Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12]([CH:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[CH2:12]([C:19]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccccc1)(Cc1ccc([N+](=O)[O-])cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.2 %

Procedure:
To a stirred solution of p-nitrobenzyl chloride (15 g) and diethyl benzylmalonate (22 g) in N,N-dimethylformamide (150 ml) was added Nail (60% in oil, 3.8 g). After stirring at room temperature for 2 days, the reaction mixture was concentrated under reduced pressure and the residue was suspended in ethyl acetate. The ethyl acetate layer was washed with aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate solution and brine, and dried (MgSO4). The organic solvent was evaporated off and the residual oil was purified by column chromatography on silica gel. Elution with ethyl acetate-hexane (1:6, v/v) gave diethyl benzyl-4-nitrobenzylmalonate (24 g, 71%) as crystals. Melting point: 70°-71° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20]C)[CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+]>Br.ClCCl>[N:1]1([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1cccc(C2CCCN2CCN2CCOCC2)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cccc(C2CCCN2CCN2CCOCC2)c1
Temperature: 25 °C
Yield: 58.4 %

Procedure:
1-[2-(4-Morpholinyl)ethyl]-2-(3-methoxyphenyl) pyrrolidine (3.6 g) in 48% hydrobromic acid (50 ml) was heated at 100° C. for 8.5 hrs. The reaction mixture was cooled to ambient temperature, neutralized with saturated sodium bicarbonate solution and diluted with dichloromethane. The layers were separated and the aqueous phase was extracted with dichloromethane (3 times). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, ether). The appropriate fractions were collected and concentrated to give 2.0 g (59%) of 3-[1 -[2-(4-morpholinyl)ethyl]-2-pyrrolidinyl}phenol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([C:9](=[O:23])[C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[S:17][C:18](=[O:22])N(C)C)C(OC)=O>C[O-].[Na+].CO>[CH3:1][O:2][C:3]([C:4]1[C:18](=[O:22])[S:17][C:11]2[C:10]([C:9]=1[OH:23])=[CH:15][C:14]([Br:16])=[CH:13][CH:12]=2)=[O:24]
Reactant: COC(=O)C(C(=O)OC)C(=O)c1cc(Br)ccc1SC(=O)N(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(O)c2cc(Br)ccc2sc1=O
Yield: 51.5 %

