Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:12]=3[N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:19](=[O:30])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])OC(C)(C)C>CN(C)C1C=CN=CC=1.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:12]=3[N:13]=2)[C:5]([N:8]([C:19]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:30])[C:19](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)cc1-c1nc2c(F)cccc2o1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)cc1-c1nc2c(F)cccc2o1
Temperature: 25 °C
Reaction time: 45 h
Yield: 89.4 %

Procedure:
N,N-dimethylpyridin-4-amine (0.190 g), was added to a stirred suspension of 5-bromo-3-(4-fluoro-1,3-benzoxazol-2-yl)pyridin-2-amine (2.4 g) and di-tert-butyl carbonate (4.83 g) in DMF (50 ml) at 25° C. under nitrogen. The resulting suspension was stirred at 25° C. for 45 hours. The DMF was evaporated under reduce pressure. The mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 0 to 2% methanol in dichloromethane. The solvent was evaporated to dryness to afford tert-butyl N-[5-bromo-3-(4-fluoro-1,3-benzoxazol-2-yl)-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (3.54 g, 89%) as a pale orange solid. NMR Spectrum: (CDCl3) 1.36 (s, 18H), 7.12 (dd, 1H), 7.38 (ddd, 1H), 7.42 (d, 1H), 8.72 (d, 1H), 8.85 (d, 1H); Mass spectrum: M+H+ 508-510 PdCl2dppf (0.278 g), potassium acetate (2.095 ml) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.923 g) were added over a period of 10 minutes, to a stirred solution tert-butyl N-[5-bromo-3-(4-fluoro-1,3-benzoxazol-2-yl)-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (3.5 g) dissolved in dioxane (30 ml) degazed and under argon. The resulting mixture was stirred at 80° C. for 3 hours. The salts were filtered; The mixture was evaporated under reduce pressure. The crude product was purified by flash chromatography on silica gel eluting with 30 to 40% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl N-tert-butoxycarbonyl-N-[3-(4-fluoro-1,3-benzoxazol-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]carbamate (3.26 g) as a pale orange solid. NMR Spectrum: (CDCl3) 1.33 (s, 18H), 1.39 (s, 12H), 7.10 (dd, 1H), 7.34 (ddd, 1H), 7.42 (d, 1H), 8.99 (d, 1H), 9.08 (d, 1H); Mass spectrum: M-(boc+pinacol)+H+ 374
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[CH3:16][C:17]([CH3:24])([C:21](Cl)=[O:22])[C:18](Cl)=[O:19]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:18](=[O:19])[C:17]([CH3:24])([CH3:16])[C:21](=[O:22])[NH:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=3)=[CH:4][CH:3]=1
Reactant: CC(C)(C(=O)Cl)C(=O)Cl
Reactant: Nc1ccccc1Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CC1(C)C(=O)Nc2ccccc2N(c2ccc(Cl)cc2)C1=O
Yield: 57.8 %

Procedure:
To a stirred refluxing solution of N1-(4-chlorophenyl)benzene-1,2-diamine (200 mg, 0.92 mmol) in toluene (20 mL) was added drop-wise a solution of 2,2-dimethylmalonyl dichloride (155 mg, 0.92 mmol). Then the mixture was refluxed for 1 h. The solvent was removed in vacuum, stirred with water (20 mL), extracted with DCM (20 mL×3). The combined organic layer was dried over Na2SO4. The mixture was concentrated in vacuum and the residue was purified by column chromatography (silica-gel, DCM: methanol=40:1) to give 1-(4-chlorophenyl)-3,3-dimethyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione as a yellow solid (167.5 mg, 58%). LRMS (M+H+) m/z: calcd 314.08. found 314.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[C:13](Cl)[CH:12]=[C:11]([Cl:16])[N:10]=1>CS(C)=O>[Cl:8][C:9]1[CH:14]=[C:13]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:12]=[C:11]([Cl:16])[N:10]=1
Reactant: C1CCNC1
Reactant: Clc1cc(Cl)nc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1cc(N2CCCC2)cc(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A mixture of pyrrolidine (0.910 g, 10.7 mmol) in dry DMSO and NaH (0.385 g, 16.0 mmol) was stirred for 30 minutes at 0° C., after which a sample of 2,4,6-trichloropyridine (1.75 g, 9.63 mmol) was added. This reaction mixture was stirred at room temperature for 4 hours, after which time ice cold water was added to quench the reaction. The reaction mixture was then extracted with ethyl acetate, and the extract was washed 3-4 times with water. The organic layer was dried over sodium sulphate and concentrated. The residue was purified by column chromatography over 100-200 mesh silica gel. Elution of the column with 20% acetone in hexanes gave the pure product as a colorless solid (yield: 75%).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21](C=O)=[CH:20][CH:19]=1>CCCCCC.O1CCCC1>[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21]([CH:8]2[O:7][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(c2ccc(C(F)(F)F)cc2)O1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared as described in General Method 1 using 10 mL of methyl acetoacetate, 3.7 g of NaH 60% dispersion in oil, 58 mL of 1.6M n-butyl lithium in hexane, 11.5 g of 4-trifluoromethylbenzaldehyde and 250 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 10 minutes at 0° C. then 30 minutes at room temperature. The crude product was triturated from diethyl ether to afford a solid (m.p. 155°-156° C.). 1H NMR (CDCl3) δ2.83 (dd, 1H), 2.99 (dd, 1H), 3.58 (dd, 2H), 5.76 (dd, 1H), 7.50-7.76 (m, 4H).
