Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[C:4]([Br:15])[CH:3]=1.[CH2:16]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][C:29]=1[F:43])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C1COCC1>[CH2:16]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[C:4]([Br:15])[CH:3]=2)=[CH:30][C:29]=1[F:43])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(OCCCOCc3ccccc3)c(F)c2)OC1(C)C
Reactant: COCCOCOc1cc(Br)cc(Br)c1
Solvent: O
Solvent: C1CCOC1
Product: COCCOCOc1cc(Br)cc(-c2ccc(OCCCOCc3ccccc3)c(F)c2)c1

Procedure:
17.0 g (50.0 mmol) 1,3-dibromo-5-(2-methoxy-ethoxymethoxy)-benzene, 19.3 g (50.0 mmol) 2-[4-(3-benzyloxy-propoxy)-3-fluoro-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 41.3 g (150 mmol) sodium metaborate-tetrahydrate are suspended in 200 ml THF and 200 ml water and 1.6 g (2 mmol) palladium(dppf) are added. The mixture is heated overnight at reflux. After partial removal of the solvent and addition of 100 ml MTB ether, the mixture is acidified with 2M hydrochloric acid. The organic layer is separated and the aqueous layer is extracted three times with MTB ether. The combined organic layers are washed with sat. aq. sodium chloride solution, dried over sodium sulfate and the solvent is removed in vacuo. The crude product is filtered through silica gel with toluene/ethylacetate (7:3 to 1:1) to yield 4-(3-benzyloxy-propoxy)-3′-bromo-3-fluoro-5′-(2-methoxy-ethoxymethoxy)-biphenyl as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:18])=[C:9]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:10]=1[CH3:11])=[O:5])[CH3:2].O.[N+]([O-])([O-])=[O:21].[NH4+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:18]=[O:21])=[C:9]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)c1[nH]c(C)c(CCC(=O)OC)c1C
Agent: O=C([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1[nH]c(C=O)c(CCC(=O)OC)c1C
Yield: 59.8 %

Procedure:
3,5-Dimethyl-4-(2-methoxycarbonylethyl)-1H-pyrrole-2-carboxylic acid ethyl ester (127 g) was dissolved in acetic acid (1900 mL), water (1900 mL) and tetrahydrofuran (1900 mL) and cooled to −30° C. Cerric ammonium nitrate (1097 g) was added in portions with stirring to give a reddish-orange suspension. The suspension was stirred at 0° C. for 2 hours, neutralized to pH 7 with sodium bicarbonate and extracted with ethyl acetate (2000 mL). The ethyl acetate layer was separated, washed with brine (200 mL) and dried over anhydrous sodium sulfate (20 g). The solvent was removed to give 80.2 g (60%) of 5-formyl-4-(2-methoxycarbonylethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester as an oil.
Reaction SMILES: [CH2:1]([C:15]1[C:16]([CH2:23][OH:24])=[C:17]([OH:22])[C:18]([CH3:21])=[N:19][CH:20]=1)[S:2][S:3][CH2:4][C:5]1[C:6]([CH2:13][OH:14])=[C:7]([OH:12])[C:8]([CH3:11])=[N:9][CH:10]=1.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>CCOCC>[CH2:4]([C:5]1[CH:10]=[N:9][C:8]([CH3:11])=[C:7]2[O:12][CH:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:14][CH2:13][C:6]=12)[S:3][S:2][CH2:1][C:15]1[CH:20]=[N:19][C:18]([CH3:21])=[C:17]2[O:22][CH:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:24][CH2:23][C:16]=12
Reactant: O=Cc1ccccc1
Reactant: Cc1ncc(CSSCc2cnc(C)c(O)c2CO)c(CO)c1O
Agent: Cl
Solvent: CCOCC
Product: Cc1ncc(CSSCc2cnc(C)c3c2COC(c2ccccc2)O3)c2c1OC(c1ccccc1)OC2
Reaction time: 4 h

