Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=[CH:12][C:11]=1Br)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=[CH:12][C:11]=1[CH:19]=[CH:18][C:17]([O:16][CH3:14])=[O:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C(=O)Oc1ccc(Br)c(CO[Si](C)(C)C(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(OC(=O)C(C)(C)C)cc1CO[Si](C)(C)C(C)(C)C
Temperature: 135 °C
Reaction time: 1 h

Procedure:
To a solution of 2-tert-butyldimethylsilyloxymethyl-4-trimethylacetyloxybromobenzene (48 g) in dry dimethylformamide (460 ml) is added bis(triphenylphosphine)palladium dichloride (2.5 g). The resulting solution is degassed and dry triethylamine (67 ml) added, followed by methyl acrylate (42.6 ml). The resulting solution is stirred at 135° C. for about 1 hour, cooled, diluted with ether, washed with water, dried over magnesium sulfate, filtered, then concentrated under reduced pressure. The residue is purified by flash chromatography, eluting with 10% ether in hexanes, to give the desired product.
Reaction SMILES: C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[CH3:16][O:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH2:27][O:28][CH3:29])[CH:23]=[CH:22][C:21]=1[CH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([OH:38])=O)[CH2:31]1.[NH2:39][OH:40]>O1CCCC1>[CH3:16][O:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH2:27][O:28][CH3:29])[CH:23]=[CH:22][C:21]=1[CH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([NH:39][OH:40])=[O:38])[CH2:31]1
Reactant: COCOc1ccc(C2CCCC(C(=O)O)C2)c(OCOC)c1
Reactant: NO
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCOc1ccc(C2CCCC(C(=O)NO)C2)c(OCOC)c1
Reaction time: 0.5 h

Procedure:
Triethylamine (11 μl) and isobutylchloroformate (10 μl) were added to a stirred solution of (±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexanecarboxylic acid in anhydrous tetrahydrofuran (2 ml) at 0° C. under argon. After 30 min, aqueous hydroxylamine solution (0.5 ml, 50 wt %) was added. The reaction mixture was partitioned between water (20 ml) and ethyl acetate (50 ml). The aqueous layer was extracted with ethyl acetate (2×20 ml) and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to give the title compound as a solid (26 mg, quant.) and a mixture of diastereoisomers; m/z (ES+) 340 (M+H)+.
Reaction SMILES: [C:1]([C:9]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:10]=1[NH:11][C:12](=[O:17])C(Cl)(Cl)Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.C([O-])(=O)C.[NH4+:34]>O>[C:2]1([C:1]2[C:9]3[C:10](=[CH:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=3)[NH:11][C:12](=[O:17])[N:34]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1cc(C(F)(F)F)ccc1NC(=O)C(Cl)(Cl)Cl
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Solvent: O
Product: O=c1nc(-c2ccccc2)c2cc(C(F)(F)F)ccc2[nH]1
Temperature: 75 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
A mixture of 1.08 g of 2′-benzoyl-2,2,2-trichloro-4′-trifluoromethylacetanilide, 10 ml of DMSO and 1.18 g of ammonium acetate was stirred at 75° C. for 1 hour. After cooling, 100 ml of water was added to the mixture. Precipitated crystals were collected by filtration. The collected substance was dissolved in a mixture of hexane:ethyl acetate=1:1, dehydrated using anhydrous magnesium sulfate, and then concentrated to obtain 765 mg of the titled compound. 1H NMR (CDCl3): 7.58-7.68 (3H, m), 7.75 (1H, d, J=8.8 Hz), 7.79-7.83 (2H, m), 7.93 (1H, dd, J=8.8, 1.7 Hz), 8.17 (1H, br. s), 13.37 (1H, br. s).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([OH:6])=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[N:29]=[CH:28][C:27]([C:39]#[N:40])=[C:26]2[NH:41][C:42]1[CH:47]=[CH:46][C:45]([F:48])=[C:44]([Cl:49])[CH:43]=1>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][C:4]([NH:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[N:33]1[CH2:34][CH2:35][O:36][CH2:37][CH2:38]1)[N:29]=[CH:28][C:27]([C:39]#[N:40])=[C:26]2[NH:41][C:42]1[CH:47]=[CH:46][C:45]([F:48])=[C:44]([Cl:49])[CH:43]=1)=[O:6]
Reactant: O=C(O)CCCl
Reactant: N#Cc1cnc2cc(N3CCOCC3)c(N)cc2c1Nc1ccc(F)c(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: N#Cc1cnc2cc(N3CCOCC3)c(NC(=O)CCCl)cc2c1Nc1ccc(F)c(Cl)c1
Reaction time: 20 h
Yield: 77.8 %

