Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:12])=[C:7]([C:10]#[N:11])[S:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3].C([O-])(O)=O.[Na+].Cl.[NH2:19][OH:20]>CO>[OH:20][NH:19][C:10]([C:7]1[S:8][CH:9]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6]=1[CH3:12])=[NH:11]
Reactant: Cc1c(CC(C)C)csc1C#N
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1c(CC(C)C)csc1C(=N)NO
Temperature: 60 °C
Reaction time: 20 h
Yield: 120.8 %

Procedure:
To a solution of 4-isobutyl-3-methyl-thiophene-2-carbonitrile (2.10 g, 11.7 mmol) in methanol (50 mL), NaHCO3 (1.38 g, 16.4 mmol) followed by hydroxylamine hydrochloride (977 mg, 14.1 mmol) is added. The mixture is stirred at 60° C. for 20 h before it is filtered. The solvent of the filtrate is evaporated and the remaining residue is dried under HV go give N-hydroxy-4-isobutyl-3-methyl-thiophene-2-carboxamidine (3.0 g) as a yellow solid; LC-MS: tR=0.67 min.
Reaction SMILES: ClC1C=CC(OC)=CC=1C1C=C(C)C2[N:14]=C(N)N=NC=2C=1.Br[C:23]1[CH:24]=[C:25]([CH:34]=[CH:35][CH:36]=1)[O:26][CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:29]1([CH2:28][CH2:27][O:26][C:25]2[CH:24]=[C:23]([NH2:14])[CH:36]=[CH:35][CH:34]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Brc1cccc(OCCN2CCCC2)c1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(N)nnc3c2)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Nc1cccc(OCCN2CCCC2)c1
Yield: 154.3 %

Procedure:
In a dry 25 mL round bottom flask, 7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamine (0.113 g, 0.377 mmol, 1 equiv), 1-[2-(3-bromo-phenoxy)-ethyl]-pyrrolidine (0.153 g, 0.565 mmol, 1.5 equiv), cesium carbonate (0.368 g, 1.13 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.044 g, 0.0753 mmol, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium (0.034 g, 0.0376 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (8 mL) and outfitted with reflux condenser. The reaction was heated to reflux for 18 hours, then filtered hot and the solvents were diluted with ethyl acetate and washed with brine. The brine layer was back extracted once with fresh ethyl acetate. The organic phases were combined and dried over sodium sulfate (Na2SO4). Filtration followed by evaporation and column chromatography (1:5 MeOH/DCM) provided desired product as a yellow powder (0.12 g, 65% yield). MS (ESI+): m/z=491.1, LC retention time: 2.94 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.Cl[CH2:25][C:26]1[C:27]([CH3:36])=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[N:15]([CH2:25][C:26]4[C:27]([CH3:36])=[N:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(C(F)(F)F)ccc1CCl
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 80 °C
Reaction time: 5.5 h
Yield: 52.4 %

Procedure:
To a solution of 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (162 mg, 0.50 mmol) and 3-(chloromethyl)-2-methyl-6-(trifluoromethyl)pyridine (137 mg, 0.65 mmol) in anhydrous DMF (1.5 mL) at room temperature was added anhydrous K2CO3 (105 mg, 0.75 mmol). The resulting yellow suspension was stirred at 80° C. for 5.5 h. Analysis by HPLC/MS indicated that starting 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one had been consumed. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (20 mL×3). The combined EtOAc extracts were washed with water, then saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (40 g) eluted with a gradient of ethyl acetate (0-70%) in hexanes to afford 130 mg (53%) of the title compound as a light brown foam. The product was further purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 90% B over 10 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The resulting residue was dissolved in EtOAc, washed with saturated aqueous Na2CO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The residue was dissolved in acetonitrile, frozen and lyophilized to afford the title compound as a light yellow powder. HPLC/MS: retention time=2.80 min, [M+H]+=496.2. 1H NMR (CDCl3, 400 MHz): δ 8.56 (d, J=6.2 Hz, 2H), 7.87 (d, J=7.0 Hz, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.27 (d, J=8.8 Hz, 2H), 7.17 (d, J=6.2 Hz, 2H), 7.05 (d, J=8.8 Hz, 2H), 6.66 (d, J=7.5 Hz, 1H), 5.23 (s, 2H), 2.75 (s, 3H).
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][C:5]1([CH2:18][OH:19])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C1OCCOCCOCCOCCOCCOC1.[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCCC1.[Cl-].[Na+].O>[OH:3][CH2:4][C:5]1([CH2:18][O:19][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(CO)CC1
Reactant: BrCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CO)(COCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.3 %