Reaction SMILES: [CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][C:4]=1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:22]([O:24][CH3:25])=[O:23])=[O:2].O1CCCC1.[BH4-].[Na+].[Cl-].[NH4+]>O>[OH:2][CH2:1][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][C:4]=1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)c1c(-c2nc3ccccn3c2C=O)ccc2ccccc12
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2nc3ccccn3c2CO)ccc2ccccc12
Yield: 94.8 %

Procedure:
The compound prepared in Example 4 (195 mg) was added to tetrahydrofuran (1.5 mL) and suspended. A solution of sodium borohydride (34 mg) in water (0.4 mL) was added to the reaction mixture on ice bath, and the reaction mixture was stirred for an hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the reaction mixture was extracted twice with ethyl acetate. The obtained organic layer was joined, and washed with water, a saturated aqueous solution of sodium hydrogen carbonate and a saturated salt solution sequentially. The obtained organic layer concentrated under reduced pressure after drying with anhydrous sodium sulfate. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=25:75) to give the title compound (186 mg) having the following physical data.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]([CH2:11][C:12]([OH:14])=[O:13])[N:9]=[N:8][N:7]=2)=[CH:2]1.[CH2:15](O)[CH2:16][CH2:17][CH2:18][OH:19].C1(N=C=NC2CCCCC2)CCCCC1.C(O)(=O)C>C(OCC)(=O)C>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][O:13][C:12](=[O:14])[CH2:11][N:10]1[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[N:7][N:8]=[N:9]1
Reactant: O=C(O)Cn1nnnc1-c1ccsc1
Reactant: OCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(Cn1nnnc1-c1ccsc1)OCCCCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
To a suspension of 1 g (4.76 mM) of [5-(3-thienyl) tetrazol-1-yl]acetic acid and 514 mg (5.71 mM) of 1,4-butanediol in 20 ml of ethyl acetate was added 1.08 g (5.23 mM) of dicyclohexylcarbodiimide at room temperature. After the mixture was stirred at room temperature for 30 min, a small amount of acetic acid was added to the mixture and then was stirred for 30 min. The mixture was filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent; chloroform/ethyl alcohol=30/1) for separation and purification, to give 520 mg (yield 38.7%) of [5-(3-thienyl)tetrazol-1-yl]acetic acid 4-hydroxybutyl ester.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=O)[O:4][C:2]2=O.CO[C:15]1[C:16]([NH2:21])=C[CH:18]=[CH:19][CH:20]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C(C)=CC=CC=1>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]1[O:4][C:5]2[CH:18]=[CH:19][CH:20]=[CH:15][C:16]=2[N:21]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: COc1ccccc1N
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1C
Product: Nc1ccccc1-c1nc2ccccc2o1
Reaction time: 8 h
Yield: 23 %

Procedure:
Isatoic anhydride (0.2 m), o-anisidine (0.22 m), and xylene (200 ml) were placed in a 3-neck, 300 ml round bottom flask fitted with thermometer, condenser, and magnetic stirrer. The reaction mixture was heated to reflux and allowed to stir at reflux overnight. Gas evolution appeared to be vigorous. Added a Dean-Stark trap and attempted to collect water. No water was evident after eight hours. Reaction mixture was cooled and allowed to stand overnight. Toluenesulfonic acid (1.5 g) was added and reaction mixture heated to reflux. Water was azeotroped from the reaction mixture. The xylene was stripped from the reaction mixture under aspirator vacuum. The residue was leached with benzene (500 ml). The benzene extract was then washed with 2% caustic until no further color was extracted. The benzene solution was filtered and evaporated to dryness. The residue was dissolved in boiling ethanol and allowed to stand in the refrigerator. The reddish crystals were filtered out and dried. Obtained 10 grams (23% yield); m.pt.=104°-107° C. Structure was confirmed by infra red (IR) and nuclear magnetic resonance (NMR) analysis.