Procedure:
To a stirred solution of 3-chloropropionic acid (0.65 g, 6.0 mmol)in 3 ml of DCM at 0° was added DCC (0.41 g, 2.0 mmol). After 15 m the mixture was warmed to 25°, recooled to 0°, and treated with 6-amino-4-(3-chloro-4-fluroanilino)-7-(4-morpholinyl)-3-quinolinecarbonitrile (0.40 g, 1.0 mmol) followed by 1 ml DCM rinse. The resulting mixture was stirred at 25° for 20 h, diluted with DCM, and stirred with aqueous sodium bicarbonate. The mixture was filtered to remove dicyclohexyl urea. The organic layer of the filtrate was washed with water, dried, and concentrated. The residue was passed as a solution in DCM onto a pad of silica gel. The product was eluted with 25:25:2:1 DCM-EtOAc-MeOH-TEA and concentrated to give 0.38 g amorphous solid; ms 488.1(M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:13]([CH2:14][CH3:15])[C:12]2[CH:16]=[CH:17][C:18]([N:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[N:23]=3)[CH3:21])=[CH:19][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([S:36]([NH2:39])(=[O:38])=[O:37])[CH:35]=1>>[ClH:28].[CH2:1]([NH:8][C:9]1[N:13]([CH2:14][CH3:15])[C:12]2[CH:16]=[CH:17][C:18]([N:20]([CH3:21])[C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:29][C:30]4[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([S:36]([NH2:39])(=[O:37])=[O:38])[CH:35]=4)[N:23]=3)=[CH:19][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCn1c(NCc2ccccc2)nc2cc(N(C)c3ccnc(Cl)n3)ccc21
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Product: CCn1c(NCc2ccccc2)nc2cc(N(C)c3ccnc(Nc4ccc(C)c(S(N)(=O)=O)c4)n3)ccc21
Product: Cl

Procedure:
The title compound was prepared following the procedure of example one with N2-Benzyl-N5-(2-chloro-pyrimidin-4-yl)-1-ethyl-N5-methyl-1H-benzoimidazole-2,5-diamine (98 mg, 0.25 mmol) and 5-amino-2-methyl-benzenesulfonamide (46 mg, 0.25 mmol) as a white solid (83 mg, 58%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 9.54 (s, 1H), 8.56 (s, 1H), 7.80 (d, J=6.3 Hz, 1H), 7.68 (dd, J=8.2 and 1.6 Hz, 1H), 7.15-7.47 (m, 10H), 7.03 (d, J=7.8 Hz, 1H), 5.69 (d, J=6.0 Hz, 1H), 4.68 (d, J=5.7 Hz, 2H), 4.21 (m, 2H), 3.46 (s, 3H), 2.50 (s, 3H), 1.28 (t, J=6.9 Hz, 3H). MS (ESI) m/z=543 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.[Cl:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30].C(N(CC)CC)C>CN(C)C=O.O>[Cl:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH:30][C:24](=[O:26])[CH2:23][N:22]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[N:15]=[C:14]1[C:11]1[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=1
Reactant: Nc1ccccc1Cl
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)Nc1ccccc1Cl
Temperature: 60 °C
Yield: 53.4 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (1.73 g, 0.014 mole) was added slowly to a stirred and chilled (10°-15° C.) suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.7 g, 0.013 mole) in 50 ml of dimethylformamide. The reaction mixture was heated at 60° C. for 5 hours. The solution of the acyl chloride prepared above was added dropwise under nitrogen atmosphere to a stirred and chilled (10°-15° C.) solution of o-chloroaniline (1.79 g, 0.014 mole), triethylamine (1.42 g, 0.014 mole), and 75 ml of dimethylformamide. After the addition, the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was poured into 200 ml of water. The crystalline solid was collected by filtration, washed with water, and dried under high vacuum overnight to give 2.76 g (54%) of crystals, mp 232°-235.5° C.
Reaction SMILES: [P:1]([Cl:5])(Cl)(Cl)=[S:2].C(N([CH2:11][CH3:12])CC)C.[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[OH:21]>C1(C)C=CC=CC=1>[P:1]([Cl:5])([O:21][C:15]1[CH:14]=[CH:19][C:18]([CH3:20])=[CH:17][C:11]=1[CH3:12])([O:21][C:15]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[CH3:13])=[S:2]
Reactant: CCN(CC)CC
Reactant: Cc1ccc(O)c(C)c1
Reactant: S=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(OP(=S)(Cl)Oc2ccc(C)cc2C)c(C)c1
Temperature: 20 °C
Yield: 89.9 %

