Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[CH:3]=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C:11]1=[O:19].[C:20]12([C:27](=[O:28])[O:26]C1=O)[CH2:23][CH2:22][CH2:21]2>>[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([C:3]([C@H:23]3[CH2:22][CH2:21][C@H:20]3[C:27]([OH:26])=[O:28])=[O:4])=[CH:16][CH:17]=2)[CH2:12][C:11]1=[O:19]
Reactant: O=C1OC(=O)C12CCC2
Reactant: O=C1Cc2ccccc2N1
Reactant: CN(C)C=O
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1Cc2cc(C(=O)[C@H]3CC[C@H]3C(=O)O)ccc2N1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
20 ml (0.26 mole) of dimethylformamide are added dropwise, while stirring, to 120 g (0.9 mole) of anhydrous aluminum chloride in the course of a few minutes, whereupon a highly exothermic reaction starts. A mixture of 11.8 g (0.089 mole) of indolin-2-one and 11.3 g (0.09 mole) of cyclobutanedicarboxylic acid anhydride is then added a little at a time at 140° C., and stirring is continued at 140° C. and for 10 minutes. The melt is now poured onto 0.5 kg of ice, the solid precipitate is filtered off with suction and the aqueous phase is extracted several times with ethyl acetate to give 21.7 g (93.6%) of cis-2-(indolin-2-on-5-oyl)cyclobutanecarboxylic acid of melting point 211°-212° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[C:12](=[O:20])[N:13]([CH3:19])[N:14]=[CH:15][C:16]=2[O:17]C)[CH:3]=1.N1CCOCC1>O>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH:11]2[C:16](=[O:17])[CH:15]=[N:14][N:13]([CH3:19])[C:12]2=[O:20])[CH:3]=1
Reactant: COc1cnn(C)c(=O)c1-n1cc(Cl)c2ccccc21
Solvent: C1COCCN1
Solvent: O
Product: CN1N=CC(=O)C(n2cc(Cl)c3ccccc32)C1=O
Temperature: 140 °C
Yield: 95 %

Procedure:
A mixture of 4-(3-Chloro-indol-1-yl)-5-methoxy-2-methyl-2H-pyridazin-3-one (1.70 g, 5.87 mmol) and morpholine (8 ml) is heated to 140° C. under microwave irradiation for 10 min. The mixture is allowed to cool then evaporated under reduced pressure to remove most of the morpholine. The residue is stirred with 1:1 v/v glacial AcOH:DCM (100 ml) to give a free-flowing semi-solid. Volatiles are removed in-vacuo and the solid obtained slurried with water. The solid is recovered by filtration under reduced pressure and dried at 1 mBar and 60° C. to give the title compound as a beige solid, 1.54 g, 95% yield. 1H nmr (DMSO-d6) δ (ppm) 7.89 (1H, s), 7.57-7.50 (2H, m), 7.24-7.17 (2H, m), 7.12-7.06 (1H, m), 3.66 (3H, s)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.N1C=CC=CC=1.[Cl:18][C:19]([Cl:24])([Cl:23])[C:20](Cl)=[O:21]>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([C:20](=[O:21])[C:19]([Cl:24])([Cl:23])[Cl:18])=[CH:6][NH:7]2
Reactant: COc1cccc2[nH]ccc12
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc2[nH]cc(C(=O)C(Cl)(Cl)Cl)c12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-methoxy-1H-indole (7.15 g, 49 mmol) and pyridine (19.7 mL, 243 mmol) in dichloromethane (50 mL) at 0° C. under nitrogen was added dropwise a solution of trichloroacetyl chloride (27.1 mL, 243 mmol) in dichloromethane (50 mL). After stirring at 0° C. for an additional 1.5 h, the mixture was concentrated in vacuo. The residue was taken up in the minimal volume of methanol necessary and placed in a freezer overnight. The precipitate was filtered, rinsed well with methanol, and dried to yield 4methoxy-3-trichloroacetyl-1H-indole. To a stirring solution of sodium methoxide (3.5 mL of a 25 weight % solution in methanol) in methanol (200 mL) at ambient temperature was added 4methoxy-3-trichloroacetyl-1H-indole (9.07 g, 31.0 mmol) in portions over 0.75 h. After stirring an additional 0.75 h, the mixture was cooled in an ice bath, diluted with ice water, acidified with concentrated hydrochloric acid, and the methanol removed in vacuo. The resulting heterogeneous mixture was cooled in an ice bath, the precipitate filtered, rinsed with water, and dried to afford methyl 4-methoxy-1H-indole-3-carboxylic ester. A slurry of this ester (5.6 g 27 mmol) in 50% aqueous sodium hydroxide (50 mL) and methanol (50 mL) was stirred at ambient temperature for 19 h. The mixture was cooled in an ice bath, acidified with concentrated hydrochloric acid, the precipitate filtered, rinsed with ice water, and dried to afford 4-methoxy-1H-indole-3-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:7].C(Cl)CCl.OC1C2N=NNC=2C=CC=1.CCN(C(C)C)C(C)C.[CH3:47][N:48]1[CH2:53][CH2:52][C:51]2[N:54]=[C:55]([NH2:57])[S:56][C:50]=2[CH2:49]1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13](=[O:15])[NH:57][C:55]2[S:56][C:50]3[CH2:49][N:48]([CH3:47])[CH2:53][CH2:52][C:51]=3[N:54]=2)[CH:11]=1)=[O:7]
Reactant: COc1ccc(C(=O)NCc2cccc(C(=O)O)c2)cc1OC
Reactant: CN1CCc2nc(N)sc2C1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3nc4c(s3)CN(C)CC4)c2)cc1OC
Reaction time: 1 h

