Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH:23]=[CH:22]3)[CH2:7][CH2:6]1.[CH:30]1([CH2:36][S:37](Cl)(=[O:39])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][N:13]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH:23]=[CH:22]3)[S:37]([CH2:36][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)(=[O:39])=[O:38])[CH2:9][CH2:10]1
Reactant: O=S(=O)(Cl)CC1CCCCC1
Reactant: COCOC1CCN(CCNCCCCOc2ccc3[nH]c(=O)ccc3c2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOC1CCN(CCN(CCCCOc2ccc3[nH]c(=O)ccc3c2)S(=O)(=O)CC2CCCCC2)CC1
Yield: 17.8 %

Procedure:
A solution of 2.5 g of 6-{4-[2-(4-methoxymethoxy-1-piperidinyl)ethyl]aminobutoxy}carbostyril, 1.5 g of cyclohexylmethanesulfonyl chloride and 1.35 ml of triethylamine in 30 ml of dichloromethane was stirred at room temperature for 16 hours. The reaction mixture was washed with water and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was purified by a silica gel column chromatography (eluant: 3% methanol/chloroform)-to obtain 620 mg of 6-[4-{N-[2-(4-methoxymethoxy-1-piperidinyl)ethyl]-N-cyclohexylmethylsulfonylamino}butoxy]carbostyril.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH:22]([CH3:24])[CH3:23])[C:4]([N:6]1[CH2:11][CH2:10][C@@:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)([OH:12])[C:8]([CH3:21])([CH3:20])[CH2:7]1)=[O:5].[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C@@:9]2([OH:12])[CH2:10][CH2:11][N:6]([C:4](=[O:5])[C@H:3]([NH:2][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]([CH3:24])[CH3:23])[CH2:7][C:8]2([CH3:20])[CH3:21])=[CH:18][CH:17]=1
Reactant: CC(C)[C@@H](N)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Reactant: O=C(O)c1ccccc1
Agent: Cl
Product: CC(C)[C@@H](NC(=O)c1ccccc1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1

Procedure:
Example 327 was prepared in a similar manner as described in Example 75 from (R)-2-amino-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methylbutan-1-one hydrochloride and benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:5]([NH:7][C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12]C)=[O:11])=[O:6].CO>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:5]([NH:7][C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([OH:12])=[O:11])=[O:6]
Reactant: COC(=O)c1ccccc1NC(=O)c1ccc(OC)c(Cl)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(=O)Nc2ccccc2C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.3 %

Procedure:
A solution of 42A (340 mg, 1.1 mmol) in THF (30 mL)/MeOH (10 mL) was treated with a solution of LiOH monohydrate (223 mg, 5.3 mmol) in water (10 mL). The reaction was stirred for 24 hours at room temperature and concentrated to a yellow solid. The crude acid was dissolved in water (100 mL) and acidified with 1 N HCl to pH 4. The resulting solid was collected by vacuum filtration and washed with water (2×100 mL) to afford 42B (260 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:13]=[N:14][C:15]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:16][C:17]=3[CH3:18])[N:7]([CH2:24][CH2:25][CH2:26][CH2:27]O)[C:6]=2[C:5]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:12]4[CH:13]=[N:14][C:15]([N:19]5[CH2:23][CH2:22][CH2:21][CH2:20]5)=[CH:16][C:17]=4[CH3:18])[CH2:27][CH2:26][CH2:25][CH2:24][N:7]3[C:6]=2[C:5]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3cnc(N4CCCC4)cc3C)n(CCCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1cnc(N2CCCC2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.9 %

Procedure:
To a solution of 4-{4-chloro-7-(1-ethylpropyl)-2-[(4-methyl-6-pyrrolidin-1-ylpyridin-3-yl)amino]-1H-benzimidazol-1-yl}butan-1-ol (Reference Example 48; 400 mg, 0.85 mmol) in pyridine (5 mL) was added methanesulfonyl chloride (0.330 mL, 4.25 mmol) dropwise at 0° C. The mixture was warmed to room temperature and stirred for 8 hr. Aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The resulting crude mesylate was dissolved in N,N-dimethylformamide (10 mL) and potassium carbonate (586 mg, 4.25 mmol) was added. The mixture was stirred at 80° C. for 16 hr. Water was added and the mixture was extracted with ethyl acetate. Organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 50-80% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give a solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound (150 mg, 0.331 mmol, 39%) as a colorless solid.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[OH:20])[O:16][C:15]([CH3:21])=[C:14]([C:22]1[CH:27]=[CH:26][C:25](OC)=[CH:24][CH:23]=1)[C:13]2=[O:30].O.CCCCCC>CN(C=O)C>[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[C:18]([Cl:1])[C:19]=1[OH:20])[O:16][C:15]([CH3:21])=[C:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:13]2=[O:30]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(-c2c(C)oc3cc(O)c(Cl)cc3c2=O)cc1
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: Cc1oc2c(Cl)c(O)c(Cl)cc2c(=O)c1-c1ccccc1
Reaction time: 3 h