Procedure:
Thiophosphoryl chloride (17.0 g) was dissolved in toluene (250 cm3) and triethylamine (21.5 g) was added. The solution was stirred at 20° C. and 2,4-dimethylphenol (24.4 g) was added in portions during 1 hr. The mixture was stirred for 2 hr. and then heated and stirred at 80° C. for a further 2 hr. and then cooled and filtered to remove triethylamine hydrochloride. The toluene was distilled under reduced pressure leaving bis(2,4-dimethylphenyl) chlorothiophosphate (oil, 30.6 g. 31P NMR in CDCl3, singlet 54.57 ppm downfield of H3PO4).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([S:24]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH3:36])=[CH:30][CH:29]=3)(=[O:26])=[O:25])[CH:22]=2)[NH:17][CH:16]=1>C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:35]([O:34][C:31]1[CH:32]=[CH:33][C:28]([NH:27][S:24]([C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[C:15]3[CH2:14][CH2:13][NH:12][C:2](=[O:3])[O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:26])=[O:25])=[CH:29][CH:30]=1)[CH3:36]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOc1ccc(NS(=O)(=O)c2ccc3[nH]cc(CCN)c3c2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOc1ccc(NS(=O)(=O)c2ccc3[nH]cc(CCNC(=O)OCc4ccccc4)c3c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl chloroformate (1.55 ml) was added portionwise to a stirred solution of the product of Example 4 (4.3 g) in a mixture of ethyl acetate (100 ml) and sodium carbonate (2 N, 100 ml) and the resulting mixture stirred at room temperature for 1 h. The aqueous layer was extracted with ethyl acetate (100 ml), the organic extracts combined, washed with hydrochloric acid (1 N, 100 ml), sodium carbonate (2 N, 100 ml) dried (MgSO4) and evaporated in vacuo to give an oil. The oil was purified by flash chromatography eluted with chloroform:methanol (19:1) to give the title compound as a foam which collapsed to a gum (2.4 g) T.l.c. Silica, Chloroform-methanol (19:1) det. u.v.+CeIVRf 0.34
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]3)=[CH:11][CH:10]=2)[C:5](=[O:26])[N:4]([CH3:27])[CH:3]=1.[ClH:28].O1CCOCC1>CO>[ClH:28].[NH:17]1[CH2:18][CH:15]([C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]3[C:5](=[O:26])[N:4]([CH3:27])[CH:3]=[C:2]([Br:1])[N:7]=3)=[CH:14][CH:13]=2)[CH2:16]1
Reactant: Cn1cc(Br)nc(Nc2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2)c1=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cn1cc(Br)nc(Nc2ccc(C3CNC3)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
A mixture of 298b (690 mg, 1.6 mmol) and HCl/1,4-dioxane (8M, 8 mL) in methanol (30 mL) was stirred at room temperature overnight. The mixture was evaporated in vacuo and the residue was purified on reverse phase Combi-flash to give 298c (100 mg, 17%). MS: [M+H]+ 335.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH3:12][C:13]([O:16][C:17]([NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:18])([CH3:15])[CH3:14]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:23]2[CH2:22][CH2:21][CH:20]([NH:19][C:17](=[O:18])[O:16][C:13]([CH3:14])([CH3:12])[CH3:15])[CH2:25][CH2:24]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)cc2[N+](=O)[O-])CC1
Yield: 95 %