Procedure:
Finely ground potassium hydroxide (248 mg, 44 mmol) was added to a stirred, cooled (10° C.) solution of 1,1-dimethylethyl 4,4-bis(hydroxymethyl)-1-piperidinecarboxylate (Description 67, 1.83 g, 7.4 mmol), 18-crown-6 (196 mg, 0.74 mmol) and benzyl bromide (884 μL, 7.4 mmol) in tetrahydrofuran (80 mL) and the mixture was stirred at room temperature for 16 hours. Brine (40 mL) was added and the layers were separated. The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (80:20 increasing to 50:50) to give the title compound (1.0 g, 40%). m/z (ES+) 336 (M+1).
Reaction SMILES: I[C:2]1[N:25]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=[CH:8][C:9]([C:10]3[C:11]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=4)=[N:12][N:13]([CH3:15])[CH:14]=3)=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[N:45][C:46]([N:49]3[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]3)=[N:47][CH:48]=2)O1.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:15][N:13]1[CH:14]=[C:10]([C:9]2[CH:8]=[CH:7][N:6]=[C:5]3[N:25]([S:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)(=[O:27])=[O:28])[C:2]([C:43]4[CH:48]=[N:47][C:46]([N:49]5[CH2:50][CH2:51][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:53][CH2:54]5)=[N:45][CH:44]=4)=[CH:3][C:4]=23)[C:11]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Cn1cc(-c2ccnc3c2cc(I)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1cc(-c2ccnc3c2cc(-c2cnc(N4CCN(C(=O)OC(C)(C)C)CC4)nc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 95 °C

Procedure:
To a solution of 2-iodo-4-[1-methyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.321 mmol) and 1,1-dimethylethyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyrimidinyl]-1-piperazinecarboxylate (0.353 mmol) in 1,4-dioxane (3 ml) was added saturated NaHCO3(aq) (0.85 ml). After degassing with argon for 10 minutes, dichlorobis(triphenylphosphine) palladium(II) (0.0161 mmol) was added and the resulting mixture was heated at 95° C. overnight. Upon cooling, the reaction was concentrated and partitioned between EtOAc and H2O. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated to yield the title compound as a yellow oil (quant.). ESMS [M+H]+: 722.2.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[C:13]([C:21]([O:23]C)=[O:22])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[C:27]([F:30])([F:29])[F:28].C1COCC1.[Li+].[OH-].Cl>O>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[C:13]([C:21]([OH:23])=[O:22])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[C:27]([F:30])([F:28])[F:29]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)ncnc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc([N+](=O)[O-])cc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)ncnc12
Yield: 97 %

Procedure:
Methyl 4-{[4-chloro-3-(trifluoromethyl)benzyl]amino}-6-nitroquinazoline-8-carboxylate (190 mg, 0.43 mmol) was treated with a mixture of 650 μL of THF and 650 μL of 2N LiOH (1.3 mmol, 3 equiv.)) at rt for 2 h. Water was added and pH was adjusted to ˜4 with 2N HCl. The precipitate was collected as the desired acid by filtration, and washing with water in 97% yield. 1HNMR (in DMSO): 4.95 (s, 2H), 7.69-7.74 (m, 2H), 7.94 (d, J=1.4 Hz, 1H), 8.81 (s, 1H), 9.02 (d, J=2.2 Hz, 1H), 9.62 (d, J=2.5 Hz, 1H). Mass: M+H+: 427.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:17][C:18](=[CH2:21])[CH2:19]O>>[CH3:19][C:18](=[CH2:17])[CH2:21][O:15][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9](=[O:10])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: C=C(C)CO
Reactant: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)O
Product: C=C(C)COC(=O)[C@H](C)NC(=O)Cc1cccc(Cl)c1