Procedure:
N-Chlorosuccinimide (0.27 g, 2 mmol) was added to a solution of 6-chloro-7-hydroxy-3-(4-methoxy-phenyl)-2-methyl-chromen-4-one (0.29 g, 1 mmol) in DMF (4 ml) and the solution stirred for 3 hrs. and at 50° C. for ˜3 hrs. The resulting solution was poured into water (50 ml) and extracted with ethyl acetate (2×30 ml). The combined extracts were washed with water (5×50 ml) and saturated aqueous sodium chloride solution (30 ml). The solution was dried over anhydrous magnesium sulphate and concentrated to give a dark yellow oil. Trituration with hexane gave 6,8-dichloro-7-hydroxy-2-methyl-3-phenyl-chromen-4-one as a pale orange powder, dried in vacuo, (0.19 g)
Reaction SMILES: C([O:8][C:9](=[O:26])[CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:12]1=[O:25])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[C:21]([O:20][C:18]([NH:17][C@@H:13]1[CH2:14][CH2:15][CH2:16][N:11]([CH2:10][C:9]([OH:26])=[O:8])[C:12]1=[O:25])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(CC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(CC(=O)O)C1=O
Yield: 95.1 %

Procedure:
Palladium on carbon (10%, 500 mg) was added to a solution of (R)-(3-tert-butoxycarbonylamino-2-oxo-piperidin-1-yl)-acetic acid benzyl ester (2.31 g, 6.37 mmol) in ethanol (50 mL). The atmosphere was replaced with hydrogen and maintained with a balloon filled with hydrogen and the above mixture was vigorously stirred. After 16 hours the hydrogen was removed and CELITE was added to the mixture with stirring and then the mixture was filtered though a pad of CELITE. The solvent was removed under reduced pressure and the resulting residue was azeotroped with toluene to provide (R)-(3-tert-butoxycarbonylamino-2-oxo-piperidin-1-yl)-acetic acid (1.65 g, 6.06 mmol, 95%). C12H20N2O5 calculated 272.3 observed [M+1]+271.2; rt=1.80 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[C:15]([O:20][CH2:21][CH2:22][O:23][C:24](=[O:27])[CH:25]=[CH2:26])(=[O:19])[C:16]([CH3:18])=[CH2:17].N[SiH3]>C(#N)C>[C:15]([O:20][CH2:21][CH2:22][O:23][C:24]([CH2:25][CH2:26][N:1]([CH2:26][CH2:25][C:24]([O:23][CH2:22][CH2:21][O:20][C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])=[O:27])[CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11])=[O:27])(=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: C=CC(=O)OCCOC(=O)C(=C)C
Agent: N[SiH3]
Solvent: CC#N
Product: C=C(C)C(=O)OCCOC(=O)CCN(CCC[Si](OCC)(OCC)OCC)CCC(=O)OCCOC(=O)C(=C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.7 %

Procedure:
43 g (0.25 mol) 3-aminopropyl triethoxysilane in 40 ml anhydrous acetonitrile are added dropwise accompanied by ice-cooling to 92 g (0.5 mol) 2-acryloyloxyethyl methacrylate in 85 ml acetonitrile. After 48 h stirring at room temperature, the aminosilane has completely reacted. The solvent is evaporated off accompanied by the introduction of air at reduced pressure at the rotary evaporator at maximally 46° C. 132.2 g (98% yield) of a lightly-coloured clear oily liquid are obtained.
Reaction SMILES: Br.Br.[CH3:3][C@H:4]1[CH2:9][NH:8][C@@H:7]([CH3:10])[CH2:6][NH:5]1.[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](Cl)=[N:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>C(OCC)(=O)C>[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([N:5]2[CH2:6][C@H:7]([CH3:10])[NH:8][CH2:9][C@@H:4]2[CH3:3])=[N:14][N:13]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: C[C@H]1CN[C@@H](C)CN1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C[C@H]1CN(c2nnc(Cl)c3ccccc23)[C@@H](C)CN1

