Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([O:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]#[CH:26])[CH2:21][CH2:20]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH:27]1([CH2:30][O:31][C:32]2[CH:33]=[CH:34][C:35](I)=[C:36]([OH:38])[CH:37]=2)[CH2:29][CH2:28]1.CN(C)C(N(C)C)=N>CN(C=O)C.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.[Cu](I)I>[C:1]([Si:5]([O:18][CH:19]1[CH2:20][CH2:21][CH:22]([C:25]2[O:38][C:36]3[CH:37]=[C:32]([O:31][CH2:30][CH:27]4[CH2:28][CH2:29]4)[CH:33]=[CH:34][C:35]=3[CH:26]=2)[CH2:23][CH2:24]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1cc(OCC2CC2)ccc1I
Reactant: C#CC1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC1CCC(c2cc3ccc(OCC4CC4)cc3o2)CC1)(c1ccccc1)c1ccccc1
Yield: 66 %

Procedure:
A solution of tert-butyl [(4-ethynylcyclohexyl)oxy]diphenylsilane (3.52 g), 5-(cyclopropylmethoxy)-2-iodophenol (2.82 g), bis(triphenylphosphine)palladium(II) dichloride (0.34 g), copper iodide (0.09 g) and 1,1,3,3-tetramethylguanidine (3.65 mL) in DMF (30 mL) was stirred at room temperature overnight under an argon atmosphere. The reaction mixture was extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (3.36 g).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[CH3:30][N:31]1[C:35]2[CH:36]=[CH:37][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:39][C:34]=2[N:33]([CH3:49])[C:32]1=[O:50].C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.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>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:38]3[CH:37]=[CH:36][C:35]4[N:31]([CH3:30])[C:32](=[O:50])[N:33]([CH3:49])[C:34]=4[CH:39]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: Cn1c(=O)n(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
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: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)n(C)c(=O)n4C)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A microwave vial was charged with (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (75 mg, 0.15 mmol), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)one (182 mg, 0.63 mmol), then Pd(PPh3)4 (22 mg, 0.02 mmol). The vial was flushed with argon, diluted with dioxane (1.5 mL) and to this was added 2M aqueous K2CO3 (0.25 mL, 0.5 mmol). The vial was sealed, heated to 100° C. for 2 hours, and then allowed to cool to room temperature. The mixture was diluted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (40-100% EtOAc/Hex gradient) to afford the desired product. LCMS-ESI+: calc'd for C31H33ClN3O4S: 578.2 (M+H+); Found: 578.3 (M+H+).
Reaction SMILES: F[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([NH:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:25]([NH2:27])=[O:26])=[O:7])=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>CN1C(=O)CCC1>[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:2]2[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]3[S:13][C:12]([NH:14][C:15]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[N:18]=[CH:17][CH:16]=4)=[N:11][C:10]=3[C:25]([NH2:27])=[O:26])=[O:7])=[CH:4][CH:3]=2)[CH2:33][CH2:32]1
Reactant: NC(=O)c1nc(Nc2ccnc3ccccc23)sc1NC(=O)c1ccc(F)cc1
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc(C(=O)Nc3sc(Nc4ccnc5ccccc45)nc3C(N)=O)cc2)CC1
Temperature: 150 °C
Yield: 69 %

Procedure:
A mixture of 5-(4-fluorobenzamido)-2-(quinolin-4-ylamino)thiazole-4-carboxamide (110 mg, 0.27 mmol) and 1-methyl-piperazine (1.5 mL) in NMP (1.5 mL) was heated at 150° C. for 4 hrs. The reaction mixture was diluted with ice water (1 mL). The resulting solids were collected by filtration and washed successively with water and ether, and dried to give 0.090 g (69% yield) of the titled compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:25])[C:3]=1[C:26]#[N:27].C(=O)([O-])[O-].[K+].[K+].[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][N:37]=1>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.COCCOC>[C:26]([C:3]1[C:2]([C:39]2[CH:38]=[N:37][C:36]([O:35][CH3:34])=[CH:41][CH:40]=2)=[N:7][C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:21])([F:22])[O:20][C:16]=4[CH:15]=3)[CH2:12][CH2:13]2)=[O:10])=[CH:5][C:4]=1[CH3:25])#[N:27]
Reactant: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(Cl)c1C#N
Reactant: COc1ccc(B(O)O)cn1
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: [K+]
Solvent: COCCOC
Product: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc(C)c2C#N)cn1
Temperature: 80 °C
Yield: 100.1 %