Procedure:
Dissolved 3-[(3,4-dimethoxy-benzoylamino)-methyl]-benzoic acid (100 mg, 0.317 mmol), EDC (105 mg, 0.55 mmol) and hydroxybenzotriazole (84.2 mg, 0.55 mmol) in 1 mL of DMF. The mixture was stirred for 1 h. To this was added DIPEA (0.12 mL, 0.64 mmol) and 5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylamine (107 mg, 0.63 mmol). The mixture was placed in a 60° C. bath with an Ar stream blowing over it. The mixture stirred 14 h resulting in a concentrated residue. LC-MS analysis indicated the desired product. Dissolved in 5 mL of DMF/H2O and purified via prep HPLC (5%-95% CH3CN/H2O) to give 121.9 mg of 3,4-dimethoxy-N-[3-(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylcarbamoyl)-benzyl]-benzamide. MS, electrospray 467.4 (M+H).
Reaction SMILES: Cl.[CH2:2]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH:5]([C:12]([OH:14])=[O:13])[CH2:4][NH:3]1.N1C=CC=C[CH:16]=1.[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH3:16][O:13][C:12]([CH:5]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:2][N:3]([C:29]([O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[CH2:4]1)=[O:14]
Reactant: c1ccncc1
Reactant: O=C(O)C1CNCC12CCCCC2
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CC12CCCCC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of (4) (3 g; 10.44 mmol) and 10% Pd (OH)2/C (0.60 g; 20% w/w) in methanol (50 mL) was stirred for 24 hours at 40° C. under at atmosphere of dry hydrogen gas. The catalyst was filtered off through a celite pad, and the filtrate was concentrated in vacuo to give 2 g (10.14 mmol; 97%) of (5) as a colorless oil which was used without any further purification. To a solution of (5) (2 g; 10.14 mmol) in dry dichloromethane (100 mL) was successively added, at 0° C., under an argon atmosphere, pyridine (2.04 mL; 25.35 mmol), and benzylchloroformate (2.89 mL; 20.24 mmol). The reaction mixture was then allowed to stir at room temperature for 2 days. The reaction mixture was washed (2×50 mL) with 1N HCl, dried over MgSO4, and concentrated in vacuo. The crude oil was purified by silica-gel flash chromatography in ether/heptane (1:1) to give 2.97 g (8.96 mmol; 88%) of (6) as a colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:13]1([CH2:2][CH2:3][O:4][C:5]2[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCNC1
Reactant: O=Cc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCN2CCCC2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
A mixture of 2.29 g of 4-(2-bromoethoxy)benzaldehyde, 1.42 g of pyrrolidine and 2.07 g of potassium carbonate in 8 ml of N,N-dimethylformamide was stirred at 60° C. for 2 hours. After cooling, water was added and the whole was extracted with ethyl acetate. The ethyl acetate layer was extracted with aqueous hydrochloric acid. The aqueous layer was made alkaline with potassium carbonate and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was distilled to give 1.72 g of colorless oil, b.p. 170° C. (5 mmHg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([NH:12][C:13](=[O:15])C)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[OH-:19].[NH4+]>>[C:7]([O:15][C:13](=[O:19])[NH:12][C:5]1[CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]([Cl:1])=[CH:3][C:4]=1[N+:16]([O-:18])=[O:17])([CH3:8])([CH3:2])[CH3:6]
Reactant: CC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1[N+](=O)[O-]
Reactant: [OH-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1[N+](=O)[O-]