Procedure:
A mixture of 0.01 moles of 5,5'-(dithiodimethylene)bis[3-hydroxy-4-hydroxymethyl-2-methylpyridine] and 100 ml. of benzaldehyde was saturated with hydrogen chloride gas at 0°-5° and then stirred at this temperature for 4 hours. At this time 800 ml. of ether were added and the resulting precipitate was separated by filtration. This solid was then added to a well stirred mixture of 200 ml. chloroform and 200 ml. of water containing 20 gm. of sodium carbonate. After 15 minutes the chloroform layer was removed, dried, and concentrated to give an oil which gradually solidified. This solid was filtered with the aid of a small amount of ether to give 5,5'-(dithiodimethylene)bis[8-methyl-2-phenyl-4H-m-dioxino[4,5-c]pyridine].
Reaction SMILES: O.[PH2]([O-])=O.[Na+].[C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1[O:28][CH3:29])#N.[H][H].C(OCC)(=[O:34])C>O.C(O)(=O)C.N1C=CC=CC=1.[Ni]>[CH:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1[O:28][CH3:29])=[O:34]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(C#N)cc23)c(OC)c1
Reactant: [H][H]
Agent: [Ni]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc(C=O)cc23)c(OC)c1
Yield: 86 %

Procedure:
A solution of sodium hypophosphite monohydrate (24.8 g) in water (40 ml) was added to a solution of methyl 4-(5-cyanoindol-3-ylmethyl)-3-methoxybenzoate (11.33 g) in acetic acid (40 ml) and pyridine (80 ml). Raney nickel (approximately 2.5 g) was added as an aqueous slurry, and the mixture was heated at 50°-55° for 3 hr (CAUTION: evolution of hydrogen!). Ethyl acetate (200 ml) was added to the cooled solution, the mixture was filtered through diatomaceous earth, the filter pad washed with ethyl acetate, the combined filtrate washed with 1M hydrochloric acid (4×200 ml, until the aqueous washings were acidic), water (2×100 ml) and brine, and dried (MgSO4). The solvent was evaporated to give an oil which was purified by flash chromatography, eluting with 3:6:1 hexane:methylene chloride:ethyl acetate, giving a foam which was crystallized from a mixture of ethyl acetate and hexane to give methyl 4-(5-formylindol-3-ylmethyl)-3-methoxybenzoate (9.85 g, 86%) as white crystals; mp 117°-120°; partial NMR (250 MHz, DMSO-d6): 3.83(s, 3H, OCH3); 3.94(s, 2H, ArCH2Ar'), 8.10(s, 1H, H4 -indole), 9.94(s, 1H, CHO), 11.45 (br s, 1H, H1 -indole).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:8][C:9]3[N:10]=[CH:11][N:12]=[C:13]([S:16][CH3:17])[C:14]=3[N:15]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=[CH:3]1.[Br:24]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:24][C:3]1[N:2]([CH3:1])[C:6]([C:7]2[S:8][C:9]3[N:10]=[CH:11][N:12]=[C:13]([S:16][CH3:17])[C:14]=3[N:15]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=1
Reactant: CSc1ncnc2sc(-c3c(-c4ccccc4)ncn3C)nc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1ncnc2sc(-c3c(-c4ccccc4)nc(Br)n3C)nc12
Temperature: 70 °C
Yield: 38.9 %

Procedure:
A mixture of 2-(1-methyl-4-phenyl-1H-imidazol-5-yl)-7-(methylthio)[1,3]thiazolo-[5,4-d]pyrimidine (Intermediate 42) (0.25 g), N-bromosuccinimide (0.26 g) and AIBN (37 mg) in carbon tetrachloride (30 mL) was heated at 70° C. for 18 hours The suspension was filtered and the residue washed well with CCl4. The solvent was evaporated in vacuo to give a yellow solid. Purification by flash chromatography on silica eluting with EtOAC:hexane (1:9) gave the title compound as a white solid (0.12 g, 39%);
Reaction SMILES: [NH:1]([C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].[CH2:15]([O:22][CH2:23]C1C=CC=CC=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na].C(Cl)(Cl)Cl.C[OH:36]>C(O)C1C=CC=CC=1.O>[NH:1]([C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])[CH:2]([C:4]([C:23]([O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:36])=[O:6])[CH3:3]
Reactant: c1ccc(COCc2ccccc2)cc1
Reactant: C[C@H](NC(=O)c1ccccc1)C(=O)O
Reactant: CO
Agent: [Na]
Solvent: O
Solvent: OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(NC(=O)c1ccccc1)C(=O)C(=O)OCc1ccccc1
Yield: 26 %