Procedure:
Method 1 was followed using 1 eq each of 4-chloro-1-fluoro-2-nitrobenzene, 4-N-Boc-aminopiperidine, and TEA yielding tert-butyl 1-(4-chloro-2-nitrophenyl)piperidin-4-ylcarbamate (95%). LCMS (m/z): 356.1 (MH+); LC Rt=3.43 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:32]([CH2:34][NH2:35])[OH:33]>C1COCC1>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][CH2:16][C:17]([NH:35][CH2:34][CH2:32][OH:33])=[O:19]
Reactant: NCCO
Reactant: COc1c(C)c(C)c(OC)c(CCCC(=O)O)c1C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1c(C)c(C)c(OC)c(CCCC(=O)NCCO)c1C
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 74.9 %

Procedure:
In 25 mL THF was dissolved 4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-butanoic acid (1.32 g, 4.96 mmol) prepared as described in Example 1. CDI (884 mg, 5.46 mmol, 1.1 equiv.) was added and the solution stirred for 1.75 h at room temperature. A small portion (2 mL) was removed for other studies. The remainder was treated with 370 μL ethanolamine (365 mg, 5.96 mmol, 1.3 equiv.) and let stir at room temperature overnight. The clear pale brown solution was concentrated and the residue dissolved into 100 mL isopropyl acetate and washed with 100 mL 1.25 M HCl, 1×100 mL saturated aqueous NaCl, 1×50 mL brine and dried over Na2SO4. The reaction mixture was concentrated yielding 1.15 g of a white powder. M++H at 310 m/z;
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1([CH2:20][CH2:21][N:22]2[C@H:27]3[CH2:28][CH2:29][C@@H:23]2[CH2:24][CH:25]([N:30]2[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[N:32]=[C:31]2[CH3:39])[CH2:26]3)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1)C(=O)OC(C)(C)C.Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.O1CCOCC1>[CH3:1][NH:2][CH2:10][C:11]1([CH2:20][CH2:21][N:22]2[C@H:27]3[CH2:28][CH2:29][C@@H:23]2[CH2:24][CH:25]([N:30]2[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[N:32]=[C:31]2[CH3:39])[CH2:26]3)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(CN(C)C(=O)OC(C)(C)C)CCc2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNCC1(CCN2[C@@H]3CC[C@H]2CC(n2c(C)nc4ccccc42)C3)CCc2ccccc21
Yield: 34.9 %

Procedure:
tert-butyl methyl[(1-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2,3-dihydro-1H-inden-1-yl)methyl]carbamate (0.7425 g, 1.404 mmole) was dissolved in 2 ml of DCM and 2 ml of 4M HCl in dioxane. After stirring the reaction was neutralized with saturated NaHCO3 and extracted with Et2O to afford N-methyl(1-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2,3-dihydro-1H-inden-1-yl)methanamine (0.21 g, 35% yield).
Reaction SMILES: [O-:1][N+:2]1[C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:6]=2[N:5]=[C:4]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH:21]([C:24]#[N:25])[CH2:20]2)[N:3]=1)[CH2:12][CH2:11][CH2:10]3.[O-:26][N+]1C2C3CCCC=3C=CC=2N=C(NCCN(CCC)CCC)N=1>>[O-:1][N+:2]1[C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:6]=2[N+:5]([O-:26])=[C:4]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH:21]([C:24]#[N:25])[CH2:20]2)[N:3]=1)[CH2:12][CH2:11][CH2:10]3
Reactant: CCCN(CCC)CCNc1nc2ccc3c(c2[n+]([O-])n1)CCC3
Reactant: N#CC1CCN(CCCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)C1
Product: N#CC1CCN(CCCNc2n[n+]([O-])c3cc4c(cc3[n+]2[O-])CCC4)C1

