Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:3]=1.[CH:12]1(/[CH:18]=[C:19](\B2OC(C)(C)C(C)(C)O2)/[CH2:20][OH:21])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[F-].[Cs+]>O1CCOCC1.C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:12]1(/[CH:18]=[C:19](\[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:3]=2)/[CH2:20][OH:21])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CS(=O)(=O)c1cccc(Br)c1
Reactant: CC1(C)OB(/C(=C\C2CCCCC2)CO)OC1(C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cccc(/C(=C\C2CCCCC2)CO)c1
Yield: 51.7 %

Procedure:
According to the procedure described for example 26b the use of 1-bromo-3-methanesulfonyl-benzene (1.07 g, 4.55 mmol), (E)-3-cyclohexyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-prop-2-en-1-ol (1.57 g, 5.92 mmol), caesium fluoride (2.07 g, 13.7 mmol) and tetrakis(triphenylphosphino)palladium(0) (525 mg, 455 μmol) in 40 mL dioxane with heating to reflux for 16 h gives a brown oil. Purify the crude product by column chromatography, eluting with a gradient from 100:0 to 0:100 hexanes:ethyl acetate to obtain (E)-3-cyclohexyl-2-(3-methanesulfonyl-phenyl)-prop-2-en-1-ol (693 mg) as a brown oil. MS (m/e): 277 [(M−H2O)+H].
Reaction SMILES: [CH3:1][C:2]([S:6]([CH3:9])(=[O:8])=[O:7])([CH3:5])[C:3]#[N:4].C(=O)=O.CC(C)=O.C([Li])CCC.CCCCCC.[F:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:30]=1[C:38](=[N:40][S:41]([C:43]([CH3:46])([CH3:45])[CH3:44])=[O:42])[CH3:39].C[Al](C)C>C1(C)C=CC=CC=1.C1COCC1>[C:3]([C:2]([S:6]([CH2:9][C:38]([NH:40][S:41]([C:43]([CH3:44])([CH3:46])[CH3:45])=[O:42])([C:30]1[CH:31]=[C:32]([N+:35]([O-:37])=[O:36])[CH:33]=[CH:34][C:29]=1[F:28])[CH3:39])(=[O:8])=[O:7])([CH3:5])[CH3:1])#[N:4]
Reactant: CC(=NS(=O)C(C)(C)C)c1cc([N+](=O)[O-])ccc1F
Reactant: CC(C)(C#N)S(C)(=O)=O
Agent: C[Al](C)C
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CC(CS(=O)(=O)C(C)(C)C#N)(NS(=O)C(C)(C)C)c1cc([N+](=O)[O-])ccc1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 59.6 %

Procedure:
A 100 ml RBF was charged with 2-methyl-2-(methylsulfonyl)propanenitrile (1.028 g, 6.99 mmol) and THF (15 ml). The solution was cooled to −78° C. (dry ice-acetone bath) and to it a butyllithium solution, 1.6 m in hexane (4.66 ml, 6.99 mmol) was added dropwise. The mixture was stirred for 20 min at −78° C. In the separate 50 ml flask solution of N-(1-(2-fluoro-5-nitrophenyl)ethylidene)-2-methylpropane-2-sulfinamide (1.00 g, 3.49 mmol) in toluene (10 ml) was cooled to −78° C. (dry ice acetone bath) and trimethylaluminum (2M in heptane) (1.921 ml, 3.84 mmol) was added. The mixture was stirred for 5 min, then transferred via syringe to the solution of the metallated sulfone (dropwise addition at −78° C.). The mixture was stirred for 1 hr at −78° C. The reaction mixture was quenched by addition of 1 ml saturated aqueous solution of Na2SO4 and the flask was removed from the bath, stirred for 40 min and diluted with 5 ml EtOAc. After filtering through pad of celite organic fractions were separated, concentrated and purified by FC on 12 g RediSep Gold column using 10-80% EtOAc in heptane to give desired N-(1-((2-cyanopropan-2-yl)sulfonyl)-2-(2-fluoro-5-nitrophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide (0.902 g, 2.081 mmol, 59.6% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1.C1(C)C=CC=CC=1>O1CCCC1>[F:24][C:25]([F:35])([F:36])[C:26]1[CH:27]=[C:28]([NH:32][C:33]([NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=2)[O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[N:11]=2)=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 55.7 %

