Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[NH:31]1[CH2:36][CH2:35][S:34](=[O:38])(=[O:37])[CH2:33][CH2:32]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[O:37]=[S:34]1(=[O:38])[CH2:35][CH2:36][N:31]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:30])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:16])([CH3:17])[C:10]=3[CH:18]=2)[CH2:32][CH2:33]1
Reactant: O=S1(=O)CCNCC1
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)c2cc(N3CCS(=O)(=O)CC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Trifluoro-methanesulfonic acid 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester (Compound B1, 30 mg, 0.069 mmol) was dissolved in 1,4-dioxane (1 mL), added with thiomorpholine 1,1-dioxide (19 mg, 2 eq.), Pd2 (dba)3 (6.3 mg, 0.1 eq.), BINAP (8.6 mg, 0.2 eq.) and K3PO4 (29 mg, 2 eq.), and stirred at 100° C. overnight. The reaction solution was added to water, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the target compound (white powder, 2.1 mg, 7%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.CC(C)([O-:15])C.[K+].Cl>C(O)(C)(C)C>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([OH:15])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)[O-]
Reactant: FC(F)(F)c1cccc(Cl)n1
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: Oc1cccc(C(F)(F)F)n1
Yield: 62.2 %

Procedure:
2-Chloro-6-trifluoromethylpyridine (5.0 g, 27.6 mmol) was dissolved in tert-butyl alcohol (135 mL). Potassium tert-butoxide (25.0 g, 220 mmol) was added and the mixture was refluxed under nitrogen for 20 h. After cooling, cold 3N HCl was carefully added to the flask until the pH was approximately 1-2. The resulting solution was extracted several times with methylene chloride. The organic layers were dried (MgSO4) and evaporated. This residue was then treated with trifluoroacetic acid 1.5 mL) at 80° C. for 2 h. The solution was neutralized with aqueous sodium bicarbonate and extracted several times with methylene chloride. The organic layer was dried (MgSO4), filtered and evaporated in-vacuo. The residue was recrystallized from methylene chloride and hexane to give 6-trifluoromethyl-2-pyridinol (2.8 g, 62% yield) as a white solid, mp=117° C. -118 ° C. Anal. Calcd. for C6H4NOF3 : C, 44.19; H, 2.47; N, 8.59
Reaction SMILES: Cl.[CH:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:18])([C:15]([OH:17])=[O:16])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:7]=1.[CH2:19]([O:21]CC)[CH3:20]>>[C:19]([C:6]1[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=1[C:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([OH:18])[C:15]([OH:17])=[O:16])(=[O:21])[CH3:20]
Reactant: CCOCC
Reactant: O=C(O)C(O)(c1ccccc1)c1ccccc1
Agent: Cl
Product: CC(=O)c1ccccc1C(O)(C(=O)O)c1ccccc1

Procedure:
Acetyl chloride (35 mL, 490 mmol) was added dropwise to a solution of benzilic acid (100 g, 438 mmol) in 300 mL THF over a period of five minutes. The solution was cooled to 0° C. and pyridine (70 mL, 865 mmol) was added dropwise over a period of 30 minutes, during which time a thick white precipitate developed. The ice bath was removed, the reaction flask was equipped with a CaCl2 drying tube and stirred overnight. The next day, the solution was filtered to isolate a white precipitate and the yellow THF supernatant was concentrated to a turbid oil. Most of the product was isolated in the precipitate as the pyridinium acetylbenzilate salt, but some was retained in the supernatant. The precipitate and oil were added to a large separatory funnel charged with 1000 mL diethyl ether and 400 mL of 1.2M HCl. The contents were thoroughly mixed, the aqueous portion separated and discarded. The ether solution was washed twice with 400 mL 1.2M HCl, once with 300 mL saturated NaCl solution, dried over MgSO4, filtered and concentrated to approximately 200 mL. The product was precipitated by addition of 800 mL hexanes, isolated by filtration, and air dried overnight. Yield 88 g (74%). 1H NMR (CDCl3): δ7.1-7.7 (m, 10H ArH), 5.7 (s, 3H, COOH), 2.08 (s, 3H, RO(O)CCH3). This synthesis could be easily modified by one of skill in the art to incorporate a thiol or amino analog of benzylic acid.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[CH:9]=2)[NH:4][CH:3]=1.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Na+]>C1C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:20]1([S:26]([N:4]2[C:5]3=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=4)[CH:9]=[C:10]3[C:2]([I:1])=[CH:3]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN(C)c1ccc(-c2cnc3[nH]cc(I)c3c2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CN(C)c1ccc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccccc2)cc1
Reaction time: 8 h
Yield: 64.1 %