Reaction SMILES: Br[C:2]1[C:11](=[S:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:3]1[O:4][C:5]2[C:10]([C:11](=[S:12])[CH:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: c1ccc2[nH]ccc2c1
Reactant: S=c1c(Br)coc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: S=c1cc(-c2cc3ccccc3[nH]2)oc2ccccc12
Temperature: 0 °C
Yield: 85.1 %

Procedure:
To an eggplant type flask (25 ml), 3-bromothiochromone (121 mg) prepared in Example 8, indole (234 mg), potassium carbonate (1382 mg), and dimethylformamide (15 ml) were added. The mixture was reacted at 80° C. for 20 hours with stirring. The reaction mixture was added to ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedby the silica gel colunm chromatography and recrystallized from benzene/hexane to give the titled compound (118.5 mg; yield=40.4%) as crystals. Melting point: 155°-156° C. 1H-NMR(CDCl3, δ ppm): 7.22 (s, H3), 8.57 (d, H5), 7.55-7.72 (m, H6), 7.55-7.72 (m, H7), 7.55-7.72 (m, H8), 7.45 (d, H2'), 6.79 (d, H3'), 7.60-7.70 (m, H4'), 7.22-7.38 (m, H5'), 7.22-7.38 (m, H6'), 7.88 (d, H7').
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.C(N(CC)CC)C.C(OC(Cl)=O)(C)C.[CH3:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32]>C1COCC1.C(Cl)Cl.CCOC(C)=O>[CH3:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][NH:32][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=1)=[O:13]
Reactant: Cc1ccccc1CN
Reactant: O=C(O)c1ccc2cnccc2n1
Agent: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccccc1CNC(=O)c1ccc2cnccc2n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 37.4 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol), in anhydrous THF (5 ml) at 0° C. was added triethylamine (44 ml, 0.316 mmol). After 5 min, isopropylchloroformate (0.316 ml, 1M solution in toluene, 0.316 mmol) was added. The mixture was stirred at 0° C. for 20 min. then 2-methylbenzylamine (53.46 ml, 0.43 mmol) was added to the mixture at 0° C. The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 5 h then diluted in CH2Cl2 (100 ml). The organic layer was washed with water, dried over anhydrous MgSO4, and concentrated to give the crude mixture. Chromatography of the crude (Hex:EtOAc=1:1 to pure EtOAc) afforded desired product as white solid (29.8 mg, 37%): m.p. 120-121° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=2)[OH:9])[CH:5]=[CH:6][CH:7]=1>ClCCl.O=[Mn]=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: OC(c1cccc(Br)c1)c1cccc(Br)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=C(c1cccc(Br)c1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
MnO2 (21.61 g, 249 mmol) was added to a solution of bis(3-bromophenyl)methanol (8.4 g, 24.5 mmol) in dichloromethane (80 mL). The mixture was stirred at 25° C. for 12 h and then filtered. The filter cake was washed with dichloromethane (60 mL×5). The filtrate was concentrated to afford 7.6 g of the title compound (22.3 mmol, 90%). LC/MS: [M+1]=341. 1H NMR (DMSO-d6), 400 MHz: δ 7.52-7.56 (m, 2H), 7.71 (d, 2H, J=7.2 Hz), 7.88-7.92 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[C:42]1([S:48](Cl)(=[O:50])=[O:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl>[C:42]1([S:48]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:50])=[O:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccccc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 86 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.171 g, 0.371 mmol) was dissolved in dichloromethane (3.5 mL), and the solution was treated with triethylamine (0.103 mL, 0.741 mmol) and benzenesulfonyl chloride (0.0570 mL, 0.446 mmol), followed by purification by flash column chromatography (chloroform/methanol=85/15) to obtain 4-benzenesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.192 g. yield 86%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].[Cl-].C[Al+]C.Cl[C:18](=[O:26])[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([C:18](=[O:26])[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:7][NH:8]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Reactant: CCOC(=O)CCC(=O)Cl
Agent: C[Al+]C
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)CCC(=O)c1c[nH]c2cccc([N+](=O)[O-])c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-nitroindole (2.00 g, 12.3 mmol) in CH2Cl2 (60 mL) at 0° C. was added dimethylaluminum chloride (1 M in hexanes, 14.8 mL, 14.8 mmol) and the mixture was stirred for 30 min. Ethyl 4-chloro-4-oxobutyrate (2.44 g, 14.8 mmol) was added dropwise and the resulting mixture was allowed to warm slowly to ambient temperature and stirred for 18 h. The reaction mixture was carefully quenched with 10% aqueous citric acid (150 mL) and extracted with CH2Cl2 (3×150 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was partially purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 65:35, and the resulting crude product was recrystallized from CH2Cl2:MeOH to give the title compound. MS: m/z=291 (M+1).