Procedure:
Reaction of N-(4-chloro-2-nitro-5-trifluoromethyl-phenyl)-acetamide [CAS 157554-77-3] (4.02 g, 14.2 mmol) with Boc-anhydride (3.26 g, 14.9 mmol) according to the general procedure A (method c) and subsequent reaction with ammonium hydroxide (25%; 4.38 ml, 28.4 mmol) gave after aqueous work up and purification by column chromatography on silica gel (hexane/ethyl acetate 4:1) compound A12.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.[CH3:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.C(Cl)Cl>O1CCOCC1>[F:24][CH:23]([F:25])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([N:27]([CH3:26])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: CNc1ccccc1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CN(c1ccccc1)c1nc(N2CCOCC2)nc(-n2c(C(F)F)nc3ccccc32)n1
Yield: 64 %

Procedure:
A mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (92 mg, 0.25 mmol) and N-methylaniline (67 mg, 0.625 mmol) in dioxane (5 mL) was heated under reflux for 1 hr and cooled. Dilution with water gave a precipitate, which was collected and dried. Chromatography on SiO2 eluting with CH2Cl2 gave 70 mg (64% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-methyl-6-(4-morpholinyl)-N-phenyl-1,3,5-triazin-2-amine: mp (hexanes) 160-162° C.; 1H NMR (CDCl3) δ 8.04 (m, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.49 (t, J=7.6 Hz, 2H), 7.45-7.06 (m, 7H), 3.91 (m, 4H), 3.81 (m, 4H), 3.56 (s, 3H); Anal. Calc. for C22H21F2N7O: C, 60.4; H, 4.8; N, 22.4. Found: C, 60.2; H, 5.0; N, 22.5%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>ClCCl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[F:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH:14]=[C:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:16]=2)=[N:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(F)cn3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reaction time: 3 h

Procedure:
A solution of tert-butyl-4-(3-(5-fluoropyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.274 g) in dichloromethane (2.5 mL, 0.28 M) was treated with trifluoroacetic acid (2.5 mL). The reaction was allowed to stir for 3 hours, then concentrated to an oil. The oil was used without purification. 0.466 g, quantitative yield.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([OH:9])=[CH:7][N:6]=[C:5](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1.[CH3:18][C:19](C)([O-:21])C.[K+].BrCC(OCC)=O>C(O)C>[C:12]1(/[CH:11]=[CH:10]/[C:5]2[NH:4][C:3]3[C:8]([O:9][CH2:18][C:19](=[O:21])[N:2]=3)=[CH:7][N:6]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)[O-]
Reactant: Nc1nc(/C=C/c2ccccc2)ncc1O
Agent: CCOC(=O)CBr
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: O=C1COC2=CN=C(/C=C/c3ccccc3)NC2=N1
Reaction time: 0.08 h

Procedure:
To a suspension of 4-amino-2-[(E)-2-phenylethenyl]-5-pyrimidinol hydrochloride (250 mg, 1.0 mmol) in absolute ethanol (5 mL) was added potassium tert-butoxide (224 mg, 2.0 mmol) at room temperature. After stirring for 5 minutes, ethyl bromoacetate (0.11 mL, 1.0 mmol) was added via dropwise addition and the reaction was stirred for 18 h. The solvent was evaporated and the residue was taken up in 10% MeOH—CHCl3 and a small amount of water. The layers were separated and the aqueous phase was extracted with 10% MeOH—CHCl3 (3×). The combined organic extracts were concentrated and the resulting solid was triterated with EtOAc. The white solid was collected by filtration, yielding 106 mg (42%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])[CH:5]=[CH:6][C:7]=1[CH3:8].C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])=[O:26])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(CSc2cccc[n+]2[O-])cc1C
Solvent: ClC(Cl)Cl
Product: Cc1ccc(CS(=O)c2cccc[n+]2[O-])cc1C