Procedure:
A mixture of 2-(5-bromo-2-dimethylcarbamoylsulfanyl-benzoyl)-malonic acid dimethyl ester (4.9 g, 11.71 mmol) in 0.5 M NaOMe/MeOH solution (94 mL) was heated to reflux for 6 h. After cooling overnight, the precipitated solid was collected by filtration and rinsed with MeOH followed by ether. The solid was dried in vacuo to provide 6-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (1.9 g) as a sodium salt. 1HNMR (200 MHz, DMSO-d6): δ (ppm)=8.164 (s, 1H), 7.524 (d, 1H), 7.23 (d, 1H), 3.56 (s, 3H).
Reaction SMILES: [OH:1][C:2]([CH3:12])([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH:13]1[CH:18]=[C:17]2[C:19]([N:21]([CH2:24][C:25](O)=[O:26])[C:22](=[O:23])[C:16]2=[CH:15][CH:14]=1)=[O:20].CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1>CN(C1C=CN=CC=1)C.ClCCl>[O:20]=[C:19]1[C:17]2[C:16](=[CH:15][CH:14]=[CH:13][CH:18]=2)[C:22](=[O:23])[N:21]1[CH2:24][C:25]([O:1][C:2]([CH3:12])([CH3:11])[C:3](=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:26]
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(O)C(=O)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: ClCCl
Product: CC(C)(OC(=O)CN1C(=O)c2ccccc2C1=O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 2-hydroxy-2-methylpropiophenone (2.0 g, 12.2 mmol), N-phthaloylglycine (2.7 g, 13.2 mmol), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (10.3 g, 24.3 mmol) and DMAP (0.34 g, 2.8 mmol) was dissolved in dichloromethane (100 mL) and stirred 5 days at room temperature. The mixture was diluted with dichloromethane and washed with 1 M HCl (2×), saturated NaHCO3 and brine, then filtered through cotton and concentrated to give 1,1-dimethyl-2-oxo-2-phenylethyl 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetate.
Reaction SMILES: [H-].[CH2:2]([Al+]CC(C)C)C(C)C.[C:11]([C:13]1[CH:14]=[C:15]([CH:19]([N:25]2[CH:29]=[C:28]([C:30]3[C:31]4[CH:38]=[CH:37][N:36]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:32]=4[N:33]=[CH:34][N:35]=3)[CH:27]=[N:26]2)[CH2:20][C:21](OC)=O)[CH:16]=[CH:17][CH:18]=1)#[N:12].C(Cl)Cl.CO.C(=O)([O-])[O-].[K+].[K+].C/C(/[O-])=C(/P(OC)(OC)=O)\[N+]#N>CCCCCC>[CH3:45][Si:43]([CH3:46])([CH3:44])[CH2:42][CH2:41][O:40][CH2:39][N:36]1[C:32]2[N:33]=[CH:34][N:35]=[C:30]([C:28]3[CH:27]=[N:26][N:25]([CH:19]([C:15]4[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=4)[C:11]#[N:12])[CH2:20][C:21]#[CH:2])[CH:29]=3)[C:31]=2[CH:38]=[CH:37]1
Reactant: CC(C)C[Al+]CC(C)C
Reactant: COC(=O)CC(c1cccc(C#N)c1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: COP(=O)(OC)/C([N+]#N)=C(/C)[O-]
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CO
Product: C#CCC(c1cccc(C#N)c1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
1 M Diisobutylaluminum hydride in hexane (0.31 mL) was added dropwise to a solution of methyl 3-(3-cyanophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanoate (100 mg, 0.0002 mol) (prepared by using a procedure analogous to Example 712, Step 1) in DCM (3 mL, 0.05 mol) and the mixture was cooled to −78° C. The reaction mixture was stirred at −78° C. for 4 h and was afterward quenched with cold methanol (3 mL, 0.07 mol). The reaction was allowed to warm to 0° C. and potassium carbonate (60 mg, 0.0004 mol) and Bestmann-Ohira reagent (1.5 eq, 57 mg) (E. Quesada et al, Tetrahedron, 62 (2006) 6673-6680) were added. The reaction was stirred at room temperature overnight, and then partitioned between ethyl acetate and water. The organic layer was washed with saturated NaCl, dried over MgSO4, filtered and concentrated to give the crude product. The crude product was purified using silica gel (EtOAC/Hexane 1:3 to 1:1) to give the desired product, 3-{1-[4-(7-{[2-(trimethylsilyl)ethoxy]-methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]but-3-yn-1-yl}benzonitrile (40 mg of mixture). m/z=469 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20]C)=O)[CH:16]=3)[NH:11][C:10]=2[OH:22])[CH:4]=1)#[N:2].[CH3:23][O:24][CH2:25][CH2:26][NH2:27]>>[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([NH:27][CH2:26][CH2:25][O:24][CH3:23])=[O:20])[CH:16]=3)[NH:11][C:10]=2[OH:22])[CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc2[nH]c(O)c(-c3cc(C#N)ccn3)c2c1
Reactant: COCCN
Product: COCCNC(=O)c1ccc2[nH]c(O)c(-c3cc(C#N)ccn3)c2c1
Reaction time: 2 h
Yield: 8 %

Procedure:
Starting material: methyl 3-(4-cyanopyridin-2-yl)-2-hydroxy-1H-indole-5-carboxylate and 2-methoxyethanamine. The product was purified on a silica gel column using chloroform/methanol/aqueous NH3, (150:10:1), as the eluent. The combined fractions were concentrated, stirred for 2 h in ethyl acetate (5 mL), and the formed precipitate was filtered off to give 0.012 g (8% yield) of the title compound as a dark-red powder: 1H NMR (DMSO-d6, 300 MHz) δ 14.67 (br s, 1H), 10.83 (s, 1H), 8.46 (br s, 1H), 8.16 (d, J=6.3 Hz, 1H), 7.98 (s, 1H), 7.81 (s, 1H), 7.56 (d, J=7.8 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 6.86 (d, J=6.3 Hz, 1H), 3.48 (br s, 4H), 3.31 (s, 3H); MS (ES) m/z 337 (M++1).
Reaction SMILES: C[Li].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:19]=2C(O)=O)=[CH:13][CH:12]=1)C1C=CC=CC=1.C([O:32][CH2:33][CH3:34])(=O)C.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:19]=2[C:33](=[O:32])[CH3:34])=[CH:13][CH:12]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(Nc2ccc(OCc3ccccc3)cc2)c(C(=O)O)c1
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(Nc2ccc(OCc3ccccc3)cc2)c(C(C)=O)c1
Reaction time: 3 h