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[N:67][C:68]([N:71]5[CH2:76][CH2:75][N:74]([S:77]([CH3:80])(=[O:79])=[O:78])[CH2:73][CH2:72]5)=[CH:69][CH:70]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[N:67][C:68]([N:71]5[CH2:76][CH2:75][N:74]([S:77]([CH3:80])(=[O:79])=[O:78])[CH2:73][CH2:72]5)=[CH:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(S(C)(=O)=O)CC5)nc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CS(=O)(=O)N1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Yield: 35 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(4-(methylsulfonyl)piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.145 mmol) was hydrolyzed with lithium hydroxide (30 mg, 0.729 mmol) in THF/methanol/water (3/2/1 mL) to yield 27 mg (35.0% yield) of the titled compound after purification by preparative HPLC. 1H NMR (CD3OD, 300 MHz): δ 8.55 (s, 2H), 8.47-8.43 (dd, 1H), 8.386-8.380 (d, 1H), 8.247 (s, 1H), 7.997-7.995 (d, 1H), 7.75 (s, 1H), 7.50-7.47 (d, 1H), 7.37-7.35 (d, 1H), 7.42-7.32 (m, 1H), 7.12-6.97 (m, 3H), 5.43 (s, 2H), 3.88-3.85 (t, 4H), 3.47-3.44 (t, 4H), 2.92 (s, 3H). MS: m/z=532.05 (M+1), HPLC: 95.94% in method A.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][C:8]#[N:9])(=[O:4])[C:2]#[CH:3].[CH2:10]([NH:12][CH2:13][CH3:14])[CH3:11]>C(Cl)(Cl)Cl>[CH2:10]([N:12]([CH2:13][CH3:14])/[CH:3]=[CH:2]/[C:1]([O:5][CH2:6][CH2:7][C:8]#[N:9])=[O:4])[CH3:11]
Reactant: CCNCC
Reactant: C#CC(=O)OCCC#N
Solvent: ClC(Cl)Cl
Product: CCN(/C=C/C(=O)OCCC#N)CC

Procedure:
A solution of 48 g (0.39 moles) of 2-cyanoethyl propiolate in 100 ml of chloroform was treated with a solution of 28.5 g (0.38 moles) of diethylamine in 100 ml of chloroform. The temperature was kept at 10° to 20° C. during the addition. The chloroform was stripped off and the product used without purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].[CH2:9]1[CH2:13]O[CH2:11][CH2:10]1>>[CH2:13]([N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1)[CH2:9][CH2:10][CH3:11]
Reactant: C1CCOC1
Reactant: Ic1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Product: CCCCn1cc(I)cn1
Temperature: 70 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred suspension of 4-iodopyrazole (0.3 g, 1.55 mmol) and 60% NaH (0.08 g, 2 mmol) in anhydrous THF (1 ml) butyl bromide (0.5 ml) was added and the mixture was stirred overnight at 70° C. The mixture was quenched with saturated NH4Cl and extracted with EtOAc (50 ml). The organic layer was washed with H2O, dried over MgSO4 and filtered. The filtrate was distilled off and the residue was dried in vacuo to give 1-butyl-4-iodo-1H-pyrazole (0.39 g, 100%), as colourless oil. 1H NMR (CDCl3) 7.47 (s, 1H); 7.39 (s, 1H); 4.09 (t, 2H, J=7.14 Hz); 1.85-1.75 (m, 2H); 1.35-1.23 (m, 2H); 0.91 (t, 3H, J=7.32 Hz). To a stirred solution of the above product (0.36 g, 1.44 mmol) in anhydrous THF (0.5 ml) 2M iPrMgCl in THF (2 ml) was added at 0° C. and after warming up to room temperature anhydrous DMF (1 ml) was added to it. This was stirred for 1 h at room temperature, than quenched with saturated NH4Cl and extracted with EtOAc (30 ml). The organic layer was washed with H2O, dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give 