Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:17]=[C:16](Br)[C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[C:13](=[O:23])[C:12]=2[CH:24]=1.BrC1C=CC2C(Br)=CC3C=CC=CC=3C(=O)C=2C=1.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>C(O)(C)(C)C>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[C:17]([N:47]3[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]3)=[CH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[C:13](=[O:23])[C:12]=2[CH:24]=1
Reactant: CN1CCNCC1
Reactant: O=c1c2cc(Br)ccc2cc(Br)c2ccccc12
Agent: CC(C)(C)[O-]
Agent: O=c1c2ccccc2cc(Br)c2ccc(Br)cc12
Agent: [K+]
Solvent: CC(C)(C)O
Product: CN1CCN(c2cc3ccccc3c(=O)c3cc(Br)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium tert-butoxide (6.8 g., 0.06 mole) was added to a stirred slurry of 3,10-dibromo-5H-dibenzo[a,d]cyclohepten-5-one and 3,11-dibromo-5H-dibenzo[a,d]cyclohepten-5-one (18.2 g., 0.05 mole), 4-methylpiperazine (10 ml.), and dry tert-butyl alcohol (200 ml.) at room temperature and under nitrogen. The dark orange mixture was heated to refluxing for 2 hours and then stirred at room temperature overnight. The mixture was poured into approximately 800 ml. of ice and water and extracted with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated. The mixture of 3-bromo-10-(4-methylpiperazinyl)-5H-dibenzo[a,d]cyclohepten-5-one and 3-bromo-11-(4-methylpiperazinyl)-5H-dibenzo[a,d]cyclohepten-5-one was obtained as a residual red-yellow gum; yield, 19.4 g. 100%.
Reaction SMILES: O[N:2]1[CH2:5][CH:4]([NH:6][C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[C:3]1=[O:17].O.[OH-].[Na+]>O1CCCC1.[Cl-].[Cl-].[Cl-].[Ti+3]>[C:7]([NH:6][CH:4]1[CH2:5][NH:2][C:3]1=[O:17])([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8]
Reactant: O=C(NC1CN(O)C1=O)OCc1ccccc1
Agent: [Ti+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1CNC1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
A solution of 118 mg (0.5 mmole) of N-hydroxy-3-(Cbz-amino)-2-azetidinone, prepared as described by Example 3, in 10 ml of tetrahydrofuran and 10 ml of water at pH 7 was added to a flask equipped with a magnetic stirrer, a buret, and a pH electrode. The solution was maintained under nitrogen and was treated with a solution of 0.8 ml of 20% titanium trichloride by dropwise addition from a syringe. The pH of the reaction mixture was maintained at 7.0 during the addition of the TiCl3 by the addition of 3.0N sodium hydroxide through the buret as needed. After the addition was complete the reaction mixture was stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to 8.0, transferred to a separatory funnel and extracted with three 25 ml portions of ethyl acetate. The combined ethyl acetate was washed with 10 ml of brine, dried over magnesium sulfate, filtered and evaporated to dryness. The residue was recrystallized from ethyl acetate-hexanes to give 69 mg (60%) of 3-(Cbz-amino)-2-azetidinone as a white solid melting at about 160° C. to about 161° C.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C>[CH2:20]([N:10]1[C:9]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[CH:7][C:8]=2[C:14](=[O:15])[NH:13][CH2:12][CH2:11]1)[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: O=C1NCCNc2c1cccc2[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1CCNC(=O)c2cccc([N+](=O)[O-])c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
9-Nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (763 mg, 3.67 mmol) was dissolved in anh DMF (10 ml). NaH (60% dispersion in mineral oil) (147 mg, 3.67 mmol) was added followed by allyl bromide (310 μL, 3.67 mmol). The resulting mixture was stirred at rt for 2 h. Reaction mixture was concentrated, diluted with CH2Cl2, and washed with H2O. The organic layer was dried over MgSO4, filtered, concentrated, and purified with silica gel chromatography (0-100% EtOAc in hexanes) to afford 1-Allyl-9-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one as an orange solid (647 mg, 71%). mp 80-82° C.; LCMS: m/z=248.27 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.67 (m, 1H), 8.30 (dd, J=8.3 Hz, 1.5 Hz, 1H), 8.17 (dd, J=7.6 Hz, 1.5 Hz, 1H), 6.78 (t, J=7.8 Hz, 1HO, 5.85 (m, 1H), 5.29 (m, 2H), 4.22 (m, 2H), 3.74 (m, 2H), 3.58 (m, 2H).