Procedure:
Following General Procedure C above, and using N-(3-chlorophenylacetyl alanine (from Example D above) and 2-methylprop-2-en-1-ol (Aldrich) the title compound can be prepared. The reaction was monitored by tlc on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant.
Reaction SMILES: Br[C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Li]C.C([Li])CCC.[CH3:41][S:42]SC>C1COCC1>[CH3:41][S:42][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CSSC
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Agent: [Li]C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1cnc2[nH]cc(NC(=O)c3cccnc3)c2c1N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
(R)-tert-Butyl 1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (150 mg, 0.291 mmol; Example 1A, Step A) was dissolved in THF (20 mL) and cooled to −78° C. MeLi (546 μL, 0.873 mmol) was then added slowly, and the reaction was stirred for 10 minutes. n-Butyl lithium (128 μL, 0.320 mmol) was added next, and the reaction was stirred for an additional 10 minutes, followed by the addition of 1,2-dimethyldisulfane (31.5 mg, 0.335 mmol). The reaction was stirred for 30 minutes and then quenched with water. The reaction was extracted several times with DCM. The organic layer was dried, filtered, and concentrated. The resulting residue was purified by reverse phase chromatography (Biotage Horizon, C-18 25M+, 10-85% CH3CN/water) to provide 50% pure (R)-tert-butyl 1-(5-(methylthio)-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate, which was used without further purification.
Reaction SMILES: [ClH:1].[F:2][C:3]1([F:23])[CH2:11][N:10]2[C@H:5]([CH2:6][CH:7]([NH:14][C@H](C3C=CC=CC=3)C)[CH2:8][C:9]2([CH3:13])[CH3:12])[CH2:4]1.[H][H]>CO>[ClH:1].[F:23][C:3]1([F:2])[CH2:11][N:10]2[C@H:5]([CH2:6][CH:7]([NH2:14])[CH2:8][C:9]2([CH3:13])[CH3:12])[CH2:4]1
Reactant: C[C@H](NC1C[C@@H]2CC(F)(F)CN2C(C)(C)C1)c1ccccc1
Reactant: [H][H]
Agent: Cl
Solvent: CO
Product: CC1(C)CC(N)C[C@@H]2CC(F)(F)CN21
Reaction time: 39 h

Procedure:
A MeOH (20 ml) solution of (8aR)-2,2-difluoro-octahydro-5,5-dimethyl-N—((S)-1-phenylethyl)indolizin-7-amine hydrogen chloride and Pd(OH)2—C (20% on activated carbon, 50% wet, 0.2 g) was hydrogenated in a Parr flask under 45 psi of hydrogen. Additional Pd(OH)2—C was added (˜0.2 g) was added at 16 hours and 24 hours, and the reaction went to completion at 39 hours monitored by LC-MS. Solid was removed by filtration through a short Celite column, washing with MeOH. Filtrate was collected, solvent was removed in vacuo. Compound (8aR)-2,2-difluoro-octahydro-5,5-dimethylindolizin-7-amine hydrogen chloride was obtained as an off-white solid and was used directly in next reaction: 0.56 g; LRMS] (M+H) m/z 204.99.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:39])[N:7]2[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([N:20]([CH2:28][C:29]2[CH:38]=[CH:37][C:32]3[O:33][CH2:34][CH2:35][O:36][C:31]=3[CH:30]=2)C(=O)OC(C)(C)C)[CH2:16][CH2:15]1.Cl.O1CCOCC1>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:39])[N:7]2[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH:20][CH2:28][C:29]2[CH:38]=[CH:37][C:32]3[O:33][CH2:34][CH2:35][O:36][C:31]=3[CH:30]=2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(Cl)cccc32)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1ccc2c(Cl)cccc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 129.1 %

Procedure:
To 0.28 g of tert-butyl (1-(2-(5-chloro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate, 6 mL of 1,4-dioxane and 2 mL of 4 mol/L hydrogen chloride/1,4-dioxane were added, and stirred at room temperature overnight. The resulting solid was filtered to give 0.16 g of 5-chloro-1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)quinolin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: [F:1][CH:2]([F:40])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:40][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([NH:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(N2CCOCC2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CCNCC2)nc(N2CCOCC2)n1