Procedure:
This compound was prepared from Bz-Ala-OH in 26% yield by the procedure described in Example PKC1, except that benzyl oxalyl chloride was used in place of ethyl oxayl chloride and sodium benzyloxide in benzyl alcohol was used for enol ester hydrolysis; single spot on tlc, Rf2 =0.69 (CHCl3 :MeOH=9:1); mp 95°-97° C.; MS, m/e=312 (M+ +1). Anal. Calcd. for C18H17O4N.1/2 H2O: C, 67.48; H, 5.66; N, 4.37. Found: C, 67.78; H, 5.55; N, 4.66.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([CH2:10]Br)=[CH:8][CH:7]=[CH:6][C:5]=1[Br:12].[C:14]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>CC(O)C>[Br:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[C:3](=[O:13])[N:22]([C:21]1[CH:23]=[CH:24][C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:19][CH:20]=1)[CH2:10]2
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: COC(=O)c1c(Br)cccc1CBr
Solvent: CC(C)O
Product: CC(C)(C)c1ccc(N2Cc3cccc(Br)c3C2=O)cc1
Reaction time: 0.08 h

Procedure:
2-Bromo-6-bromomethyl-benzoic acid methyl ester (214 mg) and 4-t-butylaniline (93 mg) were put into a microwave reaction vial along with 2 mL of iPrOH. The reaction was subjected to 170° C., 5 min of microwave. The solvent was evaporated and the residue was purified by silica gel chromatography (25 g, 10-20% EtOAc/hexanes) to afford 7-bromo-2-(4-t-butyl-phenyl)-2,3-dihydro-isoindol-1-one as a white powder.
Reaction SMILES: Br[C:2]1[N:3]([CH3:28])[CH:4]=[C:5]([C:7]([N:9]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)=[O:8])[N:6]=1.[CH3:29][O-:30].[Na+]>O1CCCC1>[CH3:29][O:30][C:2]1[N:3]([CH3:28])[CH:4]=[C:5]([C:7]([N:9]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)=[O:8])[N:6]=1
Reactant: Cn1cc(C(=O)N(Cc2cccc(OC(F)(F)F)c2)C2CCOCC2)nc1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc(C(=O)N(Cc2cccc(OC(F)(F)F)c2)C2CCOCC2)cn1C
Temperature: 60 °C
Reaction time: 72 h
Yield: 6.7 %

Procedure:
A mixture of 2-bromo-1-methyl-N-(tetrahydro-2H-pyran-4-yl)-N-[3-(trifluoromethoxy)benzyl]-1H-imidazole-4-carboxamide (100 mg), sodium methoxide (14 mg) and tetrahydrofuran (1 mL) was stirred at 60° C. for 3 days. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography (NH silica gel cartridge; hexane/ethyl acetate=3:1 to 1:1) and TLC (NH silica gel plate; hexane/ethyl acetate=1:1) to give the titled compound (6 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH:18]3[CH2:21][O:20][CH2:19]3)[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([NH:28][C:29]1[C:30]([NH2:35])=[CH:31][CH:32]=[CH:33][CH:34]=1)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[F:36][C:37]([F:42])([CH3:41])[C:38](O)=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:36][C:37]([C:41]1[N:28]([C:5]2[N:4]=[C:3]3[C:8]([N:9]=[C:10]([CH2:11][N:12]4[CH2:13][CH2:14][CH:15]([CH:18]5[CH2:21][O:20][CH2:19]5)[CH2:16][CH2:17]4)[N:2]3[CH3:1])=[C:7]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:6]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:35]=1)([F:42])[CH3:38]
Reactant: CC(F)(F)C(=O)O
Reactant: Cn1c(CN2CCC(C3COC3)CC2)nc2c(N3CCOCC3)nc(Nc3ccccc3N)nc21
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: CN(C)C=O
Product: Cn1c(CN2CCC(C3COC3)CC2)nc2c(N3CCOCC3)nc(-n3c(C(C)(F)F)nc4ccccc43)nc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.1 %