Reaction SMILES: [H-].[Na+].[Cl-].[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:5]=1.CN(C)C=O.[Cl:35][C:36]1[CH:65]=[CH:64][C:39]([CH2:40][N:41]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH2:51][C:52]4[CH:61]=[CH:60][C:59]5[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=5)[N:53]=4)=[CH:47][CH:48]=3)[C:43]([CH:62]=O)=[CH:42]2)=[CH:38][CH:37]=1>O.C(OCC)(=O)C>[Cl:35][C:36]1[CH:37]=[CH:38][C:39]([CH2:40][N:41]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH2:51][C:52]4[CH:61]=[CH:60][C:59]5[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=5)[N:53]=4)=[CH:47][CH:48]=3)[C:43]([CH:62]=[CH:10][C:6]3[CH:5]=[N:4][CH:9]=[CH:8][CH:7]=3)=[CH:42]2)=[CH:64][CH:65]=1
Reactant: O=Cc1cn(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc12
Reactant: c1ccc([P+](Cc2cccnc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1ccc(Cn2cc(C=Cc3cccnc3)c3cc(OCc4ccc5ccccc5n4)ccc32)cc1
Reaction time: 0.33 h
Yield: 30.5 %

Procedure:
A suspension of sodium hydride (60%-oil suspension, 0.39 g), 3-picolyl-triphenylphosphonium chloride (2.55 g) and N,N-dimethylformamide was stirred for 20 minutes, followed by the addition of 1-(4-chlorobenzyl)-3-formyl-5-(2-quinolylmethoxy)indole (3.0 g). The mixture was stirred for an additional 10 hours and then poured into water-ethyl acetate (50% v/v). The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The resultant crude product was purified by chromatography on silica gel using 50%-ethyl acetate in n-hexanes as eluent to yield 1-(4-chlorobenzyl)-3-(2-(3-pyridyl)ethenyl)-5-(2-quinolylmethoxy)indole (1.0 g), m.p. 169°-171° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[C:27](=[O:28])[C:26]3[C:25]4[C:20](=[CH:21][C:22]([C:29]#[N:30])=[CH:23][CH:24]=4)[NH:19][C:18]=3[C:17]([CH3:32])([CH3:31])[C:16]=2[CH:33]=1.C(N(C(C)C)CC)(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl.O>[C:29]([C:22]1[CH:21]=[C:20]2[C:25]([C:26]3[C:27](=[O:28])[C:15]4[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][NH:8][S:44]([CH3:43])(=[O:46])=[O:45])=[CH:33][C:16]=4[C:17]([CH3:31])([CH3:32])[C:18]=3[NH:19]2)=[CH:24][CH:23]=1)#[N:30]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)c2cc(OCCN)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC1(C)c2cc(OCCNS(C)(=O)=O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
Trifluoroacetic acid salt of 8-(2-amino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A8-2, 19 mg, 0.044 mmol) was suspended in dichloromethane (0.5 mL), added with diisopropylethylamine (0.0157 mL, 2 eq.) and methanesulfonyl chloride (0.0034 mL, 1 eq.), and then stirred at room temperature for 2 hr. The reaction solution was added to water, and then extracted with dichloromethane. After washing with saturated brine, the organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were separated by silica gel preparative TLC (ethyl acetate 100%) to obtain the target compound (5.5 mg, 29%).