Procedure:
A mixture of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (300 mg, 0.969 mmol), 3-(trifluoromethyl)phenyl isocyanate (667 μL, 4.84 mmol), toluene (4 mL) and tetrahydrofuran (1 mL) was stirred with heating under reflux for 3 hr. After the reaction mixture was allowed to cool to room temperature, the precipitate was collected by filtration and washed with ethyl acetate/diisopropyl ether to give the title compound (268 mg, 56%) as a white powder.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([N+:10]([O-])=O)[N:3]=1.O.NN>C(O)C.[C].[Pd]>[NH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[CH:2][N:3]=1
Reactant: COc1ccc([N+](=O)[O-])nc1Br
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(N)nc1
Temperature: 25 °C
Yield: 88 %

Procedure:
17.36 g (corresponding to 74.50 mmol) of 2-bromo-3-methoxy-6-nitropyridine was dissolved in 520 mL of ethanol, and 11.63 g (50% wet) of 10% palladium-carbon was added thereto under argon stream. To the mixture, 88.4 mL of hydrazine monohydrate was added dropwise. After the reaction mixture was refluxed for 45 minutes, the reaction solution was cooled down to room temperature. Then, after palladium-carbon was filtered off, the residue was washed with ethanol, and the washings were combined with the filtrate. The combined solution was concentrated under reduced pressure. Then, 402 mL of water and 38 mL of conc. aqueous ammonia were added to the concentrate, and the resulting mixture was extracted eight times with chloroform. The combined chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was distilled under reduced pressure to obtain 8.14 g (corresponding to 65.57 mmol) of 2-amino-5-methoxypyridine (FIG. 3, Step 3).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.[C:43]([CH:48]([CH:50]([C:52]([O:54][CH2:55][CH3:56])=[O:53])[OH:51])[OH:49])([O:45][CH2:46][CH3:47])=[O:44]>CCOCC>[F:31][C:30]([F:32])([F:33])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:51][CH:50]([CH:48]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[OH:49])[C:52]([O:54][CH2:55][CH3:56])=[O:53])=[O:11])=[CH:8][CH:7]=1
Reactant: CCOC(=O)C(O)C(O)C(=O)OCC
Reactant: O=C(Cl)c1ccc(N(CCCCCCCCCCCCCCCC(F)(F)F)C(=O)C(F)(F)F)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C(O)C(OC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1)C(=O)OCC

Procedure:
A mixture of 4-[N-trifluoroacetyl-15-(trifluoromethyl)pentadecylamino]benzoyl chloride and 1.2 g. triethylamine in 100 ml. warm ether is treated with 2.5 g. diethyl tartrate and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the product as a white, crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([CH3:13])[C:6]=2[C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([NH:12][C@H:10]([C:8]2[N:7]([CH3:13])[C:6]3[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH3:11])[N:25]=[CH:24][N:23]=1
Reactant: C[C@H](N)c1nc2ccc(F)c(-c3ccccn3)c2n1C
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(-c3ccccn3)c2n1C
Temperature: 90 °C
Yield: 69.9 %

Procedure:
(S)-1-(6-Fluoro-1-methyl-7-pyridin-2-yl-1H-benzoimidazol-2-yl)ethylamine (0.093 g, 0.35 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (53 mg, 0.35 mmol) and DIPEA (313 μL, 1.72 mmol) in IPA (5 mL) were added and the reaction mixture heated at 90° C. for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue purified by flash chromatography (Si—PPC, gradient 0-10% methanol in DCM) to give 411 as a white solid (95 mg, 72%). LCMS (Method K): RT 2.76 min [M+H]+ 389. 1H NMR (DMSO-d6, 400 MHz): δ 8.70 (1H, ddd, J=4.8, 1.7, 0.9 Hz), 7.98 (1H, s), 7.91 (1H, td, J=7.8, 1.8 Hz), 7.71-7.64 (2H, m), 7.60 (1H, dq, J=7.7, 0.9 Hz), 7.46 (1H, ddd, J=7.6, 4.9, 1.0 Hz), 7.26 (2H, br s), 7.11 (1H, dd, J=10.5, 8.8 Hz), 5.59 (1H, quin, J=7.3 HZ), 3.09 (3H, s), 1.53 (3H, d, J=6.8 Hz)
Reaction SMILES: C1C(=O)CC2C(=CC=CC=2)C1.[N-]=[N+]=[N-].[Na+].N#N.[CH2:18]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][CH2:21][C:20](=[O:29])[NH:19]1>OP(O)(O)=O.O>[CH2:21]1[C:22]2[CH:23]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:18][NH:19][C:20]1=[O:29]
Reactant: O=C1CCc2ccccc2CN1
Agent: N#N
Agent: O=C1CCc2ccccc2C1
Agent: O=P(O)(O)O
Solvent: O
Product: O=C1Cc2ccccc2CCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
beta-Tetralone (34 mmol) was suspended in 300 mL of 85% H3PO4 and treated portion wise with NaN3 (68 mmol) with vigorous stirring over a period of 1 h. During this time the reaction mixture was brought slowly to about 70° C. After stirring for a further 2 h at 70° C., no more N2 evolution was observed. The reaction mixture was cooled to RT, then poured into cold H2O (400 mL) and extracted with CHCl3 (3×). The organic layer was dried (MgSO4), concentrated and the residue was dissolved in EtOAc and the solid was filtered and washed with EtOAc to yield 4,5-dihydro-1H-benzo[d]azepin-2(3H)-one as a white solid (20% yield) along with a varying amount of the other region isomer 1,2,4,5-tetrahydrobenzo[c]azepin-3-one.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[Cl:12].[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>O1CCCC1>[Cl:12][C:4]1[CH:5]=[C:6]([NH2:9])[CH:7]=[CH:8][C:3]=1[CH2:2][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(CBr)c(Cl)c1
Solvent: C1CCOC1
Product: Nc1ccc(Cn2ccnc2)c(Cl)c1
Yield: 47 %