Procedure:
N-(6-chloro-5-cyano-4-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (369 mg, 0.94 mmol), potassium carbonate (1.45 g, 942.0 μL of 2 M, 1.88 mmol), tetrakis(triphenylphosphine)palladium (0) (54 mg, 0.047 mmol), 1,2-dimethoxyethane (9 mL), and 2-methoxypyridine-5-boronic acid (230.5 mg, 1.51 mmol) were combined in a 40 mL scintillation vial. The reaction mixture was heated to 80° C. for 6 hours. The reaction mixture was allowed to cool to room temperature, the layers were separated, and the crude material was purified on 40 g of silica gel utilizing a gradient of 0-80% ethyl acetate in hexanes to yield the pure product (0.437 g, 71%). ESI-MS m/z calc. 464.1. found 465.1 (M+1)+. Retention time 2.08 minutes.
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:4])[CH3:3].C([Li])CCC.[Br-].[Na+].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>O1CCCC1.O>[F:22][C:23]1[CH:24]=[C:25]([CH2:26][CH2:14][C:13]2[C:8]([C:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: Cc1cccnc1C(=O)NC(C)(C)C
Reactant: Fc1cccc(CBr)c1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ncccc1CCc1cccc(F)c1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Tetrahydrofuran (125 mL) and N-(1,1-dimethylethyl)-3-methyl-2-pyridine carboxamide (1 equivalent) are charged and cooled to -40° C. under nitrogen. Two equivalents of n-butyllithium are then added over 40 minutes. When half the n-butyllithium is added the mixture turns purple. Sodium bromide (1.3 g) is added and then 3-fluoro-benzyl bromide (1.05 equivalents) is added dropwise (1:1 solution in tetrahydrofuran) over 40-50 minutes while the temperature is maintained at -40° C. After 30 minutes at -40° C., the mixture is diluted with water (250 mL) and the organic phase separated. This phase is dried over sodium sulphate and the solvent removed yielding an oil from which solid product, 3-[2-(3-fluorophenyl)ethyl]-N-(1,1-dimethylethyl)-2-pyridine carboxamide, may crystallize.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:33]=[CH:32][C:12]2[N:13]([CH3:31])[C:14]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:15][C:11]=2[CH:10]=1)=[O:8].[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(N(CC)CC)C>[CH3:34][S:35]([NH:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:33]=[CH:32][C:12]2[N:13]([CH3:31])[C:14]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26][C:27]([F:28])([F:29])[F:30])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:15][C:11]=2[CH:10]=1)=[O:8])(=[O:37])=[O:36]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCN)ccc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCNS(C)(=O)=O)ccc21
Yield: 77.2 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-methanesulfonylamino-ethyl)-amide (57 mg) was prepared by following General Procedure Q starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-amino-ethyl)-amide dihydrochloride (75 mg), methanesulfonyl chloride (16 mg), and triethylamine (62 uL). LC/MS: m/z 529.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH3:21])([CH3:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=1.C[Al](C)C.N#N.FC1C=C(C=CC=1)O[CH2:33][C:34]([NH:36]/[C:37](/[CH3:43])=[CH:38]\[C:39](OC)=[O:40])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:39](=[O:40])[CH:38]=[C:37]([CH3:43])[N:36]=[C:34]2[CH3:33])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH3:21])([CH3:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=1
Reactant: COC(=O)/C=C(/C)NC(=O)COc1cccc(F)c1
Reactant: CC(C)(Cc1ccc(Cl)c(F)c1)Nc1ccc(N)cc1Cl
Agent: C[Al](C)C
Agent: N#N
Solvent: Cc1ccccc1
Product: Cc1cc(=O)n(-c2ccc(NC(C)(C)Cc3ccc(Cl)c(F)c3)c(Cl)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
To a solution of 2-chloro-N1-(1-(4-chloro-3-fluorophenyl)-2-methylpropan-2-yl)benzene-1,4-diamine (408 mg, 1.25 mmol) in toluene (15 mL) was added trimethylaluminium (2.5 mL, 5.00 mmol, 2.0 M in toluene) dropwise under N2 and the mixture was stirred at rt for 30 min after addition was completed. A solution of (Z)-methyl 3-(2-(3-fluorophenoxy)acetamido)but-2-enoate (295 mg, 1.88 mmol) in toluene (5 mL) was added slowly and the resulting mixture was stirred at rt for 22 h. Trimethylaluminium (2.0 mL, 4.00 mmol, 2 M in toluene) was then added dropwise and the mixture was stirred at rt for 30 min. A solution of (Z)-methyl 3-(2-(3-fluorophenoxy)acetamido)but-2-enoate (295 mg, 1.88 mmol) in toluene (3 mL) was added and the mixture was stirred further for 18 h. The mixture was quenched with saturated NH4Cl aqueous solution (50 mL) and filtered and the organic phase was separated from the filtrate. The aqueous phase was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL×2), dried over anhydrous Na2SO4 (15 g) and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:3) to give the title compound as a yellow solid (183 mg, 33.7%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19]Cl)[C:5]=2[CH:4]=1.C(N(CC)CC)C.[NH:30]1[CH2:35][CH2:34][CH:33]([O:36][CH2:37][CH2:38][OH:39])[CH2:32][CH2:31]1>C(C(C)=O)C.[I-].[Na+]>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19][N:30]3[CH2:35][CH2:34][CH:33]([O:36][CH2:37][CH2:38][OH:39])[CH2:32][CH2:31]3)[C:5]=2[CH:4]=1
Reactant: OCCOC1CCNCC1
Reactant: FC(F)(F)c1ccc2c(c1)N(CCCCl)c1ccccc1S2
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: OCCOC1CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1

