Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[N:20]=[CH:21][NH:22][CH:23]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[N:20]=[CH:21][N:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:23]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)c2c[nH]cn2)CC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1cnc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.4 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)-4-(1H-imidazol-4-ylcarbonyl)piperazine (Example 3, 0.60 g, 1.92 mmol), methyl bromoacetate (0.35 g, 2.3 mmol) and potassium carbonate (0.80 g, 5.8 mmol) in N,N-dimethylformamide (6.4 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 50:50 to 0:100 then ethyl acetate/methanol 100/0 to 90/10) to give the title compound (0.49 g, 66%) as a white powder.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:49])(=O)=O.[CH:52]1(B(O)O)[CH2:54][CH2:53]1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[CH:52]1([C:7]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]([C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])[C:18]4[C:23]([CH:24]=3)=[CH:22][C:21]([CH2:25][N:26]3[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][O:34][Si:35]([C:38]([CH3:40])([CH3:39])[CH3:41])([CH3:36])[CH3:37])[CH2:30][CH2:31]3)=[CH:20][CH:19]=4)=[C:12]3[C:8]=2[CH2:9][NH:10][C:11]3=[O:49])[CH2:54][CH2:53]1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)ccc21
Reactant: OB(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(C3CC3)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)ccc21
Yield: 67.9 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-trifluoromethanesulfonyloxy-7-{1-(tert-butoxycarbonyl)-5-[4-(2-tert-butyldimethylsilyloxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (81.7 mg, 0.109 mmol) was dissolved in dimethoxyethane (4.1 mL), and the solution was treated with cyclopropylboronic acid (28.0 mg, 0.327 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (7.1 mg, 0.0087 mmol), potassium carbonate (75.0 mg, 0.545 mmol) and water (0.058 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol=12/1) to obtain 4-cyclopropyl-7-{1-(tert-butoxycarbonyl)-5-[4-(2-tert-butyldimethylsilyloxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (47.7 mg, yield 68%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([C:20]1[C:21]2[N:22]([CH:27]=[CH:28][N:29]=2)[C:23](Br)=[CH:24][N:25]=1)[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[C:34]([C:47]([F:50])([F:49])[F:48])[N:33]=1.CC([O-])=O.[K+]>O1CCOCC1>[C:1]([O:5][C:6](=[O:30])[N:7]([C:20]1[C:21]2[N:22]([CH:27]=[CH:28][N:29]=2)[C:23]([C:36]2[CH:35]=[C:34]([C:47]([F:48])([F:49])[F:50])[N:33]=[C:32]([F:31])[CH:37]=2)=[CH:24][N:25]=1)[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)cc1)c1ncc(Br)n2ccnc12
Reactant: CC1(C)OB(c2cc(F)nc(C(F)(F)F)c2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)cc1)c1ncc(-c2cc(F)nc(C(F)(F)F)c2)n2ccnc12
Temperature: 85 °C
Yield: 151.4 %

Procedure:
(5-Bromoimidazo[1,2-a]pyrazin-8-yl)-(4-morpholin-4-ylphenyl)carbamic acid tert-butyl ester (50 mg, 0.11 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (126 mg, 0.21 mmol), KOAc (31 mg, 0.32 mmol) and Pd(dppf)Cl2DCM (4.3 mg, 0.0053 mmol) are stirred under N2 in dioxane (0.3 mL) and heated at 85° C. for 2.5 h. The mixture is cooled and partitioned between NaHCO3 (5% aq., 5 mL) and EtOAc (15 mL). The layers are separated and the aqueous phase extracted with further EtOAc (2×10 mL). The combined organic extracts are washed with brine (10 mL), dried over Na2SO4 and evaporated under reduced pressure to afford the title compound as a brown oil (93 mg) which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])=[C:8]([CH:17]=1)[O:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([O-:3])=[O:2].[CH3:25][C:26]([CH3:28])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[CH:26]([N:14]1[CH2:15][CH2:16][CH:11]([CH2:10][O:9][C:8]2[CH:17]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[C:18]([F:24])([F:23])[C:19]([F:20])([F:21])[F:22])[CH2:12][CH2:13]1)([CH3:28])[CH3:25]
Reactant: CC(C)=O
Reactant: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(OCC2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)N1CCC(COc2cc([N+](=O)[O-])ccc2C(F)(F)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolved 4-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-piperidine (646 mg) in DCE(6.4 mL), then added acetone (136 μl), NaBH(OAc)3 (541 mg) and finally acetic acid (105 μL). Stirred the cloudy yellow solution under N2 at RT overnight. Added another 130 μL acetone and stirred at RT over weekend. Quenched the reaction with 30 mL N NaOH/H2O and stirred 10 min. Extracted with Et2O and the organic layer was brine-washed, dried over Na2SO4, filtered and concentrated in vacuo. Dried under high vacuum for several h to obtain 1-isopropyl-4-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-piperidine as a yellow orange solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=1)[C:10]1[CH:22]=[CH:21][C:13]([C:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1.[I-].[Na+].C(N(CC)CC)C.Br[CH2:40][C:41]1[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:42]=1>C(#N)C>[CH2:17]([N:16]([CH2:19][CH3:20])[C:14]([C:13]1[CH:21]=[CH:22][C:10]([C@@H:9]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)[N:3]2[C@@H:2]([CH3:1])[CH2:7][N:6]([CH2:40][C:41]3[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:42]=3)[C@H:5]([CH3:8])[CH2:4]2)=[CH:11][CH:12]=1)=[O:15])[CH3:18]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(O)c2)N2C[C@@H](C)NC[C@@H]2C)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(O)c2)N2C[C@@H](C)N(Cc3ccc(C(=O)OC)cc3)C[C@@H]2C)cc1
Reaction time: 8 h
Yield: 64.3 %