Procedure:
The procedure employed is identical to that of Example 68 using 7.4 gm (0.03 mol) 2-(3,4-dimethylphenylmethylthio)pyridine N-oxide in 50 ml of chloroform with 6 gm (0.03 mol) MCPBA (85%) in 100 ml chloroform.
Reaction SMILES: Br[C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1.[Cu](C#N)[C:36]#[N:37].CN1CCCC1=O>O>[C:36]([C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1)#[N:37]
Reactant: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Br
Reactant: N#C[Cu]C#N
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1C#N
Temperature: 160 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
A mixture of 0.23 g of 3-{2-bromo-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine [present compound 9-7], 75 mg of copper cyanide and 2 ml of N-methyl-2-pyrrolidone was stirred at 160° C. for 2 hours. There action mixture was cooled to room temperature, water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.16 g of 3-{2-cyano-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine [present compound 9-27].
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]2=[O:18])[CH2:4][CH2:3]1.[NH:19]1[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[O:25])[CH2:20]1>>[O:18]=[C:9]1[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][N:8]1[CH:5]1[CH2:6][CH2:7][CH:2]([N:19]2[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=3)=[O:25])[CH2:20]2)[CH2:3][CH2:4]1
Reactant: O=C1CCC(n2cc(C(F)(F)F)ccc2=O)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3cc(C(F)(F)F)ccc3=O)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 1-(4-oxo-cyclohexyl)-5-trifluoromethyl-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7](I)=[N:6]1.CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC.Cl[C:46]1[N:51]=[C:50]([NH2:52])[C:49]([N+:53]([O-:55])=[O:54])=[CH:48][CH:47]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:46]2[N:51]=[C:50]([NH2:52])[C:49]([N+:53]([O-:55])=[O:54])=[CH:48][CH:47]=2)=[N:6]1
Reactant: Fc1ccccc1Cn1nc(I)c2cccnc21
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: CCCC[Sn](CCCC)CCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)ccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 8 h

Procedure:
200 mg (0.57 mmol) of the compound from example 33A were initially charged in dimethylformamide (5.3 ml) under argon, then 0.43 ml (0.85 mmol) of hexabutylditin and 160 mg (0.92 mmol) of 6-chloro-3-nitropyridin-2-amine were added, and the reaction mixture was purged with argon for 10 min. Subsequently, 231 mg (0.28 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane complex (1:1) were added and the reaction mixture was stirred at 110° C. overnight. The mixture was then cooled to RT, saturated aqueous sodium hydrogencarbonate solution was added and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was extracted by stirring in dichloromethane/methanol (1:1), and the solids were filtered off and dried under high vacuum. This gave 95 mg (54% purity, 15% of theory) of the title compound. The filtrate was chromatographed on silica gel (eluent: 20:1 cyclohexane/ethyl acetate) and the product fractions were concentrated. The residue was suspended in methanol, the solids were filtered off and drying under high vacuum afforded a further 30 mg (15% of theory) of the title compound in solid form. The fractions were combined and converted without further purification (purity approx. 60%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:32]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:33])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)C2CCCCC2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.4 %

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.46 mmol) and triethylamine (92 μL, 0.66 mmol) in methylene chloride (20 mL) was added dropwise cyclohexanecarbonyl chloride (67 μL, 0.46 mmol) in methylene chloride (5 mL). After the addition the reaction was allowed to stir at ambient temperature for 10 min and then washed with dilute aqueous sodium hydrogen carbonate. The organic phase was separated, dried (Na2SO4), filtered and evaporated in vacuo and the residue was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. This gave 71 mg (45% yield) of the title compound as white crystals: mp 183-184° C.; [α]21D +12° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 355 (56, M+).
Reaction SMILES: O[CH:2]([C:4]1([C:12]([O:14][CH3:15])=[O:13])[CH2:7][C:6]([O:10][CH3:11])([O:8][CH3:9])[CH2:5]1)[CH3:3].N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH3:11][O:10][C:6]1([O:8][CH3:9])[CH2:5][C:4]([CH:2]=[CH2:3])([C:12]([O:14][CH3:15])=[O:13])[CH2:7]1
Reactant: COC(=O)C1(C(C)O)CC(OC)(OC)C1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: C=CC1(C(=O)OC)CC(OC)(OC)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73.4 %