Procedure:
40 g of 2-trifluoromethyl-10-(3-chloropropyl)-phenothiazine were dissolved in 350 ml of methyl ethyl ketone and 17.6 g of sodium iodide, 11.8 g of triethylamine, then 17 g of 2-(4-piperidyloxy)-ethanol were successively added to this solution. It was refluxed for 20 hours and after cooling, the precipitate was removed by vacuum filtration. The filtrate was evaporated to dryness to obtain 2-trifluoromethyl-10-[3-(4-β-hydroxyethoxypiperidino)-propyl]-phenothiazine as an oil which was added to a mixture of ether and dilute hydrochloric acid. The formed precipitate was recovered by vacuum filtration and was crystallized from 95% ethanol to obtain 40.5 g of 2-trifluoromethyl-10-[-3(4-β-hydroxyethoxypiperidino)-propyl]-phenothiazine hydrochloride as white crystals. Then a current of ammonia was led into an ether suspension of this product and the formed precipitate was removed by filtration. The filtrate was evaporated to dryness to obtain 2-trifluoromethyl-10-[3-(4-β-hydroxyethoxypiperidino)-propyl]-phenothiazine as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:11]([C:17]([O:19][CH3:20])=[O:18])#[C:12][C:13]([O:15][CH3:16])=[O:14].C(O)C>CO>[CH3:16][O:15][C:13](=[O:14])[C:12]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:2]=1[Br:1])=[CH:11][C:17]([O:19][CH3:20])=[O:18]
Reactant: COc1ccc(N)c(Br)c1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CCO
Solvent: CO
Product: COC(=O)C=C(Nc1ccc(OC)cc1Br)C(=O)OC
Yield: 93 %

Procedure:
A solution of 2-bromo-4-methoxy aniline (6.02 g, 29.8 mmol) in 125 mL anhydrous methanol was treated with dimethyl acetylenedicarboxylate (3.70 mL, 30.2 mmol) and the solution was heated at reflux under nitrogen for 8 hours. The reaction mixture was cooled, concentrated, and redissolved in hot methanol. Yellow crystals were obtained by filtration (6.93 g, 68%). A second crop of crystals was obtained from ethanol (0.942 g, 9%). The filtrates were combined and purified by flash chromatography on silica gel using 4:1 hexanes:ethyl acetate to afford an additional 1.63 g (16%) for a total yield of 93%. 1H NMR (300 MHz, DMSO, d6) δ 9.60 (s, 1H, NH), 7.26 (d, 1H, Jm=2.7 Hz, ArH3), 6.93 (dd, 1H, Jo=8.7, Jm=2.7 Hz, ArH5), 6.87 (d, 1H, Jo=8.7 Hz, ArH6), 5.34 (s, 1H, C═CH), 3.76 (s, 3H, OCH3), 3.68 (s, 3H, CHCO2CH3), 3.66 (s, 3H, CNCO2CH3); Mass Spec.: calc. for [C13H14BrNO5+H]+ Theor. m/z=344, 346; Obs. 344, 346.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.C(N(CC)CC)C.[N+:16]([C:19]1[C:20]([Cl:26])=[N:21][CH:22]=[N:23][C:24]=1Cl)([O-:18])=[O:17]>O1CCCC1.C(OCC)(=O)C>[Cl:26][C:20]1[N:21]=[CH:22][N:23]=[C:24]([NH:1][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=2)[C:19]=1[N+:16]([O-:18])=[O:17]
Reactant: Nc1ccnc(Cl)c1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(Cl)ncnc1Nc1ccnc(Cl)c1
Yield: 18.7 %