Procedure:
To a solution of 2 (6.00 g, 16.5 mmol) in benzene (100 mL) was added benzenesulfonyl chloride (4.85 mL, 38.0 mmol), tetra-n-butylammonium bromide (2.82 g, 8.76 mmol) and 50% aqueous NaOH (18.5 mL), and the reaction mixture was stirred overnight. The mixture was partitioned between water—benzene. The layers were separated and the aqueous layer was extracted with benzene (5×100 mL). The combined organic extracts were dried (MgSO4) and concentrated to give orange oil, which solidified on drying in vacuum. The solid was triturated with methanol (200 mL) for 0.5 h, filtered off, and washed with ice-cold methanol (3×50 mL) to give product 3 as a tan solid (5.32 g, 64%); 1H NMR (400 MHz, CDCl3) δ 3.01 (s, 6H), 6.81 (d, J=8.9 Hz, 2H), 7.45-7.60 (m, 4H), 7.59 (tt, J=14.8, 2.1 Hz, 1H), 7.74 (d, J=2.1 Hz, 1H), 7.86 (s, 1H), 8.24 (d, J=7.6 Hz, 2H), 8.64 (d, J=2.1 Hz, 1H); MS (CI) m/z 504.10 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:5]=1[NH:16][C:17](=[O:28])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])([O-])=O.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:5]=1[NH:16][C:17](=[O:28])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)CCCCCCC(=O)Nc1cc(-c2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)CCCCCCC(=O)Nc1cc(-c2ccccc2)ccc1N
Yield: 85 %

Procedure:
To a solution of methyl 8-(4-nitrobiphenyl-3-ylamino)-8-oxooctanoate (270 mg, 0.70 mmol) and ammonium formate (177 mg, 2.8 mmol) in methanol was added catalytic amount of palladium on carbon (5%). The mixture was heated to reflux under a nitrogen atmosphere overnight and filtered. The filtrate was concentrated and purified by biotage column chromatography to give methyl 8-(4-aminobiphenyl-3-ylamino)-8-oxooctanoate (211 mg)
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])=[N:10][C:9]=2[CH:23]=1)=[O:4].[Br-].[Al+3].[Br-].[Br-].O.Cl>CSC.ClCCl>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[O:14][CH2:13][C:11]1[O:12][C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:23][C:9]=2[N:10]=1
Reactant: COC(=O)c1ccc2oc(COc3ccc(Cl)cc3Cl)nc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Solvent: CSC
Product: O=C(O)c1ccc2oc(COc3ccc(Cl)cc3Cl)nc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 73.1 %

Procedure:
To a solution of 2-(2,4-dichloro-phenoxymethyl)-benzooxazole-5-carboxylic acid methyl ester (60.0 mg, 0.17 mmol) in dimethyl sulfide (5 ml) and dichloromethane (5 ml) was added aluminum bromide (725.5 Mg, 2.72 mmol). The reaction mixture was stirred at room temperature for 2.5 h, after which water and 10% HCl were added. After stirring at room temperature for 1 h, the mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (CH2Cl2:MeOH=4:1) to give 2-(2,4-dichloro-phenoxymethyl)-benzoxazole-5-carboxylic acid as a white solid (42.0 mg, 72.9% yield).
Reaction SMILES: [O:1]1[CH2:7][CH:6]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16](B4OC(C)(C)C(C)(C)O4)=[CH:15][C:14]=3[N+:28]([O-:30])=[O:29])=[C:11]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:10]=[N:9]2)[CH2:5][O:4][CH2:3][CH2:2]1.O1[CH2:41][CH2:40][O:39][CH2:38]C1>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>[O:4]1[CH2:5][CH:6]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:41]4[C:40]([O:39][CH3:38])=[N:8][C:12]([CH3:11])=[CH:13][C:14]=4[CH3:15])=[CH:15][C:14]=3[N+:28]([O-:30])=[O:29])=[C:11]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:10]=[N:9]2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: C1COCCO1
Reactant: CCOC(=O)c1cnn(C2COCCOC2)c1-c1ccc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)c1cnn(C2COCCOC2)c1-c1ccc(-c2c(C)cc(C)nc2OC)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Water (0.3 mL), 3-bromo-2-methoxy-4,6-dimethylpyridine (32.5 mg) obtained in Preparation Example 26, Pd(PPh3)4 (7.2 mg) and cesium carbonate (122 mg) were added to a solution of ethyl 1-(1,4-dioxepan-6-yl)-5-[2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1H-pyrazole-4-carboxylate (61 mg) in 1,4-dioxane (1.2 mL), and the reaction mixture was stirred at 100° C. for 4 hours. Pd(PPh3)4 (7.2 mg) was added to the reaction mixture, and the reaction mixture was stirred at 100° C. for 1 hour and 10 minutes. The reaction mixture was returned to room temperature and partitioned by adding ethyl acetate and water, and the organic layer was separated. The resulting organic layer was sequentially washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 15 to 20%) to give the title compound (15 mg).
Reaction SMILES: C1(S(O[CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)(=O)=O)C=CC=CC=1.[C:24]([O:32][CH2:33][CH3:34])(=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].CC[O-].[Na+].CCO>CCO>[CH2:29]([O:28][C:26](=[O:27])[CH:25]([CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:15][CH2:16]1)[C:24]([O:32][CH2:33][CH3:34])=[O:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(=O)(=O)c2ccccc2)CC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 22 h

