Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([NH:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1.C(N(CC)CC)C.[Br:27][C:28]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:29]=1[C:30](Cl)=[O:31]>C(Cl)Cl>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([N:14]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:30](=[O:31])[C:29]4[CH:33]=[C:34]([N+:37]([O-:39])=[O:38])[CH:35]=[CH:36][C:28]=4[Br:27])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1
Reactant: CN(C)CCNc1ccnc2cc3c(cc12)OCO3
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCN(C(=O)c1cc([N+](=O)[O-])ccc1Br)c1ccnc2cc3c(cc12)OCO3

Procedure:
To a solution of compound 7 (259 mg, 1.0 mmol) and triethylamine (0.5 mL) in dry CH2Cl2 (20 mL) was added a solution of 2-bromo-5-nitrobenzoic acid chloride in 20 mL of CH2Cl2 (which was prepared by refluxing of 295 mg, 1.2 mmol of 2-bromo-5-nitrobenzoic acid in 10 mL of thionyl chloride for 3 h.) and reaction mixture was heated to reflux for 4 h. The reaction mixture was washed with saturated NaHCO3 solution, water and brine and dried over Na2SO4. The solvent was removed in vacuo to give a yellow solid; yield 350 mg (71.8%); mp 204–5° C.; 1H NMR (CDCl3) δ (2.3, s, 6H), 2.53–2.64 (m, 2H), 3.67–3.81 (m, 1H), 4.42–4.55 (m, 1H), 6.19 (s, 2H), 7.31 (s, 1H), 7.34 (d, 1H, J=4.8), 7.43 (s, 1H), 7.52 (d, 1H, J=8.8), 7.76 (dd, 1H, J=2.6, 8.4), 7.87 (d, 1H, J=2.6), 8.53 (d, 1H, J=4.8); 13C NMR (CDCl3) δ 45.4, 46.6, 56.4, 97.9, 102.4, 106.6, 119.4, 122.3, 122.8, 124.6, 127.2, 134.0, 139.0, 144.5, 145.9, 148.1, 148.5, 149.6, 151.5, 166.5.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C@@H:12](O)([CH2:14][CH3:15])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[CH3:13][C@@H:12]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH2:14][CH3:15]
Reactant: CC[C@H](C)O
Reactant: COC(=O)c1cccc(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC[C@@H](C)Oc1cccc(C(=O)OC)c1
Temperature: 25 °C

Procedure:
To a 0° C. solution of methyl 3-hydroxybenzoate (5.00 g, 32.9 mmol) in toluene (32.9 ml) was added (S)-(+)-sec-butanol (3.34 ml, 36.1 mmol), triphenylphosphine (9.48 g, 36.1 mmol), and DIAD (7.03 ml, 36.1 mmol). After warming to rt overnight, the reaction mixture was filtered through a fritted funnel and washed with toluene. The filtrate was concentrated. The residue was purified on a silica gel cartridge (0% EtOAc/hexanes to 10% EtOAc/hexanes) to give the desired product.
Reaction SMILES: C([Li])CCC.[C:6]1([CH:12]([CH3:16])[C:13]([OH:15])=O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN(C)CCN(C)C.[C:25]([O:30][CH2:31][CH3:32])(=[O:29])C([O-])=O.C(=O)([O-])O.[Na+]>CCCCCC.O1CCCC1>[O:15]=[C:13]([CH:12]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH3:16])[C:25]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)C(=O)[O-]
Reactant: CC(C(=O)O)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(C)c1ccccc1
Temperature: -70 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
A 1.6 N solution of n-butyllithium in hexane was run dropwise into a solution, cooled to the region of -70° C., of 33 g (0.220 mol) of (RS)-2-phenylpropionic acid in 220 cm3 of tetrahydrofuran and of 44 cm3 of N,N'-tetramethylethylenediamine. After having stirred the reaction mixture for three hours at -70° C., the reaction mixture was returned to a temperature in the region of 20° C. and the solution obtained was run into a solution of 75 cm3 (0.55 mol) of ethyl oxalate in 110 cm3 of tetrahydrofuran, the temperature being maintained at -75° C., for 1 hour. The reaction mixture was hydrolysed with 800 cm3 of a saturated aqueous sodium hydrogencarbonate solution, extracted with three times 100 cm3 of ethyl acetate, washed with three times 50 cm3 of a normal aqueous hydrochloric acid solution, dried over sodium sulphate and concentrated under reduced pressure. 44 g (97%) of ethyl(RS)-2-oxo-3-phenylbutyrate were then obtained in the form of an orange oil, the characteristics of which were as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].[N+:17]([O-])([OH:19])=[O:18].S(=O)(=O)(O)O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:4]([NH:6][CH2:7][CH3:8])=[O:5])=[C:9]([Si:13]([CH3:15])([CH3:14])[CH3:16])[C:10]([N+:17]([O-:19])=[O:18])=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])O
Reactant: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCNC(=O)c1c(Cl)ccc([N+](=O)[O-])c1[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
To a solution of the amide of example 45 (1.28 g, 5 mmol) in CH2Cl2 (20 mL) at 0° C. was added dropwise a cold mixture of 70% nitric acid (0.64 mL, 10 mmol) and concentrated sulfuric acid (5 mL) dropwise. The mixture was stirred at 0° C. for 10 min and was poured onto ice. The mixture was extracted with ether, the combined organic layers washed with sat NaHCO3, brine, dried (MgSO4) and concentrated to a solid (1.52 g, 101%). The title compound was obtained by recrystallization from ethyl acetate/hexanes in 83% yield as a white solid. m.p. 147-149° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5](=[O:20])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[CH3:19])[CH:7]=[CH:8][CH:9]=1.N1C=CN=C1.[C:26]([Si:30](Cl)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O.O>[Si:30]([O:1][CH2:2][CH2:3][C:4]1[C:5](=[O:20])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[CH3:19])[CH:7]=[CH:8][CH:9]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1-n1cccc(CCO)c1=O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Reaction time: 8 h