Procedure:
tert-Butyl 4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-1-piperidinecarboxylate (Example 5) was reacted with TFA in CH2Cl2 to give 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(4-piperidinyl)-1,3,5-triazin-2-amine, which was reacted directly with methanesulfonyl chloride to give 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine in 83% yield: mp (CH2Cl2/MeOH) 270-272° C.; 1H NMR (DMSO-d6) δ8.11-7.59 (m, 3H), 7.42 and 7.38 (2t, J=8.3. 8.4 Hz, 1H), 6.95 and 6.94 (2m, J=8.0, 7.8 Hz, 1H), 3.98 and 3.97 (2s, 3H), 3.79 (m, 4H), 3.70-3.69 (m, 4H), 3.60-3.56 (m, 2H), 3.56-3.24 (m, 1H), 2.94-2.85 (m, 5H), 2.04-1.97 (m, 2H), 1.65-1.54 (m, 2H); Anal. Calcd. for C22H28F2N8O4S: C, 49.1; H, 5.2; N, 20.8. Found: C, 49.3; H, 5.3; N, 20.9%.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[C:8]3=[C:9]([C:11]([NH:13][C:14](=[O:15])[C:7]3=[CH:6][CH:5]=[CH:4]2)=[O:12])[CH:10]=1.Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[N+:27]([C:18]1[CH:19]=[C:20]([C:23]([F:24])([F:25])[F:26])[CH:21]=[CH:22][C:17]=1[N:13]1[C:14](=[O:15])[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]3[C:8]=2[C:9](=[CH:10][CH:1]=[CH:2]3)[C:11]1=[O:12])([O-:29])=[O:28]
Reactant: O=C1NC(=O)c2cccc3cccc1c23
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2cccc3cccc(c23)C(=O)N1c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Eight-tenths mole (157.6 g.) of 1,8-naphthalimide, 260 g. (1.15 m.) of 4-chloro-3-nitrobenzotrifluoride, 64 g. (0.46 m.) of anhydrous potassium carbonate, about 4 g. (0.024 m.) of potassium iodide, and 2400 ml. of dry N,N-dimethylformamide were allowed to reflux under a nitrogen atmosphere for about 8 hours. The reaction mixture was allowed to cool to room temperature and the reaction vessel was then chilled in an ice-bath. The resulting precipitate was filtered, washed with water, and dried in vacuo to yield crude 2-[2-nitro-4-(trifluoromethyl)phenyl]-1H-benz[de]isoquinoline-1,3-(2H)-dione.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH:9]=[CH2:10])[CH:3]=1>C(OCC)(=O)C.[Pd]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: C=Cc1cc(Br)ccc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cc(Br)ccc1F

Procedure:
The yellow oil from step A (2.8 g, 10 mmol) was dissolved in Ethyl acetate (200 mL). Palladium-on-carbon (10%, 250 mg) was added and the mixture was hydrogenated under 1 atmosphere until TLC showed complete reaction. The mixture was filtered and the filtrate was concentrated to give an oil. 2.4 g, 87%.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][CH:11]2[O:15][C:14]([NH2:16])=[N:13][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:19](OCC)(=[O:22])[CH:20]=[CH2:21]>C(O)C>[C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][CH:11]2[O:15][C:14]3=[N:16][C:19](=[O:22])[CH2:20][CH2:21][N:13]3[CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(OCC2CN=C(N)O2)cc1
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: CC(C)(C)c1ccc(OCC2CN3CCC(=O)N=C3O2)cc1
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 30.7 %

Procedure:
To a solution of 5-(4-tert-butyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (520 mg, 2.10 mmol) in ethanol (10 mL) was added ethyl acrylate (273.3 mg, 2.73 mmol). The reaction mixture was heated in a microwave oven at 130° C. for 10 min, then at 140° C. for 10 min, and finally at 150° C. for 30 min. Solvent was removed under vacuum, and the residual solid washed with small amount of EtOH to afford 195 mg of 2-(4-tert-butyl-phenoxymethyl)-2,3,5,6-tetrahydro-oxazolo[3,2-a]pyrimidin-7-one as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.CN([CH2:17][C:18]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)C>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:17][C:18]3[C:26]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: Ic1ccc(N2CCNCC2)nc1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Solvent: Cc1ccccc1
Product: Ic1ccc(N2CCN(Cc3c[nH]c4ncccc34)CC2)nc1
Temperature: 25 °C
Yield: 88 %

Procedure:
To a solution of 1-(5-iodopyridin-2-yl)-piperazine (100 mg, 0.34 mmol) in toluene (2 mL) (prepared in Example 2(b)) was added 3-(N,N-dimethylaminomethyl)-1H-pyrrolo[2,3-b]pyridine (58 mg, 0.32 mmol) (prepared in Example 1(a)). The mixture was heated at reflux over night and then allowed to cool to room temperature. The resulting solid was filtered and dried in vacuo to give 3-[4-(5-iodopyridin-2-yl)-piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine as a colourless solid (118 mg, 79%). δH(300 MHz DMSO-d6) 2.47 (4H, m, piperazinyl), 3.45 (4H, m, piperazinyl), 3.68 (2H, s), 6.71 (1H, d, J=9), 7.05 (1H, dd, J=4.8 and 7.9), 7.39 (1H, s), 7.75 (1H, d, J=8.8), 8.06 (1H, d, J=7.8), 8.21 (1H, d, J=4.5), 8.23 (1H, s), 11.51 (1H, br s, NH)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([CH2:11][CH:12](Br)[CH2:13][C:14]([Cl:17])([F:16])[F:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C([O-])(=O)C.[Na+].[H][H]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([CH2:11][CH2:12][CH2:13][C:14]([Cl:17])([F:16])[F:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(CC(Br)CC(F)(F)Cl)C(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCCC(F)(F)Cl)C(=O)OCC