Procedure:
4-Amino-2-chloropyridine (8.0 g, 62.2 mmol) and triethylamine (8.7 mL) were added. successively to a suspension of 5-nitro-4,6-dichloropyrimidine (8.0 g, 41.2 mmol) in tetrahydrofuran (160 mL), and the mixture was heated under reflux for 4 hours. After cooling as it was, the reaction solution was diluted with ethyl acetate (160 ml) and washed with 160 ml water and brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue were suspended in diethyl ether, and the resulting solid was collected by filtration and air-dried, to give the title compound (2.2 g, 19%).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]=[C:7]=[NH:8])C.[C:12]([NH2:20])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CS(O)(=O)=O>C(O)C>[NH:20]1[CH:12]=[CH:13][N:8]=[C:7]1[NH:6][C:5]1[CH:4]=[C:14]([NH:20][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: CCOC(CN=C=N)OCC
Reactant: NC(=O)c1ccccc1
Agent: CS(=O)(=O)O
Solvent: CCO
Product: Cc1ccc(NC(=O)c2ccccc2)cc1Nc1ncc[nH]1
Reaction time: 8 h
Yield: 100.1 %

Procedure:
A mixture of N-(2,2-diethoxyethyl)carbodiimide (10.38 g, 65.6 mmol), 3-amino-4-methyl-phenyl]-benzamide (7.42 g, 32.8 mmol), methanesulfonic acid (3.20 mL, 49.3 mmol) in ethanol (200 mL) was heated at reflux for 19 h. The reaction mixture was concentrated (No purification was pursued in this step). The residue was dissolved in HCl solution (6N, 30 mL). After stirring for overnight, the reaction mixture was neutralized with 25% NaOH solution at 0° C. to pH=6, then basified with saturated sodium carbonate solution to pH=11. The mixture was stirred for 30 minutes, and extracted with ethanol in CH2Cl2 (100 mL), then 10% ethanol in CH2Cl2 (2×100 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated and dried under vacuum. The residue was triturated in CH2Cl2 (50 mL). The solid was collected by filtration and washed with CH2Cl2, dried to afford the title compound N-[3-(1H-imidazol-2-ylamino)-4-methyl-phenyl]-benzamide as a white solid (4.80 g, 50%). 1H NMR 600 MHz (DMSO-d6) δ 10.79 (s, 1H), 10.11 (s, 1H), 8.00 (d, 1H, J=2.4 Hz), 7.94 (d, 2H, J=7.2 Hz), 7.60 (s, 1H), 7.56 (t, 1H, J=7.2 Hz), 7.49 (t, 2H, J=7.2 Hz), 7.25 (dd, 1H, J=2.4, 8.4 Hz), 7.04 (d, 1H, J=7.8 Hz), 6.80 (br, s, 1H), 6.65 (br, s, 1H), 2.20 (s, 3H), MS m/z 293.4 (M+1).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CC(C)([O-])C.[K+].CN(C)C=O.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1Cl)([O-:21])=[O:20]>C1(C)C=CC=CC=1.O>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][C:27]=1[S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)([O-:21])=[O:20]
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Cl)c1
Reactant: Sc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1ccc([N+](=O)[O-])c(Sc2ccccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
A mixture of 2-mercaptopyridine (1.7 g), potassium t-butoxide (1.7 g) and N,N-dimethylformamide (3 ml) in toluene (15 ml) was stirred at room temperature for 30 minutes. To the mixture was added 4'-nitro-3'-chloroacetophenone (1.5 g) and the resulting mixture was stirred overnight. Water was added and the insoluble material was filtered, washed with toluene and dried to give crystals of 4'-nitro-3'-(2-pyridylthio)acetophenone (1.1 g).
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3]([O:6][C:7]([N:9]1[CH:14]2[C:15]([C:27](=[O:41])[N:28]([CH:38]3[CH2:40][CH2:39]3)[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=3[Cl:37])=[C:16]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH2:24][CH2:25]O)[CH:19]=3)[CH2:17][CH:10]1[CH2:11][N:12]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:13]2)=[O:8])([CH3:5])[CH3:4].[Cl:51][C:52]1[C:53]([F:60])=[C:54]([OH:59])[C:55]([F:58])=[CH:56][CH:57]=1>>[C:45]([O:44][C:42]([N:12]1[CH2:13][CH:14]2[N:9]([C:7]([O:6][C:3]([CH3:5])([CH3:4])[CH3:2])=[O:8])[CH:10]([CH2:17][C:16]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH2:24][CH2:25][O:59][C:54]4[C:55]([F:58])=[CH:56][CH:57]=[C:52]([Cl:51])[C:53]=4[F:60])[CH:19]=3)=[C:15]2[C:27](=[O:41])[N:28]([CH:38]2[CH2:39][CH2:40]2)[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=2[Cl:37])[CH2:11]1)=[O:43])([CH3:46])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)N1CC2CC(c3cc(CCCO)no3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Reactant: Oc1c(F)ccc(Cl)c1F
Product: CC(C)(C)OC(=O)N1CC2CC(c3cc(CCCOc4c(F)ccc(Cl)c4F)no3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C