Procedure:
To a mixture of N-[9-methyl-6-morpholin-4-yl-8-(4-oxetan-3-ylpiperidin-1-ylmethyl)-9H-purin-2-yl]benzene-1,2-diamine (0.115 g, 0.24 mmol) and 2,2-difluoropropionic acid (0.028 g, 0.25 mmol) and DIPEA (0.091 mL, 0.53 mL) in DMF (7 mL) was added HATU (0.11 g, 0.29 mmol). The reaction mixture was stirred at room temperature for 24 h, then at 90° C. for 24 h. The reaction mixture was concentrated in vacuo and the residue was loaded in MeOH onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted with 2 M NH3 in MeOH. The solution was concentrated in vacuo, the residue was diluted in acetic acid (15 mL) and the reaction mixture was stirred at 90° C. for 7 h. The reaction mixture was concentrated in vacuo and the resultant residue was purified by flash chromatography (Si—PPC, MeOH:DCM, 0:100 to 10:90) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 459 as a white solid (0.032 g, 27%). LCMS (Method I): RT=3.30 min, [M+H]+ 553.3. 1H NMR (400 MHz, DMSO-d6): δ 7.84-7.81 (m, 1 H); 7.74-7.71 (m, 1 H); 7.43-7.35 (m, 2 H); 4.40-4.15 (m, 4 H); 3.84 (s, 2 H); 3.81 (d, J=4.3 Hz, 2 H); 3.78-3.71 (m, 7 H); 3.37 (t, J=6.9 Hz, 2 H); 3.30-3.18 (m, 2 H); 2.96 (t, J=6.9 Hz, 2 H); 2.34-2.21 (t, J=19.5 Hz, 3 H); 2.20-2.08 (m, 1 H); 1.64 (d, J=12.1 Hz, 1 H); 1.50 (d, J=13.0 Hz, 2 H); 1.06 (td, J=12.1, 4.3 Hz, 2 H)
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N([CH2:17][CH3:18])CC)C.[CH2:19]([N:26]([CH2:30][CH2:31][NH2:32])[CH2:27][CH2:28][NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl.C(OCC)(=O)C.CCOCC>[CH2:19]([N:26]([CH2:30][CH2:31][NH:32][S:7]([C:4]1[CH:5]=[CH:6][C:17]([CH3:18])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH2:27][CH2:28][NH:29][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCN(CCN)Cc1ccccc1
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)NCCN(CCNS(=O)(=O)c2ccc(C)cc2)Cc2ccccc2)cc1
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To a solution of 141.2 g (0.741 mol) of p-toluenesulfonyl chloride in 250 ml of dichloromethane with 110 ml (0.8 mol) of triethylamine was added dropwise 68.0 g (0.352 mol) of 4-benzyl-1,4,7-triazaheptane in 75 ml of dichloromethane. After 2 hours, the solution was washed three times with water at pH 9, and the organic phase was dried with sodium sulfate and filtered. Evaporation gave an oil which was dissolved in about 450 ml of ethyl acetate. The solution was diluted with 200 ml of ether and left to stand at room temperature for 24 hours. The mixture was further diluted with about 50 ml of ether and refrigerated for another day. The product crystallized in massive prisms which were collected by filtration and dried under vacuum at 40° C. for 6 hours, yielding in the first crop 140 g (0.279 mol) of a colorless solid; melting point 87°-91° C. Mass spectrum (CI): m/e 502 (M+H) and 500 (M-H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])[CH2:5][C:4]([CH3:17])([CH3:16])[NH:3]1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>S(=O)(=O)(O)O>[C:19]([N:3]1[C:4]([CH3:17])([CH3:16])[CH2:5][CH:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])[CH2:7][C:2]1([CH3:18])[CH3:1])(=[O:21])[CH3:20]
Reactant: CC1(C)CC(N2CCCCCC2=O)CC(C)(C)N1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)N1C(C)(C)CC(N2CCCCCC2=O)CC1(C)C
Temperature: 120 °C
Yield: 65.2 %