Procedure:
Methyllithium (210 ml, 1.25M methyllithium-lithium bromide complex in ether) (0.263 mole) was added dropwise to a solution of 25.49 g (0.0732 mole) of 2-(4-benzyloxyphenylamino)-5-methoxybenzoic acid in 226 ml of tetrahydrofuran cooled to 0°-5° C. The reaction mixture was stirred for 3 hours at 0°-5° C. Ethyl acetate was then added and the mixture poured into ice and saturated ammonium chloride solution. The aqueous suspension was extracted with ether, the ether extracts dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from toluene to give 16.1 g of 1-[2-(4-benzyloxyphenylamino)-5-methoxyphenyl]ethanone, yellow-orange solid, m.p. 80°-81.5° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:11])[CH:4]=[CH:3]1.CN(CCN(C)C)C.C([Li])CCC.CN([CH:28]=[O:29])C.[NH4+].[Cl-]>C(OCC)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:11])[CH:4]=[C:3]1[CH:28]=[O:29]
Reactant: Cc1cccc2ccn(C)c12
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1cccc2cc(C=O)n(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
To a solution of 1,7-dimethylindole (2.85 g, 19.6 mmol) and TMEDA (3.3 mL, 21.6 mmol) in diethyl ether (30 mL) at −30° C. under N2 was added n-butyllithium (13.5 mL of a 1.6 M solution in hexanes, 21.6 mmol) dropwise. The resulting orange solution was heated to reflux for 1 h and then DMF (4.6 mL, 58.8 mmol) was added in one portion. The solution was stirred at room temperature overnight. Saturated aqueous NH4Cl solution was added and the mixture was then extracted with ethyl acetate (3×150 mL). The combined organics were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to provide an orange oil. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, 95:5) gave the title compound (1.57 g, 46%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 9.83 (s, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.21 (s, 1H), 7.09-7.02 (m, 2H), 4.39 (s, 3H), 2.79 (s, 3H).
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:5])[CH3:4].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)(Cl)Cl>ClCCl>[Br:1][CH2:2][CH:3]([O:5][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1)[CH3:4]
Reactant: CC(O)CBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(CBr)OC1CCCCO1

Procedure:
5.0 ml of 1-bromo-2-propanol was dissolved in 40 ml of dry dichloromethane, and 7.6 ml of 2,3-dihydropyran and 237 mg of dry p-toluenesulfonic acid were added thereto. The mixture was reacted at room temperature for 5 hours and then diluted by an addition of 250 ml of chloroform. The mixture was washed sequentially with a 4% sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution. Then, the chloroform layer was dried over anhydrous magnesium sulfate. After filtering the inorganic salt off, the filtrate was concentrated under reduced pressure to obtain a brown syrup. This syrup was purified by silica gel flash column chromatography (130 g of Wacogel C-300 and eluted with hexane/ethyl acetate (15/1). The eluate containing the desired product was collected and concentrated under reduced pressure to obtain 11.3 g of 1-bromo-2-(tetrahydropyran-2-yl)oxypropane as a colorless transparent volatile syrup.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[C:10]2[C:5](=[CH:6][C:7]([N+:22]([O-])=O)=[C:8]([NH:11][C:12](=O)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[N:4]([CH2:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:3]1=[O:34]>[Ni]>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[NH:11][C:8]3=[CH:9][C:10]4[C:2]([CH3:35])([CH3:1])[C:3](=[O:34])[N:4]([CH2:25][CH2:26][CH2:27][N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)[C:5]=4[CH:6]=[C:7]3[N:22]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])N(CCCN2CCOCC2)C(=O)C3(C)C)cc1
Agent: [Ni]
Product: COc1ccc(-c2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)N4CCCN2CCOCC2)cc1
Temperature: 100 °C

