poured onto crushed ice (600 ml) and adjusted to pH 6 with sodium hydroxide solution (10N). The product was extracted into dichloromethane (700 ml), dried (MgSO4) and evaporated in vacuo. The residue was dissolved in xylene (250 ml) and refluxed in a Dean-Stark apparatus for 72 hr. Filtration of the cold reaction mixture and recrystallisation from ethanol gave the title compound as a white crystals (2.99 g, m.p. 255°-256° C., Rf 0.68, CH2Cl2 /MeOH 19:1).
Reaction SMILES: N[C:2]1[C:28]([CH3:29])=[CH:27][C:5]2[C:6]([CH2:9][CH2:10][C:11]3[S:12][C:13]4[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:14]=4[C:15]=3[CH:16]([CH3:18])[CH3:17])=[N:7][O:8][C:4]=2[CH:3]=1.N([O-])=[O:31].[Na+]>OS(O)(=O)=O.O>[CH:16]([C:15]1[C:14]2[CH:19]=[CH:20][C:21]([C:23]([F:24])([F:25])[F:26])=[CH:22][C:13]=2[S:12][C:11]=1[CH2:10][CH2:9][C:6]1[C:5]2[CH:27]=[C:28]([CH3:29])[C:2]([OH:31])=[CH:3][C:4]=2[O:8][N:7]=1)([CH3:17])[CH3:18]
Reactant: Cc1cc2c(CCc3sc4cc(C(F)(F)F)ccc4c3C(C)C)noc2cc1N
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc2c(CCc3sc4cc(C(F)(F)F)ccc4c3C(C)C)noc2cc1O
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 19.9 %

Procedure:
The above-mentioned 6-amino-3-[2-[3-isopropyl-6-(trifluoromethyl)benzothiophen-2-yl]ethyl]-5-methylbenzisoxazole (100 mg, 0.239 mmol) was suspended in 25% H2SO4 (2.0 mL). A solution of sodium nitrite (25 mg, 0.36 mmol) in water (1.0 mL) was added to the suspension under cooling with ice. After the mixture was stirred for 30 min under the same conditions, and added dropwise to 75% H2SO4 (1.5 mL) that heated to 120° C. The mixture was heated for 1 h at 120° C., cooled to room temperature, diluted with ice-cold water, and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After the solvent was removed, the residue was purified by silica gel column chromatography (hexane/ethyl acetate, 5:1) to give the titled compound (20 mg) as yellow crystal (20 mg, yield 20%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1Cl.[C:16]1([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)=[N:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[O:39][C:36]1[CH:35]=[CH:34][C:33]([NH:32][C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:22]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:23][N:24]=2)=[CH:38][CH:37]=1
Reactant: Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Reactant: Clc1ccncc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Brc1cnccc1Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Temperature: 130 °C

Procedure:
A resealable reaction tube was charged with cesium carbonate (0.873 g, 0.268 mmol), 3-bromo-4-chloropyridine hydrochloride (0.205 g, 0.894 mmol) and 4-(4-phenylphthalazin-1-ylamino)phenol (0.280 g, 0.894 mmol) and purged with nitrogen for several minutes. 1.8 mL of DMSO was added, the tube was sealed, and the reaction mixture was heated to 130° C. for 3 h. Upon cooling the mixture was diluted with EtOAc and washed with water. The aqueous portion was extracted with EtOAc, and the combined organic portions were dried with MgSO4 and concentrated. N-(4-(3-bromopyridin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine was isolated as an orange solid. MS m/z=470 [M+H]+. Calc'd for C25H17BrN4O: 469.33.
Reaction SMILES: Br[CH:2]([CH2:15][CH:16]1[CH2:18][CH2:17]1)[C:3]([O:5][C@@H:6]([CH3:14])[C:7](=[O:13])[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:4].[Na+].[I-].C(N(CC)CC)C.[CH3:28][O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O1CCCC1>[CH3:28][O:29][C:30]1[CH:36]=[CH:35][C:33]([NH:34][CH:2]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:3]([O:5][C@@H:6]([CH3:14])[C:7](=[O:13])[N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:4])=[CH:32][CH:31]=1
Reactant: C[C@H](OC(=O)C(Br)CC1CC1)C(=O)N1CCCC1
Reactant: COc1ccc(N)cc1
Agent: O=S([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(NC(CC2CC2)C(=O)O[C@@H](C)C(=O)N2CCCC2)cc1
Temperature: 40 °C
Reaction time: 20 h
Yield: 57.6 %