Procedure:
A solution of 50.5 g (0.2 mole) of N-(2,2,6,6-tetramethylpiperidin-4-yl)-epsilon-caprolactam, prepared in Example 1, in 102 g of acetic anhydride with 0.2 g of sulfuric acid catalyst is heated for four hours at 120° C. At the end of this period the excess acetic anhydride is removed in vacuo. The residue is then dissolved in 200 ml of methylene chloride, washed thrice with 100 ml portions of water, then with 10% aqueous sodium bicarbonate and finally dried over anhydrous magnesium sulfate. The solvent is allowed to evaporate to give a crude product which when recrystallized from toluene:hexane (1:3) yields 38.4 g of white solid melting at 104°-108° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.CCN(C(C)C)C(C)C.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2([CH2:37][NH2:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:26]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[Cl:1][C:2]1[C:6]([C:7]([NH:38][CH2:37][C:31]2([C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)=[O:9])=[CH:5][N:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: O=C(O)c1cn(-c2ncccn2)nc1Cl
Reactant: NCC1(c2cccnc2)CCCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)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: O=C(NCC1(c2cccnc2)CCCCC1)c1cn(-c2ncccn2)nc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 3-chloro-1-pyrimidin-2-yl-1H-pyrazole-4-carboxylic acid (75 mg, 0.33 mmol) in 1.0 mL of DMF is added sequentially DIEA (0.11 mL, 0.66 mmol), 1-(1-pyridin-3-ylcyclohexyl)-methanamine (63 mg, 0.33 mmol), and BOP (177 mg, 0.40 mmol). The resulting mixture is stirred at RT for 20 h. Water (3 mL) is added, and the mixture is extracted with EtOAc (5 mL). The EtOAc layer is dried (Na2SO4), filtered, and evaporated in vacuo. The residue is purified by preparative chromatography (5% MeOH/CH2Cl2) to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.17 (1H, s), 8.90 (2H, d, J 4.8), 8.58 (1H, s), 8.37 (1H, d, J 3.6), 8.05 (1H, s), 7.76 (1H, d, J 8.4), 7.56 (1H, t, J 4.8), 7.31 (1H, m), 2.16 (2H, m), 1.60 (4H, m), 1.43 (1H, m), 1.21 (5H, m). MS (M+1)=397.16; RT=1.07 min. *IC50.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7]1([CH3:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([NH2:1])[CH2:5][CH2:4][CH2:3][CH2:2][CH2:11][CH2:12][CH2:7][CH2:8][CH2:9][CH2:10][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:7][CH3:13]
Reactant: Cc1ccccc1
Reactant: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCN

Procedure:
A mixture of 43 parts by mass of the polymer (white solid) obtained through the production of an intermediate, 20 parts by mass of n-octadecylamine, 1 part by mass of pyridine, and 420 parts by mass of toluene is stirred at a temperature of 100° C. for 3 hours. After the mixture is cooled, the reaction solution is added to 8000 parts by mass of methanol in 15 minutes while stirring and is further stirred for 1 hour. The precipitated solid is filtered and is dried under depressurization, whereby 43 parts by mass of light yellowish white solid (specific copolymer) is obtained. The molecular weight measured through the use of a high-speed liquid chromatography method is 14,000. As the result of neutralization titration using a potassium hydroxide ethanol solution, the ratio of the semi-maleic acid amide component and the maleinimide component is 6:4.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.CCCCCC.C([Li])CCC.Br[CH2:18][CH2:19][CH2:20][CH2:21][Cl:22]>O1CCCC1.O>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCCBr
Reactant: c1ccoc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: ClCCCCc1ccco1
Temperature: -25 °C
Reaction time: 4 h
Yield: 90.6 %