Procedure:
A solution of 10 g of 4-bromomethyl-3-chloro nitrobenzene and 5.44 g of imidazole in 125 ml of tetrahydrofuran was refluxed for 4 hrs. The solvent was removed and the residue was dissolved in ethyl acetate. The solution was washed with water and dried over magnesium sulfate. The solvent was removed and the residue was extracted several times with ether. The ether extracts were diluted with two volumes of hexanes. 1-(2-Chloro-4-nitrobenzyl)-1H-imidazole (4.3 g) crystallized as a white solid. A 4 g portion of this material was mechanically stirred at reflux with 153 ml of methanol, 52 ml of water, 8.1 g of ammonium chloride, and 6.6 g of iron powder for 2 hrs. The hot mixture was filtered and solids were washed with hot methanol-tetrahydrofuran mixtures. Solvents were removed from the combined filtrates. The residue was extracted several times with hot ethyl acetate, The ethyl acetate solution was treat with magnesium sulfate and activated charcoal. Filtering and removing the solvent gave the 3.9 g of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:60])[C@@H:5]([O:57][CH2:58][CH3:59])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[CH:15]=[C:16](\[CH3:56])/[C:17]#[C:18][C:19]2[CH:31]=[CH:30][C:29]3[C:28]4[C:23](=[CH:24][C:25]([C:32]#[C:33]/[C:34](/[CH3:54])=[CH:35]/[CH2:36][O:37][C:38]5[CH:43]=[CH:42][C:41]([CH2:44][C@H:45]([O:51][CH2:52][CH3:53])[C:46]([O:48]CC)=[O:47])=[CH:40][CH:39]=5)=[CH:26][CH:27]=4)[C:22](=[O:55])[C:21]=3[CH:20]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[C:46]([C@@H:45]([O:51][CH2:52][CH3:53])[CH2:44][C:41]1[CH:40]=[CH:39][C:38]([O:37][CH2:36]/[CH:35]=[C:34](\[CH3:54])/[C:33]#[C:32][C:25]2[CH:24]=[C:23]3[C:28]([C:29]4[CH:30]=[CH:31][C:19]([C:18]#[C:17]/[C:16](/[CH3:56])=[CH:15]/[CH2:14][O:13][C:10]5[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:57][CH2:58][CH3:59])[C:4]([OH:60])=[O:3])=[CH:12][CH:11]=5)=[CH:20][C:21]=4[C:22]3=[O:55])=[CH:27][CH:26]=2)=[CH:43][CH:42]=1)([OH:48])=[O:47]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)C#Cc2ccc3c(c2)C(=O)c2cc(C#C/C(C)=C/COc4ccc(C[C@H](OCC)C(=O)OCC)cc4)ccc2-3)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)C#Cc2ccc3c(c2)C(=O)c2cc(C#C/C(C)=C/COc4ccc(C[C@H](OCC)C(=O)O)cc4)ccc2-3)cc1)C(=O)O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
To a solution of (E)(E)(S)(S) 2-ethoxy-3-{4-[5-(7-{5-[4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenoxy]-3-methyl-pent-3-en-1-ynyl}-9-oxo-9H-fluoren-2-yl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-propionic acid ethyl ester (example 13) (185 mg, 0.23 mmol) in ethanol (10 mL) was added 1N sodium hydroxide (2.3 mL). After stirring at 60° C. for 30 min., the reaction mixture was concentrated in vacuo, added water and 1N hydrochloride acid to pH 1. The product was extracted with dichloromethane (×3) and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to give 160 mg of the title compound as a crystalline product.
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].Cl.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Cl)[CH:19]=1>CCO>[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][C:6]([NH:5][C:2](=[O:4])[CH3:3])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:19]=1
Reactant: ClCc1cccnc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cc1cccnc1)(NC(C)=O)C(=O)OCC
Yield: 30.2 %