Procedure:
A mixture of 1-tert-butoxycarbonylpiperidin-4-ol, triethylamine, benzenesulfonyl chloride, and methylene chloride was stirred at ambient temperature for 2 days to yield 1-tert-butoxycarbonylpiperidin-4-yl benzenesulfonate. A mixture of 1-tert-butoxycarbonylpiperidin-4-yl benzenesulfonate obtained, diethyl malonate, 20% NaOEt-EtOH, and EtOH was heated under reflux with stirring for 22 hours to yield diethyl[1-(tert-butoxycarbonyl)piperidin-4-yl]malonate. A mixture of diethyl [1-(tert-butoxycarbonyl)piperidin-4-yl]malonate obtained, lithium borohydride, toluene, and THF was stirred at 60° C. for 18 hours to yield 2-(1-tert-butoxycarbonylpiperidin-4-yl)propane-1,3-diol, which was stirred together with 4M HCl-dioxane solution in MeOH at ambient temperature for 1 hour to yield 2-piperidin-4-ylpropane-1,3-diol hydrochloride.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][CH:10]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[CH2:11]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[O:4][CH2:3][CH:2]([OH:1])[CH2:15][N:27]1[CH2:26][CH2:25][N:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH3:16])[CH2:29][CH2:28]1)[C:12](=[O:14])[CH3:13]
Reactant: CC(=O)Cc1cccc(OCC2CO2)c1
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(CC(O)COc2cccc(CC(C)=O)c2)CC1