Procedure:
Furan (1.36 g) was dissolved in tetrahydrofuran (50 ml) and cooled to -25° C. Hexane solution (12.5 ml) of n-butyllithium of 1.68 mol/l was added to the reaction solution, which was stirred at -15° C. for 4 hours. Subsequently, 1-bromo-4-chlorobutane (3.43 g) was dissolved in tetrahydrofuran (2.5 ml) and added to the reaction solution. This solution was further stirred at -15° C. for 1 hour and stood overnight at room temperature. The reaction solution was poured into icy water and extracted with ether. The extracted solution was successively washed with water, a saturated ammonium chloride solution and a saturated sodium chloride solution. It was then dried over magnesium sulfate and filtered. The filtrate was concentrated and the resultant oil-like product was purified by distillation under reduced pressure (130° C./12 mmHg). The object compound (2.87 g) was obtained in the form of oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:24]1[CH:25]=[C:26]([CH2:30][NH:31][S:32]([CH2:35][CH3:36])(=[O:34])=[O:33])[CH:27]=[N:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CCOC(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>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[C:24]1[CH:25]=[C:26]([CH2:30][NH:31][S:32]([CH2:35][CH3:36])(=[O:33])=[O:34])[CH:27]=[N:28][CH:29]=1
Reactant: CCS(=O)(=O)NCc1cncc(Br)c1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)c(Cl)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NCc1cncc(-c2cc3c(cc2Cl)N(C)C(=O)CC3)c1
Temperature: 120 °C
Yield: 30 %

Procedure:
A mixture of 7-chloro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (20 mg, 0.06 mmol), ethanesulfonic acid (5-bromo-pyridin-3-ylmethyl)-amide (intermediate A-11, 26 mg, 0.09 mmol), bis(triphenylphosphine)-palladium(II) chloride (4.2 mg, 0.006 mmol) and sodium carbonate (2 N aq., 0.06 mL) in DMF (1 mL) was heated in a microwave at 120° C. for 30 minutes. The mixture was diluted with EtOAc, washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep-HPLC to afford the title product (7.1 mg, 30%) as a white solid. MS, 394.2 (M+H+)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:18][C:17](=[O:19])[C:16]4[CH:20]=[C:21]([C:25]#[N:26])[CH:22]=[C:23]([CH3:24])[C:15]=4[N:14]=3)=[CH:11][C:10]([C:27]([F:30])([F:29])[F:28])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[NH4+:32]>O1CCCC1>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([NH:14][C:15]3[C:16]([C:17]([NH2:32])=[O:19])=[CH:20][C:21]([C:25]#[N:26])=[CH:22][C:23]=3[CH3:24])=[O:18])=[CH:11][C:10]([C:27]([F:29])([F:30])[F:28])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: Cc1cc(C#N)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(C(N)=O)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of 2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the cyanobenzoxazinone product of Step E) (200 mg, 0.46 mmol) in tetrahydrofuran (5 mL) was added dropwise ammonium hydroxide (0.5 mL, 12.8 mmol) at room temperature. The reaction mixture was then stirred for five minutes, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford 620 mg of the title compound, a compound of the present invention, as a solid melting at 200-202° C.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:18]([C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][C:3]=1[CH2:4][NH:5][CH2:6][CH2:7][NH:8][C:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10].[Br].[N:30]#[C:31]C#N>C(O)C>[NH2:30][C:31]1[N:5]([CH2:6][CH2:7][NH:8][C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH2:4][C:3]2[C:2](=[CH:20][CH:19]=[C:18]([C:21](=[O:28])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:17]=2)[N:1]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1CNCCNC(=O)C1CCCCC1
Reactant: N#CC#N
Agent: [Br]
Solvent: CCO
Product: NC1=Nc2ccc(C(=O)c3ccccc3)cc2CN1CCNC(=O)C1CCCCC1
Temperature: 25 °C

Procedure:
A mixture of cyclohexanecarboxylic acid [2-(2-amino-5-benzoyl-benzylamino)-ethyl]-amide (0.0032 mol) in ethanol (30 mL) was stirred at room temperature. Cyanogen bromine (0.0048 mol) was added. The reaction mixture was stirred and refluxed for 2 hours, then cooled and stirred overnight at room temperature resulting in a precipitate. The precipitate was filtered off, washed with diisopropyl ether and dried to yield the title compound as a residue.