Procedure:
38 g (138 mmol) of the compound from Example 14A are dissolved in 200 ml of anhydrous N,N-dimethylformamide, and 12.2 g (198 mmol) of imidazole and, a little at a time, 46 g (135 mmol) of tert-butyl(chloro)diphenylsilane are added at 0° C. The mixture is stirred overnight and then diluted with water and extracted three times with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue is applied to silica gel and chromatographed using a gradient of cyclohexane and ethyl acetate. The product-containing fractions are combined and evaporated to dryness under reduced pressure. This gives 62 g (88% of theory) of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([NH:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18](O)=[O:19])=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[CH2:21]([C@H:17]([NH:16][C:14](=[O:15])[O:13][C:9]([CH3:11])([CH3:10])[CH3:12])[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1ccc(Br)cc1
Reaction time: 24 h
Yield: 97.7 %

Procedure:
To a solution of 4-bromoaniline (1.1 g), (2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoic acid (1.87 g) and diisopropylethylamine (1.82 g) in N,N-dimethylformamide (30 mL) was added (O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HATU) (2.68 g) and the mixture was stirred for 24 hours. Water was added and the mixture was extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to afford tert-butyl {(1S)-1-benzyl-2-[(4-bromophenyl)amino]-2-oxoethyl}carbamate (2.62 g).
Reaction SMILES: CN(C)C=O.[H-].[Na+].[Cl:8][C:9]1[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:10]=1[CH2:11][N:12]1[C:16]2[CH:17]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH3:26].[CH2:32](Br)[CH2:33][CH2:34][CH3:35]>C(OCC)(=O)C.O>[CH2:32]([O:31][C:29]1[CH:28]=[CH:27][C:10]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[CH3:26])=[C:9]([Cl:8])[CH:30]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCBr
Reactant: CCOC(=O)c1ccc2nc(C)n(Cc3ccc(O)cc3Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOc1ccc(Cn2c(C)nc3ccc(C(=O)OCC)cc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
N,N-dimethylformamide (5 ml) was added to 60% sodium hydride (0.20 g, oily). Crystals of 1-(2-chloro-4-hydroxybenzyl)-6-(ethoxycarbonyl)-2-methylbenzimidazole (0.80 g) were added gradually thereto at room temperature. After stirring for 1 hour at room temperature, n-butyl bromide (0.28 g, 4.14 mmol) was added to the mixture. After further stirring for 15 hours at room temperature, water and subsequently ethyl acetate were added to the solution to effect extraction. The organic layer was separated, washed twice with water, and concentrated to obtain 0.62 g of oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:32])/[C:3](=[N:9]\[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:14][CH:13]=1)/[C:4]([O:6]CC)=[O:5].Cl>O1CCCC1.CO.[OH-].[Na+]>[CH3:1][CH:2]([CH3:32])/[C:3](=[N:9]\[O:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[O:23][C:24]=2[CH3:25])=[CH:16][CH:17]=1)/[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)/C(=N/OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(/C(=O)O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
Ethyl E-3-methyl-2-[4(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyrate (1.27 g) was dissolved in tetrahydrofuran (10 ml)-methanol (5 ml), and 1N aqueous solution of sodium hydroxide (5 ml) was added and the mixture was stirred for 2 hours at room temperature. 1N HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain E-3-methyl-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyric acid (1.02 g, yield: 85%) as colorless crystals. m.p. 128-129° C.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:15])=[CH:7][CH:8]=2)[N:3]=1.[N-:16]=[N+:17]=[N-:18].[Na+].CN(C=O)C>O.[Na+].[Cl-]>[Cl:15][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[C:11]([C:12]([OH:14])=[O:13])[C:2]3[N:3]2[N:16]=[N:17][N:18]=3)=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1cc2ccc(Cl)cc2nc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cc2ccc(Cl)cc2n2nnnc12
Temperature: 70 °C
Reaction time: 24 h
Yield: 40.2 %