1-butyl-1H-pyrazole-4-carbaldehyde (0.27 g; 100%), as pale oil. 1H NMR (CDCl3) 9.82 (s, 1H); 7.93 (s, 1H); 7.89 (s, 1H); 4.13 (t, 2H, J=7.11 Hz); 1.9-1.8 (m, 2H); 1.4-1.22 (m, 2H); 0.92 (t, 3H, J=7.29 Hz). To a stirred solution of above aldehyde (0.22 g, 1.44 mmol) in the mixture of dioxane and H2O (15 ml: 3 ml) KMnO4 (0.25 g; 1.58 mmol) was added over a period of 30 min. The mixture was evaporated to dryness and the residue was treated in the mixture of EtOAc and MeOH (20 ml: 5 ml) and filtered through Celite pad. The filtrate was evaporated to dryness to give the title compound (0.24 g; 100%), as creamy crystalline solid. 1H NMR (CDCl3) 7.8 (s, 1H); 7.56 (b, 1H); 4.05 (b, 2H); 1.7 (b, 2H); 1.18 (b, 2H); 0.83 (b, 3H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:24])[N:9]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10]2=[O:15])(=[O:4])=[O:3].Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[O:32]1[CH2:33][CH2:34][N:29]([CH2:28][CH2:27][N:5]([C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[C:8](=[O:24])[N:9]([CH2:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C:10]3=[O:15])[S:2]([CH3:1])(=[O:3])=[O:4])[CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2cccc(NS(C)(=O)=O)c2C1=O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN1C(=O)c2cccc(N(CCN3CCOCC3)S(C)(=O)=O)c2C1=O
Temperature: 75 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A mixture of tert-butyl 2-(4-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (196 mg, 0.553 mmol) (prepared with an analogous procedure to that described in, Example 29, Scheme 29, Steps 1, 2, 3, 4 for the preparation of Compound 160), 4-(2-chloroethyl)morpholine hydrochloride (108 mg, 0.581 mmol), and K2CO3 (168 mg, 1.217 mmol) in acetonitrile (10 ml) was stirred at 75° C. overnight. The solvent was removed under vacuum, and the residue was taken up in a EtOAc/DCM/Et2O mixture and filtered through Na2SO4 to remove the inorganic salts. After evaporation of the solvent, tert-butyl 2-(4-(N-(2-morpholinoethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate was obtained (256 mg, 0.548 mmol, 99% yield, MS/ESI+ 467 [MH]+).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:36]1[C:40]2[C:41]([CH:45]=O)=[CH:42][CH:43]=[CH:44][C:39]=2[CH2:38][CH2:37]1>C1COCC1.O>[O:36]1[C:40]2[C:41]([CH:45]=[CH:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:42][CH:43]=[CH:44][C:39]=2[CH2:38][CH2:37]1
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc2c1OCC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC=Cc1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (2-carboxyethyl)triphenylphosphonium bromide (617 mg, 1.5 mmol) in THF (20 mL) was added NaHMDS (1.5 mL, 3.0 mmol) at −20° C., and the reaction was stirred for 20 min. 2,3-Dihydro-1-benzofuran-7-carbaldehyde (200 mg, 1.4 mmol) was added to the reaction at −78° C., and the reaction was stirred overnight while warming to rt. The reaction was diluted with water (30 mL) and extracted with EtOAc (3×30 mL). Organics were washed with brine (30 mL), dried (Na2SO4), and concentrated to give the crude title compound as a yellow solid. [M+H] Calc'd for C12H12O3, 205. Found, 205.