Procedure:
To a solution of methyl 1-(1-hydroxyethyl)-3,3-dimethoxycyclobutanecarboxylate (3.28 g, 15.03 mmol) and pyridine (2.4 mL, 29.83 mmol) in CH2Cl2 (65 mL) was added trifluoromethanesulfonic anhydride (3.0 mL, 17.86 mmol) at −78° C. The mixture was stirred for 10 minutes and then warmed to 0° C. After stirring for 15 minutes at 0° C., DBU (9.0 mL, 60.18 mmol) was added to the reaction mixture and the resulting mixture was stirred for 1 hour at room temperature. The mixture was partially evaporated under reduced pressure and filtrated through the pad of silica gel and washed with CH2Cl2. The filtrate was washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, and evaporated. The residue was diluted with hexane/EtOAc=4:1 and added small amount of CHCl3 and filtrated through the pad of silica gel to give methyl 3,3-dimethoxy-1-vinylcyclobutanecarboxylate (2.21 g).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[N:8][C:9](I)=[C:10]([Cl:13])[CH:11]=2)[N:6]=[C:5]1[O:15][C@@H:16]1[CH2:20][O:19][C@@H:18]2[C@H:21]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:22][O:23][C@H:17]12)[CH:2]=[CH2:3].CC1(C)C(C)(C)OB([C:40]2[CH:45]=[CH:44][C:43]([N:46]3[CH2:50][CH2:49][CH2:48][CH2:47]3)=[CH:42][CH:41]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl>[CH2:1]([N:4]1[C:12]2[C:7](=[N:8][C:9]([C:40]3[CH:41]=[CH:42][C:43]([N:46]4[CH2:47][CH2:48][CH2:49][CH2:50]4)=[CH:44][CH:45]=3)=[C:10]([Cl:13])[CH:11]=2)[N:6]=[C:5]1[O:15][C@@H:16]1[CH2:20][O:19][C@@H:18]2[C@H:21]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:22][O:23][C@H:17]12)[CH:2]=[CH2:3]
Reactant: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O[Si](C)(C)C(C)(C)C)nc2nc(I)c(Cl)cc21
Reactant: CC1(C)OB(c2ccc(N3CCCC3)cc2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O[Si](C)(C)C(C)(C)C)nc2nc(-c3ccc(N4CCCC4)cc3)c(Cl)cc21
Temperature: 80 °C
Reaction time: 15 h

Procedure:
1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichlormethane complex (17.1 mg, 0.021 mmol) was added to a stirred suspension of [(3R,3aR,6R,6aS)-3-(1-allyl-6-chloro-5-iodo-imidazo[4,5-b]pyridin-2-yl)oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy-tert-butyl-dimethyl-silane (99.8 mg, 0.173 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine (59.6 mg, 0.218 mmol), and tripotassium phosphate (225.0 mg, 1.060 mmol) in dioxane (1.38 ml) and water (0.35 ml). The reaction mixture was degassed (3×) and placed under nitrogen before being heated to 80° C. After 15 hours, the reaction mixture was cooled to room temperature. The reaction mixture was partitioned between EtOAc (40 ml) and water (40 ml). The aqueous layer was extracted with EtOAc (2×20 ml). The organic layers were combined, washed with brine, dried over MgSO4, filtered, and evaporated under reduced pressure to give an amber residue. This residue was dissolved in DCM, loaded onto a 5 g silica solid load cartridge and purified using an ISCO Rf and a 4 g silica column (CV=4.8 ml). The column was eluted as follows: 100% hexane (5 CV), 0-30% EtOAc/hexane gradient (70 CV), 30% EtOAc/hexane (21 CV) at 18 ml/min. The product fractions were combined and evaporated under reduced pressure to give the title compound as a yellow residue. LC-MS: calculated for C31H41ClN4O4Si 596.26 observed m/e: 597.39 (M+H)+ (Rt 1.34/2 min).