Procedure:
To a dry reaction vial with a screw cap was placed 2,7-dichloroquinoline-3-carboxylic acid (0.241 g, 1 mmol), sodium azide (0.078 g, 1.2 mmol) and dry DMF (3 mL) and shaken at 65-75° C. for a period of 24 h. The reaction mixture was diluted with water (100 mL), saturated with NaCl, the resulting solid was filtered and dried to give 0.100 g (41%) of the carboxytetrazole 5. TLC Rf: 0.06 (20% MeOH/EtOAc); 1H NMR (DMSO d6+CDCl3): δ 8.71 (bs, 1H), 8.60 (s, 1H), 8.30 (d, 1H, J=7.8 Hz), 7.79 (d, 1H, J=7.5 Hz); LCMS (ret. time): 21.28; MS (m/z): 249 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[O:25]1[C:29]2[CH:30]=[CH:31][C:32](B(O)O)=[CH:33][C:28]=2[O:27][CH2:26]1.O1CCOCC1>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([C:2]3[N:7]4[N:8]=[CH:9][CH:10]=[C:6]4[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]4[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=4)[CH:3]=3)=[CH:33][C:28]=2[O:27][CH2:26]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(-c3ccc4c(c3)OCO4)n3nccc3n2)cc1
Temperature: 100 °C
Yield: 47.3 %

Procedure:
A suspension of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 200 mg, 0.604 mmol), benzo[d][1,3]dioxol-5-ylboronic acid (200 mg, 1.21 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (35 mg, 48 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (2 mL of 1,4-dioxane and 1 mL of saturated aqueous NaHCO3) was prepared in a 2 mL microwave reaction vessel and the sealed reaction vessel warmed to 100° C. for 20 minutes. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC, 5-95% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a green solid (119 mg, 47%). 1H NMR (DMSO-d6) δ: 11.23 (s, 1H), 8.19 (d, J=2.3 Hz, 1H), 7.94-8.10 (m, 3H), 7.72 (d, J=1.5 Hz, 1H), 7.57-7.67 (m, 3H), 7.17 (d, J=8.3 Hz, 1H), 6.57 (d, J=2.3 Hz, 1H), 6.18 (s, 2H), 5.20 (s, 1H), 1.46 (s, 6H). ESI-MS: m/z 417.0 (M+H)+.
Reaction SMILES: Cl/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:27]=[CH:26][S:25][CH:24]=3)[CH:18]=2)[CH:10]=1)[CH2:6][CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N)CCC.[CH3:52][CH:53]([CH2:56][CH3:57])[C:54]#[CH:55]>O1CCCC1.[Pd](Cl)Cl.[Cu]I>[CH3:52][CH:53]([CH2:56][CH3:57])[C:54]#[C:55]/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:27]=[CH:26][S:25][CH:24]=3)[CH:18]=2)[CH:10]=1)[CH2:6][CH3:7]
Reactant: C#CC(C)CC
Reactant: CCN(C/C=C/Cl)Cc1cccc(OCc2cccc(-c3ccsc3)c2)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCN
Product: CCC(C)C#C/C=C/CN(CC)Cc1cccc(OCc2cccc(-c3ccsc3)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 71 %