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].CC1C=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1.CI>C1COCC1>[CH2:10]([C:9]1[CH:8]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1)[CH3:11]
Reactant: [Li]CCCC
Reactant: Cc1cc(Cl)ccn1
Solvent: CI
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCc1cc(Cl)ccn1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 24 %

Procedure:
To a stirred solution of diisopropylamine (0.86 ml, 6.1 mmol) in THF (15 ml) at −20° C. was added dropwise a solution of n-butyllithium in hexanes (1.2M, 5.07 ml, 6.1 mmol). The reaction mixture was stirred at −20° C. for 20 minutes and was then cooled to −70° C. A solution of 2-methyl-4-chloropyridine (0.74 g, 5.8 mmol) in THF (10 ml) was added dropwise over 20 minutes and the reaction mixture was stirred for 1 hour at −70° C. Methyl iodide (0.38 ml, 6.1 mmol) was then added dropwise and the reaction was allowed to warm to room temperature with stirring. The solvent was evaporated at reduced pressure and the resulting residue purified by FCC. 1H NMR indicated a ˜2.2:1 mixture of 2-ethyl and 2-(1-methylethyl) compounds. Re-purification by silica FCC [pentane/ether eluting with gradient 9:1 to 1:1] gave the title compound (209 mg, 24%) as colourless oil.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)=[O:14])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O1[CH2:33][CH2:32]OCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:7]1[C:32]2[C:33](=[C:10]([C:2]3[CH:10]=[C:9]4[C:5]([CH:6]=[N:7][N:8]4[CH3:11])=[C:4]([NH:12][C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=4)=[O:14])[CH:3]=3)[CH:2]=[CH:3][CH:4]=2)[CH:5]=[CH:6]1
Reactant: C1COCCO1
Reactant: Cc1cccc(C(=O)Nc2cc(Br)cc3c2cnn3C)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: Cc1cccc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3c2cnn3C)n1

Procedure:
A mixture of N-(6-bromo-1-methyl-1H-indazol-4-yl)-6-methyl-2-pyridinecarboxamide (50 mg, 0.14 mmol), indole-4-boranepinacoloate ester (40 mg, 0.18 mmol, commercially available), Pd(dppf)Cl2 (22 mg, 0.03 mmol) and sodium carbonate (2M aqueous, 0.26 ml) in 1,4-dioxane (2 ml) was heated to 150° C. under microwave conditions for 10 minutes. The mixture was extracted with dichloromethane (2×15 ml) and concentrated in vacuo and the residue was purified by HPLC (Method B) to afford the title compound (23 mg).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH3:7][N:8]([CH3:12])[CH2:9][C:10]#[CH:11]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[CH3:7][N:8]([CH3:12])[CH2:9][C:10]#[C:11][C:2]1[S:3][CH:4]=[CH:5][N:6]=1
Reactant: C#CCN(C)C
Reactant: Brc1nccs1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CN(C)CC#Cc1nccs1
Reaction time: 0.08 h

Procedure:
A mixture of 5.02 g of 2-bromothiazole, 20 ml of triethylamine, and 4.3 ml of 1-dimethylamino-2-propyne is stirred under argon for 5 minutes. Seven hundred and fifty milligrams of bis(triphenylphosphine) palladium (II) chloride and 0.450 mg of copper (I) iodide is added and the stirred reaction is heated at 80°-85° C. for 3 hours. The reaction mixture is cooled, partitioned between diethyl ether and 65 ml of 10% sodium carbonate, and the layers are separated. The organic layer is filtered through diatomaceous earth, washed with aqueous sodium chloride and dried over magnesium sulfate. The crude product is purified by chromatography using silica gel as absorbant followed by filtration of the product band through a pad of magnesium silicate to give 0.35 g of the desired product as an oil, MH+ 167. Purity is determined by 1H PMR spectroscopy and by thin layer chromatography.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH3:11][N:12]([CH3:25])[CH2:13][CH2:14][CH2:15][C:16]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[NH:18][CH:17]=1.[OH-].[Na+]>O.ClCCl>[CH3:25][N:12]([CH3:11])[CH2:13][CH2:14][CH2:15][C:16]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[NH:18][C:17]=1[CH:3]=[O:4]
Reactant: CN(C)CCCc1c[nH]c2c1CCCC2
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CN(C)CCCc1c(C=O)[nH]c2c1CCCC2
Temperature: 25 °C
Yield: 79.2 %

Procedure:
Dimethylformamide (0.8 g) and 13 mL of dichloromethane was cooled to −9° C. Phosphorus oxychloride (1.7 g) was rapidly added via a dropping funnel. 3-(3-dimethylaminopropyl)-4,5,6,7-tetrahydro-1H-indole (2 g) was added in portions with vigorous stirring. The mixture was warmed to room temperature and then refluxed for 10 minutes. It was then cooled to 5° C., and diluted with 20 mL of water. The pH was adjusted to 10 with 10N sodium hydroxide. The layers were separated. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated to give 1.8 g (80%) of 3-(3-dimethylaminopropyl)-2-formyl-4,5,6,7-tetrahydro-1H-indole as a dark oil which solidified.
Reaction SMILES: [CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[CH:19]=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[CH:23]=[N:24][N:25](COCC[Si](C)(C)C)[CH:26]=4)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:25]1[CH:26]=[C:22]([C:15]2[N:14]=[C:13]([C:11]3[CH:10]=[N:9][N:8]([CH:4]([CH:1]4[CH2:3][CH2:2]4)[CH2:5][C:6]#[N:7])[CH:12]=3)[N:18]3[CH:19]=[CH:20][N:21]=[C:17]3[CH:16]=2)[CH:23]=[N:24]1
Reactant: C[Si](C)(C)CCOCn1cc(-c2cc3nccn3c(-c3cnn(C(CC#N)C4CC4)c3)n2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCC(C1CC1)n1cc(-c2nc(-c3cn[nH]c3)cc3nccn23)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
To a solution of 3-cyclopropyl-3-(4-(7-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (Example 32, 65.0 mg, 0.137 mmol) in DCM (2 mL) was added trifluoroacetic acid (2 mL) and the mixture was stirred at ambient temperature for 1.5 hours. The mixture was concentrated and the residue was partitioned into EtOAc (3 mL) and saturated NaHCO3 (3 mL). The biphasic mixture was stirred for 15 minutes and NaCl was added until saturated. The EtOAc layer was removed and the remaining aqueous portion was extracted with EtOAc. The combined EtOAc extracts were dried over MgSO4, filtered through a Celite plug and concentrated. The residual solid was dissolved in 10% MeOH/EtOAc and eluted through a SiO2 column using 10% MeOH/EtOAc for elution. The solution was concentrated to give the title compound (46 mg, 98% yield) as a white solid. MS (apci) m/z=345.2 (M+H).