Procedure:
2-(4-Methoxy-phenyl)-7,7-dimethyl-5-(3-morpholin-4-yl-propyl)-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one is prepared from N-[3,3-dimethyl-1-(3-morpholin-4-yl-propyl)-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl]-4-methoxy-benzamide (575 mg) by hydrogenation at 70° C. as described in Example 1b using Raney-nickel (70 mg). The catalyst is filtered off and the filtrate is heated at 100° C. for 2 h. By adding concentrated ammonia the desired compound (360 mg) precipitates and is collected by filtration.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:16]([Mg]Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[NH4+]>C(OCC)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([OH:7])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][CH:15]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: Nc1ccc(C(O)(Cc2ccccc2)c2ccccc2)cc1
Reaction time: 18 h

Procedure:
Combine 4-aminobenzophenone (50 g, 0.25 mol) and diethyl ether (500 mL). Slowly, add benzylmagnesium chloride (1 L of a 1M solution in diethyl ether over 1.5 hours. After 18 hours, pour the reaction onto ice and an aqueous solution of ammonium chloride. Separate the layers, extract the organic layer with water, dry over MgSO4, filter, and evaporate in vacuo to give a residue. Recrystallize from isopropanol to give 1-(4-aminophenyl)-1,2-diphenyl-ethanol: mp; 105°-107° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][C:22]=2[C:31]([F:34])([F:33])[F:32])O1>>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=1[C:31]([F:32])([F:34])[F:33])[CH:11]=[CH:10]2
Reactant: Oc1ccc2nc(Cl)ccc2c1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C(F)(F)F)c1
Product: O=C(O)c1ccc(-c2ccc3cc(O)ccc3n2)c(C(F)(F)F)c1

Procedure:
Followed Scheme 3: starting with 2-chloroquinolin-6-ol and methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzoate (Intermediate 5). 1H NMR (DMSO-d6, 400 MHz): δ 10.21 (brs, 1H), 8.35-8.25 (m, 3H), 7.89 (d, J=9.2 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.38 (dd, J=9.2, 2.8 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H). MS (ESI): m/z 333.7 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[C:12]([CH3:24])=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[F:35][C:36]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[CH:38][C:37]=1[C:51]1[CH2:56][CH2:55][N:54]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:53][CH:52]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:35][C:36]1[CH:41]=[C:40]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[C:12]([CH3:24])=[N:13][N:14]([CH2:16][C:17]5[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=5)[CH:15]=4)=[CH:9][N:8]([S:25]([C:28]4[CH:29]=[CH:30][C:31]([CH3:32])=[CH:33][CH:34]=4)(=[O:26])=[O:27])[C:5]3=[N:6][CH:7]=2)[CH:39]=[CH:38][C:37]=1[C:51]1[CH2:56][CH2:55][N:54]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:53][CH:52]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cn(Cc4cccc(F)c4)nc3C)c3cc(Br)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2F)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cn(Cc4cccc(F)c4)nc3C)c3cc(-c4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Yield: 61.8 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-3-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (300 mg, 0.55 mmol) was coupled with tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (intermediate 70) (270 mg, 0.66 mmol) using sodium carbonate (175 mg, 1.65 mmol) and Pd(PPh3)2Cl2 (20 mg, 0.027 mmol) in DME/water (10/2.5 ml) to afford 250 mg (61.2% yield) of the pure product after column purification using 50% ethyl acetate in hexane as eluent. MS: m/z=736.4 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[C:6](=[C:10]([O:12][CH3:13])[CH:11]=1)[C:7]([OH:9])=[O:8].Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[NH:14][C:16](=[O:18])[O:9][C:7](=[O:8])[C:6]2=[C:10]([O:12][CH3:13])[CH:11]=1
Reactant: COc1cc(N)c(C(=O)O)c(OC)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)c2c(=O)oc(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 262.9 %

Procedure:
To a cooled (0° C.) brown solution of 4,6-dimethoxy anthranilic acid (76.0 g, 0.385 mol), [Newman, H.; Angier, R. B. J. Org. Chem., 1969, 34(11), 3484] in THF (1.3 L) was added triphosgene (40.0 g, 0.135 mol) in portions over a 20 min period. After 30 min, the reaction was warmed to room temperature and stirred for an additional 1.5 h. The reaction mixture was poured into cold (0° C.) water (4 L). Additional water (2 L) was added to facilitate the stirring of the thick solid formed. After stirring for 30 min, the reaction mixture was filtered to give a beige solid. The solid was washed with water, air-dried, and then dried under high vacuum to give 79.2 g (92%) of the 4,6-dimethoxyisatoic anhydride.
Reaction SMILES: O=[C:2]([CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:3]([OH:5])=O.[CH2:12]([C:19]1[C:20]([NH2:31])=[N:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([C:19]1[NH:24][C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:22][N:21]2[C:3](=[O:5])[C:2]([CH2:6][C:7]3[S:8][CH:9]=[CH:10][CH:11]=3)=[N:31][C:20]=12)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ncc(-c2ccccc2)nc1Cc1ccccc1
Reactant: O=C(O)C(=O)Cc1cccs1
Product: O=c1c(Cc2cccs2)nc2c(Cc3ccccc3)[nH]c(-c3ccccc3)cn1-2