Procedure:
H2O2 (70%, 0.67 mL, ca. 13.3 mmol) was added dropwise to a stirred solution of TFAA (1.9 mL, 13.3 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 56 (449 mg, 1.3 mmol) and TFA (0.51 mL, 6.6 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 8 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with DCM (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 56 (198 mg, 44%) and (ii) 1,4-dioxide 57 (70 mg, 15%) as a red gum: 1H NMR δ 8.15 (br t, J=5.3 Hz, 1H, NH), 8.12 (s, 1H, H-9), 8.08 (s, 1H, H-5), 3.62-3.68 (m, 2H, CH2N), 3.15-3.23 (m, 2H, CH2N), 3.11 (br t, J=7.5 Hz, 2H, H-6), 3.07 (br t, J=7.5 Hz, 2H, H-8), 2.90-2.95 (m, 1H, CHCN), 2.73 (t, J=6.3 Hz, 2H, CH2N), 2.50-2.61 (m, 2H, CH2N), 2.33-2.43 (m, 1H, CH2), 2.11-2.24 (m, 3H, CH2, H-7), 1.91 (p, J=6.3 Hz, 2H, CH2); 13C NMR δ 155.7, 149.4, 145.7, 138.0, 129.6, 122.0, 115.8, 111.5, 57.3, 53.5, 52.8, 41.0, 33.4, 32.3, 29.1, 26.9, 26.1, 25.3; MS (FAB+) m/z 355 (MH+, 30%), 339 (10); HRMS (FAB+) calcd for C18H23N6O2 (MH+) m/z 355.1883, found 355.1893.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](OS(C(F)(F)F)(=O)=O)=[C:7]([Cl:19])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][NH2:30])[CH:25]=[CH:26][CH:27]=1.CN([CH:36]=[O:37])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:36]([NH:30][CH2:29][CH2:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:31])([F:32])[F:20])[CH:23]=2)=[O:37])=[C:7]([Cl:19])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=O
Reactant: NCCc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)c1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)c1ccc(C(=O)NCCc2cccc(C(F)(F)F)c2)c(Cl)c1
Temperature: 70 °C
Yield: 39 %

Procedure:
633 mg (2 mmol) of trifluoro-methanesulfonic acid 4-tert-butyl-2-chloro-phenyl ester (prepared as described in example S80) and 416 mg (2.2 mmol) of 2-(3-trifluoromethyl-phenyl) ethyl amine were dissolved in 10 ml DMF. Under argon at rt 13.4 mg (0.06 mmol) of palladium acetate and 24.8 mg (0.06 mmol) of dppp were added. The reaction mixture was evacuated and charged with carbon monoxide gas three times. The reaction mixture was heated to 70° C. under a carbon monoxide atmosphere for 1 h. Water was added and the reaction mixture was extracted twice with EtOAc. The combined organic layers were washed with 1N aqueous HCl solution, once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (45 g silica gel, heptane/EtOAc 7:3) to yield 298 mg (39%) of 4-tert-butyl-2-chloro-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide as a light yellow solid. 1H NMR (DMSO-d6, 300 MHz): δ 8.43 (t, 1H), 7.61-7.55 (m, 4H), 7.41 (s, 1H), 7.36 (d, 2H), 7.22 (d, 1H), 3.50 (q, 2H), 2.93 (t, 2H), 1.27 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:59])[C:3]1[N:4]=[C:5]([CH2:55][CH2:56][CH2:57][CH3:58])[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]=1[C:8]([O:10]CC1C=CC=CC=1)=[O:9]>CCO.[Pd]>[CH3:1][N:2]([CH3:59])[C:3]1[N:4]=[C:5]([CH2:55][CH2:56][CH2:57][CH3:58])[N:6]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:32][N:33]=[N:34][N:35]=3)=[CH:23][CH:24]=2)[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCCCc1nc(N(C)C)c(C(=O)OCc2ccccc2)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCc1nc(N(C)C)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
The title material can be prepared by treating a mixture of 4-(dimethylamino)-2 butyl 5-benzyloxycarbonyl-1-(2'-(N-triphenylmethyltetrazol-5-yl)biphen 4-yl)methylimidazole and 5 weight % of 10% Pd-C with H2 (at 40 psi) in EtOH for 16 hours, followed by filtration (Celite) and purification (SiO2 '35:65:1 CH2Cl2 /MeOH/NH4OH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:36][O:37][C:4]=2[CH:3]=1)[CH2:13][CH2:12][N:11]([C:14]([C:16]1[CH:17]=[N:18][C:19]2[N:20]([N:30]=[CH:31][C:32]=2[C:33](O)=[O:34])[C:21]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)=[O:15])[CH2:10][CH2:9]3.[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:36][O:37][C:4]=2[CH:3]=1)[CH2:9][CH2:10][N:11]([C:14]([C:16]1[CH:17]=[N:18][C:19]2[N:20]([N:30]=[CH:31][C:32]=2[C:33]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:34])[C:21]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)=[O:15])[CH2:12][CH2:13]3
Reactant: Cc1ccc(Nc2c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc3c(C(=O)O)cnn23)cc1
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc(C)cc3)c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc12
Yield: 59.9 %