Procedure:
65.9 g of 2-(2-bromo-4-chloro-4,4-difluoro-but-1-yl)malonic acid diethyl ester, 600 ml of ethanol, 14.8 g of sodium acetate and 6.6 g of 5% palladium on activated carbon are treated with hydrogen at from 20° to 25° and under normal pressure until the absorption of hydrogen can no longer be detected. The reaction mixture is filtered over silica gel and then concentrated to dryness by evaporation in a rotary evaporator. The residue is taken up in 500 ml of n-hexane, the solution is filtered and the hexane phase is again concentrated to dryness by evaporation. The title compound is obtained in the form of a colourless oil.
Reaction SMILES: ClC1C(C(=O)N(CCCC)CCCC)=NN(C2C=CC(C(=O)NS(C3C=CC4C(=CC=CC=4)C=3)(=O)=O)=CC=2C(O)=O)C=1C.[Cl:44][C:45]1[C:46]([C:86](=[O:96])[N:87]([CH2:92][CH2:93][CH2:94][CH3:95])[CH2:88][CH2:89][CH2:90][CH3:91])=[N:47][N:48]([C:51]2[CH:61]=[CH:60][C:59]([C:62](=[O:85])[NH:63][S:64]([C:67]3[CH:68]=[C:69]4[C:73](=[CH:74][CH:75]=3)[N:72]([CH2:76][C:77]3[CH:82]=[CH:81][C:80]([Cl:83])=[C:79]([Cl:84])[CH:78]=3)[CH2:71][CH2:70]4)(=[O:66])=[O:65])=[CH:58][C:52]=2[C:53]([O:55]CC)=[O:54])[C:49]=1[CH3:50]>>[Cl:44][C:45]1[C:46]([C:86](=[O:96])[N:87]([CH2:92][CH2:93][CH2:94][CH3:95])[CH2:88][CH2:89][CH2:90][CH3:91])=[N:47][N:48]([C:51]2[CH:61]=[CH:60][C:59]([C:62](=[O:85])[NH:63][S:64]([C:67]3[CH:68]=[C:69]4[C:73](=[CH:74][CH:75]=3)[N:72]([CH2:76][C:77]3[CH:82]=[CH:81][C:80]([Cl:83])=[C:79]([Cl:84])[CH:78]=3)[CH2:71][CH2:70]4)(=[O:65])=[O:66])=[CH:58][C:52]=2[C:53]([OH:55])=[O:54])[C:49]=1[CH3:50]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4c(c3)CCN4Cc3ccc(Cl)c(Cl)c3)cc2C(=O)OCC)c(C)c1Cl
Agent: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)O)c(C)c1Cl
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4c(c3)CCN4Cc3ccc(Cl)c(Cl)c3)cc2C(=O)O)c(C)c1Cl
Yield: 85 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 91F, ethyl 2-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-5-(1-(3,4-dichlorobenzyl)indolin-5-ylsulfonylcarbamoyl)benzoate (355 mg, 0.44 mmol) was converted to the title compound (290 mg, 85%). 1H NMR (DMSO-d6) δ 8.14 (d, J=2.0 Hz, 1H), 8.17 (dd, J=8.3, 2.1 Hz, 1H), 7.69-7.57 (m, 5H), 7.32-7.30 (m, 1H), 6.65 (d, J=8.6 Hz, 1H), 4.45 (s, 2H), 3.53 (t, J=8.7 Hz, 2H), 3.40-3.28 (m, 4H), 3.05 (t, J=8.4 Hz, 2H), 2.11 (s, 3H), 1.56-1.41 (m, 4H), 1.33-1.27 (m, 2H), 1.15-1.08 (m, 2H), 0.91 (t, J=7.3 Hz, 3H), 0.74 (t, J=7.4 Hz, 3H); MS(ESI+) m/z 776.2 (M+H)+.