Procedure:
Synthesized from method C using 2-oxo-3-(thiophen-2-yl)propanoic acid and 3-benzyl-5-phenylpyrazin-2-amine as starting materials. 1H NMR (300 MHz, dmso) δ 8.85 (s, 1H), 7.99 (d, J=6.8, 2H), 7.63-7.02 (m, 10H), 6.94 (dd, J=3.5, 5.1, 1H), 4.62 (s, 2H), 4.58 (s, 2H), 2.69 (contaminate); exact mass calculated for C24H20N3OS+ m/z+398.13, found m/z+398.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[C:6]([C:11]([O:13][CH3:14])=[O:12])=[N:7][CH:8]=[CH:9][CH:10]=1.N1C=CC=CC=1.[CH2:21]([O:28][C:29](ON1C(=O)CCC1=O)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[CH2:21]([O:28][C:29]([NH:1][CH2:2][CH2:3][NH:4][C:5]1[C:6]([C:11]([O:13][CH3:14])=[O:12])=[N:7][CH:8]=[CH:9][CH:10]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: COC(=O)c1ncccc1NCCN
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ncccc1NCCNC(=O)OCc1ccccc1

Procedure:
A solution of methyl 3-[(2-aminoethyl)amino]pyridine-2-carboxylate (3.9 g, 18.6 mmol) in CHCl3 (25 mL) was treated with pyridine (3 mL, 37.3 mmol) then 1-{[(benzyloxy)carbonyl]oxy}pyrrolidine-2,5-dione (Aldrich, 5.57 g, 22.3 mmol) for ½ hr. The reaction was quenched with water and extracted three times with CHCl3. The organic layer was dried with Na2SO4, filtered and evaporated to give an oil. The crude was purified on silical gel using an ISCO normal phase system and eluting with a gradient of 50% to 90% EtOAc Hexanes. The clean fractions were combined to give the product as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[Li]CCCC.CCCCCC.F[C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C1COCC1>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([NH:31][S:28]([C:25]2[CH:26]=[CH:27][C:22]([NH:1][CH2:2][CH2:3][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)=[CH:23][CH:24]=2)(=[O:30])=[O:29])=[CH:37][CH:36]=1
Reactant: O=S(=O)(Nc1ccc(Cl)cc1)c1ccc(F)cc1
Reactant: NCCN1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=S(=O)(Nc1ccc(Cl)cc1)c1ccc(NCCN2CCOCC2)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 62 %

Procedure:
N-(2aminoethyl)morpholine (293 μL, 2.25 mmol) was dissolved in THF (7.5 mL) and was cooled down to −78° C. A 2.5N solution of nBuLi in hexane (1 mL, 2.5 mmol) was added dropwise. After 5 min. at −78° C., the mixture was stirred 1 h at −40° C. N-aryl-benzenesulfonamide building block XIII, e.g. 4-fluoro-N-(4-chlorophenyl)benzenesulfonamide (214 mg, 0.75 mmol), was added as a solid. The reaction mixture was stirred 2 h at room temperature, then overnight at 60° C. The reaction was quenched at room temperature with NH4Cl saturated solution in water (5 mL). The desired product was extracted with three portions of ethyl acetate (3×10 mL). Combined organic phases were dried over magnesium sulfate before filtering and removal of solvent. The crude product was purified by flash chromatography, using pure ethyl acetate as eluent. The desired product, e.g. N-(4-chlorophenyl)-4-{[2-(4-morpholinyl)ethyl]amino}benzenesulfonamide (184.2 mg, 62% yield) was obtained as a colorless oil, in 97% purity by BPLC (MaxPlot detection between 230 and 400 nm). This intermediate was used in the next step without further purification.