Procedure:
Sodium metal (1.40 g, 61 mmol) was dissolved in EtOH (100 mL) containing diethyl acetamidomalonate (6.62 g, 30.5 mmol) and 3-picolyl chloride hydrochloride (5.00 g, 30.5 mmol) were added. The mixture was heated to reflux for 6 hr, and then cooled and filtered to remove NaCl (washed with EtOH). The solvent was removed in vacuo and the mixture was taken up into saturated aqueous NaHCO3 (100 mL) and extracted with EtOAc (3×100 mL). The solvent was removed and the residue purified by silica gel flash chromatography (95:5 CH2Cl2/MeOH) to give diethyl 2-(3-pyridylmethyl)-2-acetamidomalonate (2.84 g, 30%).
Reaction SMILES: [F:1][C:2]([F:11])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH2:3][OH:4].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:4][CH2:3][C:2]([F:1])([F:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: OCC(F)(F)c1ccccn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCC(F)(F)c2ccccn2)cc1

Procedure:
reacting 2,2-difluoro-2-pyridin-2-ylethanol with 4-toluenesulfonyl chloride to form 2,2-difluoro-2-pyridin-2-ylethyl 4-methylbenzenesulfonate, which is converted to compound of formula (K2); and
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:20].Br[C:22]1[CH:23]=[N:24][CH:25]=[C:26]([C:28]2([CH3:33])[O:32][CH2:31][CH2:30][O:29]2)[CH:27]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:22]3[CH:23]=[N:24][CH:25]=[C:26]([C:28]4([CH3:33])[O:32][CH2:31][CH2:30][O:29]4)[CH:27]=3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:20]
Reactant: CN1C(=O)Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CC1(c2cncc(Br)c2)OCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CN1C(=O)Cc2cc(-c3cncc(C4(C)OCCO4)c3)ccc21
Temperature: 105 °C

Procedure:
To 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (109 mg, 0.4 mmol), prepared as described in Example 3a, was added 3-bromo-5-(2-methyl-1,3-dioxolan-2-yl)pyridine (CAS#59936-01-5, 107 mg, 0.44 mmol), 1,2-dimethoxyethane (3.0 mL), and 2 M aqueous sodium carbonate (0.45 mL, 0.9 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (182 mg, 0.02 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 105° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 6%) to afford 1-methyl-5-[5-(2-methyl-[1,3]-dioxolan-2-yl)-pyridin-3-yl]-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 311.1395 (M+H)+; 1H NMR (400 MHz, CDCl3) δppm 1.73 (s, 3H), 3.28 (s, 3H), 3.62 (s, 2H), 3.82-3.88 (m, 2H), 4.08-4.16 (m, 2H), 6.94 (d, J=7.8 Hz, 1H), 7.49-7.58 (m, 2H), 7.97 (s, 1H), 8.71 (d, J=2.0 Hz, 1H), 8.77 (d, J=2.3 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][CH2:25][C:24]1[CH:27]=[CH:28][C:21]([Cl:20])=[CH:22][CH:23]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCc1ccc(Cl)cc1
Yield: 85 %

Procedure:
The compound prepared in Example 3 was reacted with 4-chloro-benzylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 85%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:29].[K+].[K+].C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:27])=[O:29])=[CH:22][CH:21]=3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: CSc1ccc(-c2nc(-c3cccc(C)c3)c(-c3ccnc(C)c3)s2)cc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc(-c2nc(-c3ccc(S(C)=O)cc3)sc2-c2ccnc(C)c2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 26.5 %

Procedure:
To a solution of 4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-2-[4-(methylthio)phenyl]-1,3-thiazole (0.55 g, 1.4 mmol) in acetic acid (15 mL) was added a solution of potassium persulfate (0.43 g, 1.6 mmol) in water (8 mL), and the mixture was stirred for 14 hours at room temperature. An aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and extracted with ethyl acetate. The extracts were washed with water, dried, then, the solvent was distilled off. The residue was purified by column chromatography (filler: Chromatorex NH DM1020 (trade name, manufactured by Fuji Silysia Chemical Ltd.), hexane-ethyl acetate=1:4), and recrystallized from ethyl acetate-hexane to obtain a title compound (0.15 g, yield 26%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12]([CH:14]([CH2:18][CH2:19][CH2:20][CH3:21])[C:15](Cl)=[O:16])[CH3:13].C(Cl)Cl.O>N1C=CC=CC=1>[CH2:12]([CH:14]([CH2:18][CH2:19][CH2:20][CH3:21])[C:15]([NH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11])=[O:16])[CH3:13]
Reactant: CCCCC(CC)C(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC(CC)C(=O)Nc1cc([N+](=O)[O-])ccc1O
Reaction time: 1 h