Procedure:
(2S,5S)-2,5-dimethylpiperazine dihydrobromide (1.16 g, 4.20 mmol), 1,4-dichlorophthalazine (700 mg, 3.52 mmol), potassium carbonate (973 mg, 7.04 mmol), and N-methylpyrrolidinone (7 mL) were heated at 120° C. for 22 hours. The reaction was taken up in ethyl acetate (80 mL) and washed with aqueous K2CO3 (10%), water, and saturated sodium chloride. The organics were dried (MgSO4) and evaporated to give an orange oil. Chromatography over silica gel with a gradient of hexanes+2.5% triethylamine/0-100% ethyl acetate+2.5% triethylamine gave a pale yellow semi-solid. MS (M+H)+=277.8.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=1[S:40](Cl)(=[O:42])=[O:41]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:34]4[CH:35]=[CH:36][CH:37]=[C:38]([Cl:39])[C:33]=4[Cl:32])(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cccc(Cl)c4Cl)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2,3-dichloro-benzenesulfonyl chloride. Purity (ELSD, based on MW=630.5)=70%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[CH:8](Cl)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.[Cu](C#N)[C:26]#[N:27]>ClC(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[CH:8]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:26]#[N:27]
Reactant: O=c1cnn(-c2ccc(C(Cl)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Reactant: N#C[Cu]C#N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: N#CC(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 180 °C
Yield: 11.2 %

Procedure:
A mixture of 12 parts of 2-[3-chloro-4-[chloro(4-chlorophenyl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione and 5.4 parts of copper cyanide was stirred and heated first for 3 hours at 130° C. and for 3 hours at 180° C. After cooling, the precipitated product was dissolved in a mixture of trichloromethane and methanol (90:10 by volume). The inorganic precipitate was filtered off and the filtrate was evaporated in vacuo. The residue was purified four times by column chromatography over silica gel using first a mixture of trichloromethane and acetonitrile (90:10 by volume), second a mixture of tetrachloromethane and methanol (93:7 by volume) and then twice a mixture of tetrachloromethane and acetonitrile (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was further purified by column chromatography (HPLC) over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated in vacuo. The residue was dried, yielding 1.3 parts (11.2%) of 2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetonitrile; mp. 196.8° C. (compound 22).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][C@@H:5]([C:11]([CH3:13])=[CH2:12])[C@@H:4]1[CH2:14][OH:15].[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C@H:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][C@@H:5]([C:11]([CH3:13])=[CH2:12])[C@H:4]1[CH2:14][O:15][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: C=C(C)[C@@H]1CCC(C)(C)[C@H](OC)[C@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(C)[C@@H]1CCC(C)(C)[C@H](OC)[C@@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 83 %

Procedure:
A mixture of the above alcohol (621 g) and sodium hydride (141 mg, 60% dispersion in oil) and benzyl bromide (0.41 ml) in dry N,N-dimethylformamide (2.5 ml) was stirred for 10 hrs at room temperature. After the mixture was cooled to 0° C., the reaction was quenched by addition of water. The pH of the mixture was adjusted to pH 7 with 0.1N hydrochloric acid. The mixture was extracted with diethyl ether, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue by flash column chromatography (using n-hexane:ethyl acetate=20:1 as an eluent) gave benzyl [(1S,2R,6R)-2-methoxy-3,3-dimethyl-6-(1-methylvinyl)cyclohexyl]methyl ether (726 mg, 83% yield).
Reaction SMILES: [N:1]1([C:30](OC(C)(C)C)=[O:31])[CH2:29][CH2:28][CH2:27][C@H:2]1[C:3]([NH:5][C@H:6]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:16])[NH:12][N+:13]([O-:15])=[O:14])=[O:4].Cl.CCOC(C)=O.[NH:44]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C@H:45](C(ON1C(=O)CCC1=O)=O)[CH3:46]>CCN(CC)CC>[NH:44]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C@H:45]([C:30]([N:1]1[CH2:29][CH2:28][CH2:27][C@H:2]1[C:3]([NH:5][C@H:6]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:16])[NH:12][N+:13]([O-:15])=[O:14])=[O:4])=[O:31])[CH3:46]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1