Procedure:
3-(2,3-Epoxypropoxy)-phenylacetone is reacted with 2-methoxyphenylpiperazine analogously to Example 2(a). 1-[3-(Propan-2-on-yl)-phenoxy]-3-[4-(2-methoxyphenyl)-piperazin-1-yl]-propan-2-ol is obtained as a syrupy product.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17]Cl)[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:20]([CH:22]([CH2:26][CH2:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[N:1]1[N:2]([C:10]2[C:11]([OH:19])=[C:12]([CH:13]=[C:14]([CH3:16])[CH:15]=2)[CH2:17][O:25][C:23](=[O:24])[CH:22]([CH2:20][CH3:21])[CH2:26][CH2:27][CH2:28][CH3:29])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Cc1cc(CCl)c(O)c(-n2nc3ccccc3n2)c1
Reactant: CCCCC(CC)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(CC)C(=O)OCc1cc(C)cc(-n2nc3ccccc3n2)c1O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
2-(2H-Benzotriazol-2-yl)-6-chloromethyl-4-methyl-phenol (10.0 g, 33 mmol) is suspended in a mixture of 2-ethylhexanoic acid (11.9 g, 82 mmol) and tetrahydrofuran (75 g) and stirred at 70° C. for 30 minutes. Sodium carbonate (10.5 g, 99 mmol) is added. The reaction mixture is stirred at 60° C. for 15 minutes and evaporated to dryness. The residue is dissolved in ethyl acetate and extracted with an aqueous potassium carbonate solution (10%) and brine. The organic layer is dried over sodium sulphate, filtered and evaporated to dryness. The crude product is purified by column chromatography (ethyl acetate/heptane 1:12) to yield 11.2 g of 2-Ethyl-hexanoic acid 3-(2H-benzotriazol-2-yl)-2-hydroxy-5-methyl-benzyl ester.
Reaction SMILES: [Mg].[O:2]=[C:3]([CH3:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[N+:13]([C:16]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19])([O-:15])=[O:14].Cl>C(O)C.CCOCC.C(Cl)(Cl)(Cl)Cl>[N+:13]([C:16]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:17]=1[C:18]([CH:4]([C:3](=[O:2])[CH3:12])[C:5]([O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:6])=[O:19])([O-:15])=[O:14]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Mg]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Solvent: CCOCC
Product: CC(=O)C(C(=O)OC(C)(C)C)C(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A mixture of magnesium turnings (4.8 g) and carbon tetrachloride (2 ml) in pure ethanol (30 ml) was stirred and warmed gently to 50° C. until the reaction was initiated (effervescence observed). Ether (100 ml) was added cautiously with stirring. A solution of t-butyl 3-oxobutanoate (31.6 g) in ether (100 ml) was added dropwise at such a rate as to maintain the mixture at reflux. Stirring and heating at reflux was continued for 2 hours. A solution of 2-nitro-4-trifluoromethylbenzoyl chloride (50.7 g) in ether (100 ml) was added dropwise and the resultant solution was stirred and heated at reflux for 25 hours. The cooled reaction mixture was treated with hydrochloric acid (2M, 100 ml) with stirring and the two layers were separated. The organic phase was extracted with aqueous sodium hydroxide solution (2M, 2×50 ml) and water (4×50 ml). The combined aqueous layers were acidified to pH 1 and extracted with ether (2×100 ml). The combined organic layers were washed with water (50 ml), dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness to give t-butyl 2-(2-nitro-4-trifluoromethylbenzoyl)-3-oxobutanoate (62.2 g) as a crude red oil which was not further purified.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([NH2:9])=[O:8])[NH:5][CH:6]=1.[C:10]([NH:14][C:15]1[C:24]([CH3:25])=[N:23][C:22]2[C:17](=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:19]=[CH:20][CH:21]=2)[N:16]=1)([CH3:13])([CH3:12])[CH3:11].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O>[C:10]([NH:14][C:15]1[C:24]([CH3:25])=[N:23][C:22]2[C:17]([N:16]=1)=[C:18]([C:2]1[CH:3]=[C:4]([C:7]([NH2:9])=[O:8])[NH:5][CH:6]=1)[CH:19]=[CH:20][CH:21]=2)([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1nc2cccc(B3OC(C)(C)C(C)(C)O3)c2nc1NC(C)(C)C
Reactant: NC(=O)c1cc(Br)c[nH]1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2cccc(-c3c[nH]c(C(N)=O)c3)c2nc1NC(C)(C)C
Temperature: 100 °C
Reaction time: 16.5 h
Yield: 50.7 %

Procedure:
A mixture of 4-bromo-1H-pyrrole-2-carboxamide (100 mg, 0.529 mmol), N-(tert-butyl)-3-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxalin-2-amine (174b; 311 mg, 0.529 mmol), K3PO4 (337 mg, 1.587 mmol), XPhos (Strem Chemicals, Inc.; 25.2 mg, 0.053 mmol), and (Aldrich; 24.22 mg, 0.026 mmol) in a mixture of dioxane (4.0 mL) and water (1.0 mL) was stirred under argon at 100° C. for 16.5 h. The reaction mixture was then concentrated onto silica gel and chromatographically purified (silica gel, 0-100% EtOAc/hexanes) to provide 4-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-2-carboxamide (86.7 mg, 0.268 mmol, 51% yield) as a light-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (1H, br. s.), 7.78 (1H, dd, J=2.6, 1.5 Hz), 7.61 (1H, dd, J=7.3, 1.3 Hz), 7.54 (1H, dd, J=8.1, 1.5 Hz), 7.44 (1H, br. s.), 7.31 (1H, t, J=7.7 Hz), 7.22-7.26 (1H, m), 6.94 (1H, br. s.), 5.78 (1H, s), 2.53 (3H, s), 1.53 (9H, s). m/z (ESI, +ve) 324.0 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH2:20][CH3:21])[C:14]=1[C:15](OCC)=[O:16])[CH3:8]>C1COCC1>[CH2:20]([C:13]1[CH:12]=[N:11][CH:10]=[C:9]([CH2:7][CH3:8])[C:14]=1[CH2:15][OH:16])[CH3:21]
Reactant: CCOC(=O)c1c(CC)cncc1CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cncc(CC)c1CO
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a suspension of LAH (0.805 g, 21.22 mmol) in anhydrous THF (20 mL) at 0° C. was added a dropwise a solution of ethyl 3,5-diethylpyridine-4-carboxylate (2.20 g, 10.61 mmol) in THF (30 mL). After stirring for 1 hour, the reaction mixture was slowly quenched with 15% NaOH solution and then diluted with water. Ethyl acetate was added, the mixture was stirred for 10 minutes, and the precipitated white solid was filtered off. The solid was washed with ethyl acetate (2×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to provide (3,5-diethylpyridin-4-yl)methanol as a thick oil (1.50 g, 86% yield) which was used for the next step without any further purification; 1H NMR (400 MHz, DMSO-d6): δ 1.15 (t, 6H), 2.70 (q, 4H), 4.50 (s, 2H), 5.06 (bs, 1H), 8.22 (s, 2H), M+ 208.5; M+ 166.2.
Reaction SMILES: [F:1][C:2]1[C:7](/[CH:8]=[CH:9]\[Sn](CCCC)(CCCC)CCCC)=[CH:6][CH:5]=[CH:4][N:3]=1.[F:23][C:24]1[C:29](I)=[CH:28][CH:27]=[CH:26][N:25]=1>C1(C)C=CC=CC=1.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:23][C:24]1[C:29](/[CH:9]=[CH:8]\[C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: CCCC[Sn](/C=C\c1cccnc1F)(CCCC)CCCC
Reactant: Fc1ncccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: Fc1ncccc1/C=C\c1cccnc1F