Procedure:
To a solution of 100 mg (0.25 mmol) of (E)-N-(3-chloro-2-propenyl)-N-ethyl-3-[3-(3thienyl)benzyloxy]benzylamine in 2 ml of tetrahydrofuran were added 6.0 mg (0.023 mmol) of triphenylphosphine, 4.0 mg (0.023 mmol) of palladium chloride, 6.0 mg (0.032 mmol) of copper (i) iodide, 100 μl (1 mmol) of n-butylamine and 0.5 ml (5.12 mmol) of 3-methyl-1-pentyne. The mixture was stirred for 48 hours at room temperature, and concentrated under reduced pressure. The residue was treated with a mixture of ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (n-hexane→n-hexane/ethyl acetate=9/1). The desired fractions were put together and concentrated under reduced pressure. The residue was subjected to thin layer chromatography to obtain 79 mg (yield: 71%) of the above identified compound as a brown oil.
Reaction SMILES: CO[C:3]([C:5]1(OC)[CH2:9][CH2:8][CH:7]([O:10][CH3:11])[O:6]1)=O.[CH:14]1([N:20]2[C:29]3[C:24](=[CH:25][C:26]([C:31]([F:34])([F:33])[F:32])=[C:27]([NH2:30])[CH:28]=3)[NH:23][C:22](=[O:35])[C:21]2=[O:36])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>COC1CCC(OC)O1.C(O)(=O)C>[CH:14]1([N:20]2[C:29]3[C:24](=[CH:25][C:26]([C:31]([F:32])([F:33])[F:34])=[C:27]([N:30]4[CH:3]=[CH:5][CH:9]=[C:8]4[C:7]([O:10][CH3:11])=[O:6])[CH:28]=3)[NH:23][C:22](=[O:35])[C:21]2=[O:36])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: COC(=O)C1(OC)CCC(OC)O1
Reactant: Nc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2C1CCCCC1
Agent: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: COC(=O)c1cccn1-c1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2C1CCCCC1

Procedure:
In place of 2,5-dimethoxytetrahydrofuran, 1.2 g (6.1 mmol) of 2-methoxycarbonyl-2,5-dimethoxytetrahydrofuran were dissolved with 2 g (6.1 mmol) of 1-cyclohexyl-6-trifluoromethyl-7-amino-2,3(1H,4H)-quinoxalinedione in 100 ml of acetic acid and refluxed for 30 minutes. The mixture was then worked up as in Example 3f.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([C:26](=[O:28])[CH3:27])=[N:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.O>CN(C)C=O>[CH3:30][O:29][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:3][CH2:2][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:15][C:16]1[C:17]([C:26](=[O:28])[CH3:27])=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: C1COCCN1
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCCN1CCOCC1
Temperature: 60 °C
Reaction time: 48 h
Yield: 27 %

Procedure:
1-{3-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-quinolin-2-yl}-ethanone (37 mg) was dissolved in N,N-dimethylformamide (1 ml) to prepare a solution. Potassium carbonate (242 mg) and morpholine (0.1 ml) were added to the solution, and the mixture was stirred at 60° C. for 2 days. Water was added to the reaction solution and was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (11 mg, yield 27%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9]=2[CH:10]=1.S(Cl)(Cl)=O.[CH3:19][C@H:20]1[O:25][C@@H:24]([CH3:26])[CH2:23][N:22]([CH2:27][C:28]([NH:30][NH2:31])=[O:29])[CH2:21]1.CCN(C(C)C)C(C)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([NH:31][NH:30][C:28](=[O:29])[CH2:27][N:22]2[CH2:23][C@H:24]([CH3:26])[O:25][C@H:20]([CH3:19])[CH2:21]2)=[O:14])[C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9]=2[CH:10]=1
Reactant: Cn1ncc2c(C(=O)O)cc(Br)cc21
Reactant: C[C@@H]1CN(CC(=O)NN)C[C@H](C)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: C[C@@H]1CN(CC(=O)NNC(=O)c2cc(Br)cc3c2cnn3C)C[C@H](C)O1
Temperature: 100 °C
Yield: 60.7 %