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C@@H:7]2[C@@H:10]([C:13]([F:16])([F:15])[F:14])[O:11][CH2:12][C@:6]2([C:17]2[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:18]=2[F:26])[N:5]=[C:4]1[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:2].[H][H]>C(O)C.[Pd]>[NH2:23][C:21]1[CH:20]=[CH:19][C:18]([F:26])=[C:17]([C@:6]23[CH2:12][O:11][C@H:10]([C:13]([F:16])([F:14])[F:15])[C@H:7]2[C:8](=[O:9])[N:3]([CH2:1][CH3:2])[C:4]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[N:5]3)[CH:22]=1
Reactant: [H][H]
Reactant: CCN1C(=O)[C@@H]2[C@@H](C(F)(F)F)OC[C@]2(c2cc([N+](=O)[O-])ccc2F)N=C1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCN1C(=O)[C@@H]2[C@@H](C(F)(F)F)OC[C@]2(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Yield: 99.2 %

Procedure:
A solution of tert-butyl ((4aS,5S,7aS)-3-ethyl-7a-(2-fluoro-5-nitrophenyl)-4-oxo-5-(trifluoromethyl)-3,4,4a,5,7,7a-hexahydrofuro[3,4-d]pyrimidin-2-yl)carbamate (0.225 g, 0.46 mmol) in ethanol (30 mL) was hydrogenated over 10% Pd/C (50 mg) at RT under a balloon of hydrogen for 2 h. The catalyst was removed by filtration through Celite-washing with ethanol. The filtrate was evaporated to give the title compound (0.21 g, colourless foam). 1H NMR (400 MHz, CDCl3) δ ppm 1.14 (t, J=6.95 Hz, 3H) 1.53 (s, 9H) 3.90-4.12 (m, 3H) 4.31 (d, J=9.60 Hz, 1H) 4.45 (dd, J=9.60, 3.28 Hz, 1H) 4.47-4.56 (m, 1H) 6.46 (dd, J=6.32, 2.78 Hz, 1H) 6.63 (ddd, J=8.59, 3.79, 2.78 Hz, 1H) 6.94 (dd, J=11.12, 8.84 Hz, 1H) 10.49 (br. s., 1H).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][C:28]([OH:30])=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[C:31]([C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)(=[O:33])[CH3:32].[Li+].CC([N-]C(C)C)C>C1COCC1.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.CCOC(C)=O>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH2:22][CH:23]([CH2:26][CH2:27][C:28](=[O:30])[CH2:32][C:31](=[O:33])[C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[CH2:24][CH2:25]1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(=O)c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Agent: CC(C)[N-]C(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)CC(=O)c2ccncc2)CC1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
CDI (0.63 g, 3.9 mmol) was added to a solution of 4-(2-carboxyethyl)piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 3.9 mmol) in anhydrous THF (7.6 ml), then the mixture was stirred for 45 min. In a separate vessel, 4-acetylpyridine (0.49 g, 4.1 mmol) was added slowly to a stirred solution of LDA (2.04 ml of a 2.0M solution in heptane-THF-ethylbenzene, 4.1 mmol) in anhydrous THF (15.3 ml) at −78° C. After 45 min, the solution of the acylimidazole was added slowly via cannula to the lithiated 4-acetylpyridine while maintaining the temperature at −78° C. The reaction was allowed to warm to rt over 2 h, before being diluted with EtOAc (150 ml). The solution was washed with 10% aqueous citric acid (2×15 ml), saturated aqueous NaHCO3 (2×15 ml), and brine (20 ml), before being dried (MgSO4). Filtration, concentration, and purification by RP-HPLC afforded the title compound: m/z (ES+)=261.2 [M-Boc+H]+.
Reaction SMILES: CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:49][C:50]1[CH:55]=[C:54](I)[C:53]([Cl:57])=[CH:52][N:51]=1.[NH2:58][C:59]1[C:68]([F:69])=[CH:67][CH:66]=[CH:65][C:60]=1[C:61]([NH:63][CH3:64])=[O:62]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:49][C:50]1[CH:55]=[C:54]([NH:58][C:59]2[C:68]([F:69])=[CH:67][CH:66]=[CH:65][C:60]=2[C:61]([NH:63][CH3:64])=[O:62])[C:53]([Cl:57])=[CH:52][N:51]=1
Reactant: Clc1cc(I)c(Cl)cn1
Reactant: CNC(=O)c1cccc(F)c1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CNC(=O)c1cccc(F)c1Nc1cc(Cl)ncc1Cl
Temperature: 80 °C
Yield: 49.7 %

Procedure:
Palladium(II) acetate (35.9 mg, 0.16 mmol) was added to 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (139 mg, 0.24 mmol), cesium carbonate (2604 mg, 7.99 mmol), 2,5-dichloro-4-iodopyridine (1094 mg, 4.00 mmol) and 2-amino-3-fluoro-N-methylbenzamide (672 mg, 4.00 mmol) in dioxane (20 mL) under an atmosphere of nitrogen. The resulting suspension was heated at 80° C. for 24 hours and then allowed to cool to room temperature. The mixture was evaporated and the residue dissolved in EtOAc (150 mL) and then washed sequentially with a saturated solution of NaHCO3 (100 mL), water (100 mL), and then with a saturated solution of NaCl (100 mL). The organic layer was dried over MgSO4 and then evaporated. The residue was purified by chromatography on silica, eluting with a gradient of 0-100% EtOAc in isohexane. Fractions containing product were evaporated to afford 2-[(2,5-dichloropyridin-4-yl)amino]-3-fluoro-N-methylbenzamide (624 mg, 50% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 1H NMR (300.132 MHz, DMSO) δ 2.74 (3H, d), 6.39 (1H, d), 7.42 (1H, td), 7.49-7.59 (2H, m), 8.25 (1H, s), 8.64 (1H, m), 9.31 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+ =314.20 and 316.20 and 318.17.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:33])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]([CH3:32])[CH3:31])[CH:25]=2)[CH:18]=[CH:19][C:20]=1[CH3:21].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:32][N:30]([CH3:31])[C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:23]([NH:22][C:17]1[CH:18]=[CH:19][C:20]([CH3:21])=[C:15]([NH:14][C:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)=[O:13])[CH:16]=1)=[O:33]
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccc2ncccc2c1
Yield: 24.4 %

Procedure:
6-Quinolinecarboxylic acid (0.173 g) was added to a stirred suspension of N-(3-amino-4-methylphenyl)-3-dimethylaminobenzamide (0.135 g), diisopropylethylamine (0.325 ml), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (0.39 g) in DMF (10 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The solvent was evaporated and the residue was dissolved in methylene chloride and washed with a saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate and evaporated. The residue was triturated under a mixture of ethyl acetate and isohexane. There was thus obtained the title compound as a solid (0.052 g); NMR Spectrum: (DMSOd6) 2.24 (s, 3H), 2.95 (s, 6H), 6.89 (d, 1H), 7.25 (m, 4H), 7.6 (m, 2H), 7.85 (s, 1H), 8.12 (d, 1H), 8.4 (d, 1H), 8.52 (d, 1H), 8.65 (m, 1H), 8.99 (d, 1H), 10.11 (s, 1H), 10.16 (s, 1H); Mass Spectrum: M+H+ 425.
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2(Cl)[CH:17]([OH:18])[C:16]([C:19]([CH3:21])=[O:20])=[C:15](Cl)[S:14]2)[CH:9]=[CH:10][C:11]=1[Cl:12].S(Cl)(Cl)(=O)=O.O>CC(O)C>[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2[S:14][CH:15]=[C:16]([C:19]([CH3:21])=[O:20])[C:17]=2[OH:18])[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: CC(=O)C1=C(Cl)SC(Cl)(c2ccc(Cl)c(Cl)c2)C1O
Solvent: O=S(=O)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: -20 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
A chloroform (967 mL) solution of 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonyl-2,5-dichlorothiophene (96.7 g, 221 mmol, purity: 63%) was cooled to −18° C., and to this solution, a chloroform (193 mL) solution of sulfuryl chloride (19.5 mL, 1.15 equivalent amounts) was dropwise added over a period of 20 minutes, followed by stirring at −20° C. for 1 hour. The temperature of the solution was raised to 0° C., and water (193 mL) was dropwise added over a period of 5 minutes, followed by liquid separation. The obtained chloroform solution was sequentially washed with water, a saturated salt solution, a saturated sodium hydrogencarbonate aqueous solution, a saturated sodium thiosulfate aqueous solution and a saturated salt solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to obtain a crude product. To the obtained crude product, 2-propanol (967 mL) was added, followed by stirring at 5° C. for 1 hour. The formed crystals were subjected to filtration to give the desired product as a pale yellow solid (49.4 g, yield: 51%).