Procedure:
77 g 2-amino-4-nitrophenol were dissolved in 1600 ml pyridine. 81 g 2-ethylhexanoic acid chloride were added at 15 C. over 1 hour and the batch was subsequently heated at 35 C. for 5 hours. 250 ml methylene chloride and 700 ml water were added thereto, and the organic phase was washed with water and dilute hydrochloric acid and dried over Na2SO4, and the solvent was distilled off. The crude product was purified by means of column chromatography (silica gel 60, mobile phase toluene/ethyl acetate (4:1)) and was recrystallised from aqueous ethanol: 39 g of yellow solid with a melting point of 151 to 152 C.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:22][CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[NH:26][C:25]1=[O:33].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(C(C)=O)C(C)C>[OH:8][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH2:22][CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[NH:26][C:25]2=[O:33])[CH2:11][CH2:10]1
Reactant: O=c1[nH]c2ccccc2n1CCBr
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccccc2n1CCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 2.7 g (0.01 mole) of alpha,alpha-diphenyl-4-piperidinemethanol, 2.4 g (0.01 mole) of 1-(1-bromo-2-ethyl)-2-benzimidazolone, 1.2 g of sodium carbonate (Na2CO3), and a crystal of sodium iodide in 75 ml of methyl isobutyl ketone is heated at reflux temperature for 18 h.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[NH:30][C:13]2=[CH:14][C:15]3[C:16](=[O:29])[N:17]([C:22]4[CH:23]=[N:24][C:25]([F:28])=[CH:26][CH:27]=4)[C:18](=[O:21])[C:19]=3[CH:20]=[C:12]2[N:11]=1.Cl.[F:32][C:33]1[C:38]([F:39])=[CH:37][C:36]([F:40])=[C:35]([F:41])[C:34]=1[CH2:42][C@@H:43]([NH2:45])[CH3:44].C(N(CC)C(C)C)(C)C>O1CCOCC1.C(O)CCC>[F:28][C:25]1[N:24]=[CH:23][C:22]([N:17]2[C:16](=[O:29])[C:15]3[CH:14]=[C:13]4[NH:30][C:10]([C:3]5[C:4](=[O:8])[NH:5][CH:6]=[CH:7][C:2]=5[NH:45][C@@H:43]([CH3:44])[CH2:42][C:34]5[C:35]([F:41])=[C:36]([F:40])[CH:37]=[C:38]([F:39])[C:33]=5[F:32])=[N:11][C:12]4=[CH:20][C:19]=3[C:18]2=[O:21])=[CH:27][CH:26]=1
Reactant: C[C@H](N)Cc1c(F)c(F)cc(F)c1F
Reactant: COc1nccc(Cl)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(c1ccc(F)nc1)C3=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cc1c(F)c(F)cc(F)c1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(c1ccc(F)nc1)C3=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
2-(4-Chloro-2-methoxypyridin-3-yl)-6-(6-fluoropyridine-3-yl)imidazo[4,5-f]isoindole-5,7(1H, 6H)-dione (0.15 g, 0.35 mmol) was dissolved in 10 mL of 1,4-dioxane and 5 mL of concentrated HCl at rt. The reaction mixture was stirred at rt overnight. Then, the volatile was removed to give a yellow-brown solid. This solid was mixed with (S)-1-(2,3,5,6-tetrafluorophenyl)propan-2-amine (55 mg, 0.26 mmol), N,N-diisopropylethylamine (1 mL) and n-butanol (20 mL) in a flask. The reaction mixture was stirred and heated to reflux overnight under argon. Then, volatiles were removed under reduced pressure. The residue solid was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a yellow-brown solid product, 80 mg, 63.0% yield. MS: 578.8 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 13.48 (s, 1H), 11.35 (d, 1H, J=6.0 Hz), 10.91 (d, 1H, J=8.5 Hz), 8.40 (d, 1H, J=2.0 Hz), 8.26 (s, 1H), 8.18-8.14 (m, 1H), 8.04 (s, 1H), 7.77-7.70 (m, 1H), 7.42-7.39 (m, 2H), 6.19 (d, 1H, J=7.5 Hz), 4.27-4.24 (m, 1H), 3.18-3.10 (m, 2H), 1.39 (d, 3H, J=6.0 Hz).