Procedure:
The desired compound was prepared from 28.9 g of Boc-Pro-Arg(NO2)-OBzl, 150 ml of 4N HCl-AcOEt, 8 ml of Et3N and 16.3 g of Boc-Ala-OSu in the same manner as in Example 8-(1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([C:36]2[C:37]([CH3:43])=[N:38][N:39]([CH3:42])[C:40]=2[CH3:41])[C:34]=1[Cl:35])[C:30]#[N:31].C(O)(C(F)(F)F)=O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.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.[Fe+2].O1CCOCC1>[Cl:35][C:34]1[C:33]([C:36]2[C:37]([CH3:43])=[N:38][N:39]([CH3:42])[C:40]=2[CH3:41])=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=1[NH:26][C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:19][CH2:20]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: Cc1nn(C)c(C)c1-c1cc(C#N)cc(N)c1Cl
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(-c4c(C)nn(C)c4C)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 100 °C

Procedure:
2-Chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (42.6 mg, 0.120 mmol), 3-amino-4-chloro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzonitrile, TFA (45 mg, 0.120 mmol), palladium acetate (8.09 mg, 0.036 mmol), DPPF (6.66 mg, 0.012 mmol), Xantphos (6.95 mg, 0.012 mmol), and cesium carbonate (117 mg, 0.360 mmol) were combined in a vial and dioxane (801 μl) was added. The vial was evacuated and backfilled with nitrogen (3×), then heated at 100° C. 4 h. The reaction mixture was diluted with ethyl acetate and vacuum filtered through a pad of Celite. The filtrate was concentrated in vacuo and the crude material purified by column chromatography on the ISCO system (12 g, 0-5% MeOH/CH2Cl2). 2-((2-Chloro-5-cyano-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (30 mg) was isolated as a pale yellow solid.
Reaction SMILES: B(F)(F)[F:2].CCOCC.N[C:11]1[C:12]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:13][C:14]2[CH2:15][CH2:16][C@@H:17]3[C@@H:26]([C:27]=2[CH:28]=1)[CH2:25][CH2:24][C@@:22]1([CH3:23])[C@H:18]3[CH2:19][CH2:20][C:21]1=[O:29].N(OC(C)(C)C)=O.CCCCC>C(Cl)Cl>[F:2][C:11]1[C:12]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:13][C:14]2[CH2:15][CH2:16][C@@H:17]3[C@@H:26]([C:27]=2[CH:28]=1)[CH2:25][CH2:24][C@@:22]1([CH3:23])[C@H:18]3[CH2:19][CH2:20][C:21]1=[O:29]
Reactant: FB(F)F
Reactant: COCCOc1cc2c(cc1N)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Agent: CC(C)(C)ON=O
Solvent: CCCCC
Solvent: ClCCl
Solvent: CCOCC
Product: COCCOc1cc2c(cc1F)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 14 %

Procedure:
To neat BF3-Et2O (126 μL, 141 mg, 1.00 mmol) at −15° C. under Ar (g) was added a solution of compound 95 (228 mg, 0.66 mmol) in dry CH2Cl2 (4 mL) followed by the dropwise addition t-butyl nitrite (95 μL, 82 mg, 0.80 mmol). This solution was stirred at −15° C. for 10 min then at 0° C. for 1.5 h. Pentane (16 mL) was added to the cold solution and a red gummy solid precipitated. The solvent was decanted and the residue was rinced with cold Et2O (5 mL). The residue was dried under vacuum to give a foamy orange-red solid. This solid was heated under vacuum with a heatgum for 5 min. The residue was purified by flash chromatography (SiO2) using 3:7 to 1:1 EtOAc/Hexanes as eluent to give compound 96 (32 mg, 14%) as a solid. 1H NMR (CDCl3) δ 0.90 (3H, s), 1.25-1.64 (m, 6H), 1.92-2.29 (6H, m), 2.50 (1H, dd, J=18.9 Hz, 8.9 Hz), 2.82 (2H, dd, J=8.4 Hz, J′=3.5 Hz), 3.45 (3H, s), 3.75 (2H, t, J=4.7 Hz), 4.15 (2H, t, J=4.5 Hz), 6.71 (1H, d, J=8.7 Hz), 6.98 (1H, d, J=13.2 Hz); 13C NMR(CDCl3) δ 13.8, 21.5, 25.9, 26.5, 29.0, 29.7, 31.5, 35.8, 38.0, 43.9, 47.9, 50.3, 59.2, 69.2, 71.0, 113.1 (d, J=18.7 Hz), 116.1, 132.6 (d, J=87.0 Hz), 144.5, 149.5, 152.7, 220.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:18]2[C:19](=[O:28])[C:20]([CH3:27])=[C:21]([CH3:26])[C:22](=[O:25])[C:23]=2[CH3:24])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](O)=[O:16])=[CH:5][CH:4]=1.Cl.[NH2:30][OH:31].C(=O)([O-])O.[Na+].C(OCC)(=O)C>ClCCl.C(Cl)(=O)C(Cl)=O.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:18]2[C:19](=[O:28])[C:20]([CH3:27])=[C:21]([CH3:26])[C:22](=[O:25])[C:23]=2[CH3:24])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:30][OH:31])=[O:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(CCCCCC(=O)O)C2=C(C)C(=O)C(C)=C(C)C2=O)cc1
Reactant: NO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(C(CCCCCC(=O)NO)C2=C(C)C(=O)C(C)=C(C)C2=O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 45.5 %