Procedure:
To (1S)-1-methyl-2-oxo-2-tetrahydro-1-H-1-pyrrolylethyl 2-bromo-3-cyclopropylpropanoate (418 mg, 1.3 mmol), NaI (198 mg, 1.3 mmol), triethylamine (214 g, 2.1 mmol) and tetrahydrofuran (5 mL) were added. To the solution, p-methoxyaniline (211 mg, 1.7 mmol) and tetrahydrofuran (3 mL) were added. The mixture was stirred at room temperature for 24 hours and further at 40° C. for 20 hours. To the mixture, a saturated sodium sulfite aqueous solution and ethyl acetate were added for extraction. The obtained extract was dried with anhydrous magnesium sulfate, and the solvent was removed away under reduced pressure. The residue was purified with silica gel chromatography to obtain 270 mg of the target compound (yield: 57%, The diastereo ratio calculated by NMR analysis was 92:8.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:10]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[N:32]1[N:33]=[C:34]([SH:37])[NH:35][CH:36]=1.Cl>CC(C)=O.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:10][S:37][C:34]1[NH:35][CH:36]=[N:32][N:33]=1)[CH2:22][CH:23]([CH3:24])[CH3:25])([CH3:2])([CH3:3])[CH3:4]
Reactant: Sc1nnc[nH]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)C[C@@H](CSc1nnc[nH]1)NC(=O)OC(C)(C)C
Yield: 79.6 %

Procedure:
To 250 mg of toluene-4-sulfonic acid (S)-2-tert-butoxycarbonylamino-4-methyl-pentyl ester in 2.5 ml acetone and 0.5 ml water were added 112 mg of potassium carbonate, followed by the addition of 75 mg 4H-1,2,4-triazole-3-thiol. The reaction was heated in a microwave reactor for 5 min to 100° C. The pH was then adjusted to 7 by the addition of 2 M aqueous hydrochloric acid and the mixture was extracted with ethyl acetate twice. The combined organic phases were dried over sodium sulphate and concentrated in vacuo. 161 mg (80%) of [(S)-3-Methyl-1-(4H-[1,2,4]triazol-3-ylsulfanylmethyl)-butyl]-carbamic acid tert-butyl ester were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:25]1[C:26](=[O:42])[N:27]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:28]=[C:29]([N+:31]([O-:33])=[O:32])[CH:30]=1>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:25]1[C:26](=[O:42])[N:27]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:40])([CH3:39])[CH3:41])[CH:28]=[C:29]([N+:31]([O-:33])=[O:32])[CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)CCOCn1cc([N+](=O)[O-])cc(I)c1=O
Reactant: CN1CCN(c2ccc3c(ccn3C(=O)OC(C)(C)C)c2)CC1
Product: CN1CCN(c2ccc3c(c2)cc(-c2cc([N+](=O)[O-])cn(COCC[Si](C)(C)C)c2=O)n3C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared by the route outlined in Scheme 10 and using the experimental from Example 37, Step 3, with intermediate (10c), 5-(4-methyl-piperazin-1-yl)-indole-1-carboxylic acid tert-butyl ester (2.33 g, 7.4 mmol) and 3-iodo-5-nitro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyridin-2-one (2.66 g, 6.7 mmol) which had been synthesised according to the protocol described for intermediate (6a) in example 20. The resultant solid was purified via trituration using diethyl ether, to afford the title compound as a pale brown solid, 1.73 g, 40%.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][NH:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][C:27]=1[N+:28]([O-])=O)[C:12]([N:14]([CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13]>C(OCC)(=O)C.CO.[Pd]>[NH2:28][C:27]1[CH:26]=[CH:25][C:11]([C:12]([N:14]([CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:20][CH2:21][CH:22]([CH3:23])[CH3:24])=[O:13])=[CH:10][C:9]=1[NH:8][CH2:7][CH2:6][CH:2]1[O:1][CH2:5][CH2:4][O:3]1
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(NCCC2OCCO2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc(N)c(NCCC2OCCO2)c1
Temperature: 20 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
3-{[2-(1,3-dioxolan-2-yl)ethyl]amino}-N,N-bis(3-methylbutyl)-4-nitrobenzamide (2.4 g) in solution in a mixture of ethyl acetate/methanol 2:1 (100 ml), and 10% palladium on carbon (240 mg) are introduced into an autoclave. After stirring for 4 hours under a hydrogen atmosphere (3 bar) at a temperature of approximately 20° C., the catalyst is eliminated by filtration on celite and the filtrate is concentrated under reduced pressure at 40° C. in order to produce the expected compound in the form of an oil (2.02 g; 89% yield).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[C:13]([NH2:14])=[N:12][NH:11][C:10]=3[C:5]2=[C:4]([CH3:15])[CH:3]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl.C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:14][C:13]2[C:9]3[S:8][C:6]4[C:5]([C:10]=3[NH:11][N:12]=2)=[C:4]([CH3:15])[CH:3]=[C:2]([CH3:1])[N:7]=4)=[CH:20][CH:19]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cc1cc(C)c2c(n1)sc1c(N)n[nH]c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(CNc2n[nH]c3c2sc2nc(C)cc(C)c23)cc1
Reaction time: 1 h
Yield: 73.9 %