Procedure:
A mixture of Z-2-fluoro-3-(2-tributylstannylethenyl)pyridine (1.39 g), 2-fluoro-3-iodopyridine (0.75 g) and bis(triphenylphosphine)palladium dichloride (0.010 g) in toluene (20 mL) was refluxed under argon for 4 hours. Most of the solvent was evaporated and the residue was treated overnight with aqueous potassium fluoride. The organic phase was dried and evaporated to give Z-1,2-di-(2-fluoropyridinyl)ethylene as a solid which was recrystallized from hexane/ethyl acetate (0.47 g) mp 93°-95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[C:32]([S:37](Cl)(=[O:39])=[O:38])[CH:33]=[C:34]([F:36])[CH:35]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[S:37]([C:32]2[CH:31]=[C:30]([F:29])[CH:35]=[C:34]([F:36])[CH:33]=2)(=[O:39])=[O:38])=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Product: O=C1OC2(CCN(C(=O)c3cn(S(=O)(=O)c4cc(F)cc(F)c4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure VII as described above, the sulphonylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with commercially available 3,5-difluorobenzenesulfonyl chloride gave the title compound. ES-MS m/e (%): 575.3(M+H+).
Reaction SMILES: CS(O[CH2:6][C@@:7]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Br:26])[CH:20]=1)([OH:18])[CH2:8][CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])(=O)=O.[K].C1(=O)[NH:32]C(=O)C2=CC=CC=C12.[Cl-].[NH4+].O.NN>CN(C=O)C.C(OCC)(=O)C>[NH2:32][CH2:6][C@@:7]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Br:26])[CH:20]=1)([OH:18])[CH2:8][CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)[Si](C)(C)OCC[C@](O)(COS(C)(=O)=O)c1ccc(F)c(Br)c1
Agent: NN
Agent: [Cl-]
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCC[C@](O)(CN)c1ccc(F)c(Br)c1
Temperature: 25 °C
Yield: 114.7 %

Procedure:
The compound (1.79 g, 3.80 mmol) obtained in Example 91e was dissolved in N,N′-dimethylformamide (60 mL), the mixture was stirred at room temperature, a potassium salt of phthalimide (1.41 g, 7.60 mmol) was added, and the mixture was stirred at 110° C. for 18 hours. After the reaction was completed, saturated aqueous ammonium chloride was added to the reaction mixture under ice cooling, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue (3.0 g) was dissolved in ethanol (60 mL), the mixture was stirred at room temperature, hydrazine monohydrate (0.74 mL, 15.2 mmol) was added, and the mixture was stirred at 60° C. for 3.5 hours. After the reaction was completed, the reaction mixture was filtered, and the filtrate was washed with ethyl acetate. The solvent was evaporated under reduced pressure to give the crude title compound (1.71 g) as a pale yellow oily substance.