Procedure:
This compound is prepared from compound E6 and 3-chloro-2,6-difluorophenol, according to the above-described procedure A. LC-MS: tR=1.30 min, ES+: 941.29.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[CH:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)([CH3:23])[CH3:22]>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:27]3[CH:28]=[CH:29][C:24]([CH:21]([CH3:23])[CH3:22])=[CH:25][CH:26]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccc(C(C)C)cc3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 4-isopropyl-phenylboronic acid (53 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: ClC1C=C2C(C)(C)C(/C=C/C(/C3C=CC=C(CCC(O[N:58]4[C:62](=[O:63])[CH2:61][CH2:60][C:59]4=[O:64])=O)C=3)=C/C=C3/N(CCCS([O-])(=O)=O)C4C(C/3(C)C)=CC(S([O-])(=O)=O)=CC=4)=NC2=[N+](CCCS([O-])(=O)=O)C=1.[Na+:65].[Na+].[C:67]([CH2:70][CH2:71][C:72]1[CH:77]=[CH:76][C:75](/[C:78](/[CH:103]=[CH:104]/[C:105]2[C:106]([CH3:123])([CH3:122])[C:107]3[C:108]([N:121]=2)=[N+:109]([CH2:114][CH2:115][CH2:116][S:117]([O-:120])(=[O:119])=[O:118])[CH:110]=[C:111]([Cl:113])[CH:112]=3)=[CH:79]\[CH:80]=[C:81]2\[N:82]([CH2:96][CH2:97][CH2:98][S:99]([O-:102])(=[O:101])=[O:100])[C:83]3[C:88]([C:89]\2([CH3:91])[CH3:90])=[CH:87][C:86]([S:92]([O-:95])(=[O:94])=[O:93])=[CH:85][CH:84]=3)=[CH:74][CH:73]=1)([OH:69])=[O:68].[Na+].[Na+]>>[Cl:113][C:111]1[CH:112]=[C:107]2[C:106]([CH3:123])([CH3:122])[C:105](/[CH:104]=[CH:103]/[C:78](/[C:75]3[CH:74]=[CH:73][C:72]([CH2:71][CH2:70][C:67]([O:69][N:58]4[C:62](=[O:63])[CH2:61][CH2:60][C:59]4=[O:64])=[O:68])=[CH:77][CH:76]=3)=[CH:79]/[CH:80]=[C:81]3/[N:82]([CH2:96][CH2:97][CH2:98][S:99]([O-:102])(=[O:101])=[O:100])[C:83]4[C:88]([C:89]/3([CH3:90])[CH3:91])=[CH:87][C:86]([S:92]([O-:95])(=[O:93])=[O:94])=[CH:85][CH:84]=4)=[N:121][C:108]2=[N+:109]([CH2:114][CH2:115][CH2:116][S:117]([O-:120])(=[O:118])=[O:119])[CH:110]=1.[Na+:65].[Na+:65]
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2cccc(CCC(=O)ON3C(=O)CCC3=O)c2)=Nc2c1cc(Cl)c[n+]2CCCS(=O)(=O)[O-]
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2ccc(CCC(=O)O)cc2)=Nc2c1cc(Cl)c[n+]2CCCS(=O)(=O)[O-]
Agent: [Na+]
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2ccc(CCC(=O)ON3C(=O)CCC3=O)cc2)=Nc2c1cc(Cl)c[n+]2CCCS(=O)(=O)[O-]

Procedure:
Compound 13 is prepared analogously to compound 11 (Example 11), except that compound 12 is used as a starting material.