Procedure:
The 6,8-dimethyl-1H-pyrazolo[3′,4′:4,5]thieno[2,3-b]pyridin-3-amine (70 mg, 0.32 mmol) was stirred in DCE (3.2 mL). To this solution was added 4-methoxybenzaldehyde (0.12 mL, 0.96 mmol), acetic acid (0.040 mL, 0.64 mmol) and NaBH(AcO)3 (140 mg, 0.64 mmol). The resulting slurry was stirred for 1 hr, LC\MS indicates the reaction is nearly complete. The reaction was stirred another hour, then diluted with DCM (15 mL) and treated with aqueous 1N NaOH (12 mL). The aqueous layer was separated and extracted with DCM. The combined organic layers were dried over Na2SO4, and concentrated under vacuum to give 180 mg of crude residue. The residue was purified by reverse-phase HPLC to give 80 mg of the pure product as a yellow TFA salt. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.30 (d, J=8.6 Hz, 2H), 7.11 (s, 1H), 6.85 (2H, J=8.6 Hz, 2H), 5.74 (s, 1H), 4.32 (s, 2H), 3.70 (s, 3H), 2.62 (s, 3H), 2.50 (s, 3H). LC/MS: RT=0.63 min., m/z=339.0 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:14][C:15](=O)[C:16]1([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)C1C=CC=CC=1>CCOCC>[C:25]([O:24][C:22]([N:19]1[CH2:18][CH2:17][C:16]([CH2:15][OH:14])([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:21][CH2:20]1)=[O:23])([CH3:27])([CH3:28])[CH3:26]
Reactant: Cc1ccccc1CC1(C(=O)OCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1ccccc1CC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h

Procedure:
To a suspension of lithium aluminum hydride (0.32 g, 8.4 L s mmol) in anhydrous ether (50 ml) was added a solution of 4-(2-methylbenzyl) N-t-butoxycarbonyl isonipecotic acid benzyl ester (3.0 g, 7.1 mmol) in anhydrous ether (25 ml) over 15 min. The resulting mixture was heated gently at reflux for 1 h. The reaction mixture was then quenched with the slow and successive addition of H2O (0.32 ml), 15% aqueous NaOH, and H2O (0.96 ml). After sirring for 30 min., the mixture was filtered through Celite and the filtrate washed with brine, dried (MgSO4), and concentrated in vacuo to a colorless syrup. Purification by column chromatography on silica with 25%-50% EtOAc/hexane as eluent afforded the product as a colorless gum. This material was recrystallized from EtOAc and hexane to afford a white solid. m.p. 104°-106° C.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:23][C:24]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:25]=1[CH2:26][NH:27][NH2:28]>C(O)C>[NH2:10][C:6]1[NH:28][N:27]([CH2:26][C:25]2[CH:29]=[CH:30][CH:31]=[C:32]([Cl:33])[C:24]=2[Cl:23])[C:4](=[O:3])[CH:5]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1cccc(Cl)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2cccc(Cl)c2Cl)[nH]1
Reaction time: 8 h

Procedure:
16.7 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulphonic acid were dissolved in 100 ml of ethanol and 20.2 g of 2,3-dichlorobenzylhydrazine were added. After standing overnight at room temperature, the precipitate which had formed was filtered off and dissolved in 2 N sodium hydroxide solution. The alkaline solution was again extracted with ether and subsequently slightly acidified with dilute acetic acid. Hereupon the compound identified above precipitated and after recrystallisation from ethanol the melting point was 161°-162°C. Yield: 11 g (40%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:33]#[C:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:8][C:9]=1[N:10]([C:24]([C@H:26]1[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]1)=[O:25])[CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:33]#[C:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[CH:8][C:9]=1[N:10]([C:24]([C@H:26]1[CH2:27][CH2:28][C@H:29]([CH3:32])[CH2:30][CH2:31]1)=[O:25])[CH:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from step IV (5.198 g) is dissolved in 30 mL of CH2Cl2 and treated with 20 mL of trifluoroacetic acid. The mixture is stirred at room temperature overnight, then it is evaporated to dryness, obtained residue is redissolved in CH2Cl2 and washed with aqueous NaHCO3 and brine. Organic fraction is separated, dried over Na2SO4, and concentrated to give 5.340 g of crude 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(piperidin-4-yl)amino]-thiophene-2-carboxylic acid methyl ester.