Procedure:
6-Bromo-1-methyl-1H-indazole-4-carboxylic acid (480 mg, 1.882 mmol) was suspended in thionyl chloride (4.12 ml, 56.5 mmol) and heated to 100° C. for 30 mins. The thionyl chloride was removed in vacuo and excess azeotroped with dry diethyl ether to give a yellow solid. This was dissolved in dry tetrahydrofuran (THF) (15 ml) and 2-[(2R,6S)-2,6-dimethyl-4-morpholinyl]acetohydrazide (529 mg, 2.82 mmol) and DIPEA (1.315 ml, 7.53 mmol) were added. The reaction mixture was heated to 60° C. for 20 mins. Solvent was removed in vacuo and the residue partitioned between dichloromethane (15 ml) and water (15 ml). The layers were separated and the organic phase concentrated in vacuo to give a green solid which was purified by column chromatography, loading in dichloromethane and purified on Flashmaster 11 silica (Si) 20 g using a 0-100% ethyl acetate-cyclohexane+0-20% MeOH over 30 mins. The appropriate fractions were combined and evaporated in vacuo to afford the title compound as a yellow solid (485 mg). LCMS (Method A) Rt 0.49 min, MH+ 424.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:31]=[O:32])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=[CH:5][CH:4]=1.[C-]#N.[Na+].[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>C1COCC1.[O-2].[Mn+4].[O-2]>[CH3:41][O:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:43][CH:42]=2)[C:9]2[N:10]=[C:11]([C:16]3[C:21]([NH:22][C:23]4[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)=[N:20][CH:19]=[C:18]([C:31]([N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)=[O:32])[CH:17]=3)[N:12]=[C:13]([CH3:15])[N:14]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: C1COCCN1
Agent: [Mn+4]
Agent: [C-]#N
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(=O)N4CCOCC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
A solution of 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-((6-methoxy-3-pyridinyl)amino)-3-pyridinecarbaldehyde (0.127 g, 0.220 mmol) in THF (2.00 mL) was treated with sodium cyanide (10.77 mg, 0.220 mmol), morpholine (0.096 mL, 1.099 mmol) and manganese (IV) oxide (0.287 g, 3.30 mmol) at ambient temperature. After 30 min, more manganese (IV) oxide (0.287 g, 3.30 mmol) was added and the mixture was stirred overnight at ambient temperature. The mixture was filtered through Celite® (diatomaceous earth) and the organic layer was washed with water followed by saturated NaCl (aq.) and then dried over anhydrous Na2SO4, filtered and concentrated to give N,N-bis(4-methoxybenzyl)-4-(2-((6-methoxy-3-pyridinyl)amino)-5-(4-morpholinylcarbonyl)-3-pyridinyl)-6-methyl-1,3,5-triazin-2-amine (0.128 g, 0.193 mmol, 88% yield) as a brown foam. 1H NMR (400 MHz, CDCl3) δ 11.95 (s, 1H); 8.90 (d, J=2.54 Hz, 1H); 8.39 (d, J=2.35 Hz, 1H); 8.28 (d, J=2.74 Hz, 1H); 7.89 (dd, J=8.80, 2.74 Hz, 1H); 7.13-7.24 (m, 4H); 6.81-6.90 (m, 4H); 6.73 (d, J=8.80 Hz, 1H); 4.85 (s, 2H); 4.82 (s, 2H); 3.94 (s, 3H); 3.81 (s, 3H); 3.78 (s, 3H); 3.57-3.69 (m, 8H); 2.59 (s, 3H). m/z (ESI, +ve ion) 663.2 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([CH:19]=O)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+]>C(O)C.O>[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([CH:19]=[N:22][OH:23])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc2c(C=O)cn(CC3CCCCC3)c12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cccc2c(C=NO)cn(CC3CCCCC3)c12
Temperature: 25 °C
Reaction time: 64 h
Yield: 44.8 %

Procedure:
To a solution of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carbaldehyde (780 mg, 2.9 mmol) in a mixture of ethanol (8 ml) and water (2 ml) was added hydroxylamine hydrochloride (403 mg, 5.8 mmol) and sodium acetate (713 mg, 8.7 mmol) and the solution stirred for 64 h at room temperature. The mixture was concentrated in vacuo and the residue diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). The product was recrystallised from diethyl ether/hexane to yield 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carbaldehyde oxime (380 mg, 1.3 mmol) as a yellow powder.