Procedure:
In the same manner as in Example 1, step 6 and using 6-(6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)-7-(4-methylphenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.031 g, 0.062 mmol) obtained in step 4 and ethanesulfonamide (0.034 g, 0.309 mmol), the title compound (0.022 g, 60%) was obtained.
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:37][N:38]1[CH:42]=[C:41](B(O)O)[CH:40]=[N:39]1>C(#N)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>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:41]4[CH:40]=[N:39][N:38]([CH3:37])[CH:42]=4)=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: Cn1cc(B(O)O)cn1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
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: O
Solvent: CC#N
Product: COc1cccc(-c2c(-c3cnn(C)c3)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 80 °C
Yield: 35.1 %

Procedure:
A mixture of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (Example 33) (50 mg, 0.095 mmol), tetrakis(triphenylphosphine)palladium(0) (5.51 mg, 4.77 μmol), sodium carbonate (20.23 mg, 0.191 mmol) and (1-methyl-1H-pyrazol-4-yl)boronic acid (12.02 mg, 0.095 mmol) in acetonitrile (1 mL) and water (0.250 mL) was heated at 80° C. under nitrogen, overnight (ca. 18 h). The reaction mixture was then cooled to RT and concentrated. The residue was purified by chromatography on silica, eluting with a gradient of 0-50% ethyl acetate in DCM, to give the title compound (17.5 mg). LCMS (A) m/z: 525 [M+1]+, Rt 1.34 min (acidic).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH2:22][C:23](=[O:32])[NH:24][C:25](=[NH:31])[N:26]3[CH:30]=[CH:29][CH:28]=N3)[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)=[CH:7][CH:6]=1)[CH3:2].NCCC[OH:38].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]([NH:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH2:22][C:23]([NH:24][C:25]([NH2:31])=[N:26][CH2:30][CH2:29][CH2:28][OH:38])=[O:32])[C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCNC(=O)c1ccc(-c2ccc(-c3ccccc3)n2CC(=O)NC(=N)n2cccn2)cc1
Reactant: NCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=O)c1ccc(-c2ccc(-c3ccccc3)n2CC(=O)NC(N)=NCCCO)cc1
Yield: 29.4 %

Procedure:
To a slurry of ˜0.12 mmol ethyl benzamide from Step 5 in 2 mL CH2Cl2 was added 27 mg (0.36 mmol, 3 equiv.) 3-aminopropanol and 62 μL (0.36 mmol) diisopropylethylamine and the reaction was mixed overnight at room temperature. The reaction was concentrated and the residue was purified by preparative 6HPLC to afford 15.8 mg of the title compound [5LC-MS data (molecular ion and retention time): m/z 448 (M+H); 1.90 min] as an oil.