Procedure:
7-(4-Methoxyphenyl)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-heptanoic acid (1.3 g, 3.3 mmol) was dissolved in dichloromethane (20 ml), to which oxalyl chloride (1 ml) was added at room temperature. The reaction mixture was stirred at 50° C. for 1 hour, and the solvent was evaporated under reduced pressure. The resultant residue was dissolved in THF (5 ml), which was added dropwise at room temperature to a mixture of hydroxylamine hydrochloride (1 g, 14 mmol) in THF (10 ml) and saturated solution of aqueous sodium hydrogencarbonate (10 ml). After being stirred at room temperature for 1 hour, ethyl acetate (20 ml) was added to the reaction mixture. The organic layer was washed with water, dried, and concentrated under reduced pressure, to give 7-(4-methoxyphenyl)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-heptanohydroxamic acid (0.6 g, 42%). The physical properties are shown in the column of Compound No.8 in Table 1. In the similar manner, Compounds Nos. 1, 4, 10, 11, 12, 13, 14, 15, 16, 17, 19, 20, 21, 22, 23, 24, 25, and 26 were synthesized.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[CH2:9]Br.[Mg].[C:13]([NH:20][C:21]([CH3:25])([CH3:24])[CH:22]=O)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>CCOCC>[C:13]([NH:20][C:21]([CH3:25])([CH:24]=[CH:9][CH:3]1[C:2]([CH3:11])([CH3:1])[CH2:6][CH2:5][C:4]1([CH3:8])[CH3:7])[CH3:22])([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14]
Reactant: CC1(C)CCC(C)(C)C1CBr
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(C=CC1C(C)(C)CCC1(C)C)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
A solution of 2,2,5,5-Tetramethyl-1-cyclopentylmethyl bromide in ether is added slowly to magnesium turnings until the Grignard reagent begins to form. The remainder of the alkyl bromide is then added and the mixture is stirred until all the magnesium dissolves. At 0° C. a solution of N-Boc-2-amino-2-methylpropanal is then added and the mixture is stirred overnight. The reaction is quenched with 1M HCL, and extracted with ether and the extracts are evaporated. The residue is dissolved in dioxane and 2M H2SO4 is added. The mixture is heated until the alcohol is dehydrated, as shown by thin layer chromatography. Water is added and the mixture is extracted with ether. The organic layer is dried over MgSO4 and evaporated to give N-Boc-2-amino-2-methyl-4-(2,2,5,5-tetramethyl-1-cyclopentyl)butene.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[O:31]1[C:35]2([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[O:34][CH2:33][CH2:32]1>>[N:25]1([C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:15]=[CH:16][C:10]4[O:9][C:8]([CH2:7][CH2:6][N:38]5[CH2:39][CH2:40][C:35]6([O:34][CH2:33][CH2:32][O:31]6)[CH2:36][CH2:37]5)=[CH:12][C:11]=4[CH:13]=3)=[N:18][CH:19]=2)=[O:24])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Reactant: C1CC2(CCN1)OCCO2
Product: O=C(c1ccc(-c2ccc3oc(CCN4CCC5(CC4)OCCO5)cc3c2)nc1)N1CCOCC1

Procedure:
The product from Example 44E and 1,4-dioxa-8-azaspiro[4.5]decane were processed as described in Example 1D to provide the titled compound. 1HNMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.95 (m, 3H), 7.58 (d, J=8.7 Hz, 1H), 6.82 (s, 1H), 3.3-4.1 (m, 20H), 2.05 (m, 4H); MS (DCI) m/z 478 (M+H)+;