Procedure:
The 4-[(S)-((2S,5R)-2,5-dimethylpiperazin-1-yl)(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide (0.51 g, 1.29 mmol) was dissolved in 10 mL of dry acetonitrile. Sodium iodide (20 mg, 0.13 mmol) was added and the reaction was stirred under nitrogen at room temperature during the addition of triethylamine (0.72 mL, 5.16 mmol), followed by methyl 4-(bromomethyl)benzoate (0.59 g, 2.58 mmol). The reaction mixture was stirred under nitrogen overnight. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with water, dried over Na2SO4/MgSO4 and concentrated under reduced pressure. The residual light yellow oil was purified by chromatography on silica gel (50% EtOAc in CH2Cl2) to give 0.45 g (0.83 mmol) of methyl 4-{(2R, 5S)-4-[(S)-(4-diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl]-2,5-dimethyl-1-piperazinylmethyl}-benzoate as a white amorphous solid.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C(N(CC)CC)C.[OH:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[CH:26]=2)[N:21]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:20]=1.C([O-])(O)=O.[Na+]>C(#N)C>[O:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][O:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[CH:26]=3)[N:21]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:20]=2)[CH2:6][CH2:7]1
Reactant: CCOC(=O)n1nc(O)c2cc([N+](=O)[O-])ccc21
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)n1nc(OCCN2CCOCC2)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Yield: 42.2 %

Procedure:
To a solution of 4-(2-chloroethyl)morpholine hydrochloride (390 mg, 2.10 mmol) in acetonitrile (25 mL) was added triethylamine (0.56 mL, 4.0 mmol) and ethyl 3-hydroxy-5-nitro-1H-indazole-1-carboxylate (563 mg, 1.91 mmol) and the mixture heated to reflux for 2 days. Additional portions of 4-(2-chloroethyl)morpholine hydrochloride (178 mg, 0.955 mmol) and triethylamine (130 μL, 0.95 mmol) were added and the reaction mixture was heated at reflux for a further 3 hr and then cooled to RT. Saturated aq. NaHCO3 (50 mL) was added and the mixture was extracted with EtOAc (2×100 mL). The organic extracts were combined, dried and evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, 40 g, 0-100% EtOAc in isohexane, gradient elution) to afford ethyl 3-(2-morpholinoethoxy)-5-nitro-1H-indazole-1-carboxylate as a yellow solid (294 mg, 41%); Rt 1.26 min (Method 2, acidic); m/z 365 (M+H)+ (ES+).
Reaction SMILES: [C:1]12([CH2:11][N:12]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:21]5[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=5)[CH:19]=4)[CH2:14][C:13]3=[O:29])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl[CH2:31][C:32]1[N:33]=[CH:34][N:35]([C:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:36]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[C:1]12([CH2:11][N:12]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:21]5[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=5)[CH:19]=4)[C:14]([CH2:31][C:32]4[N:33]=[CH:34][N:35]([C:37]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)[C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)[CH:36]=4)([CH2:31][C:32]4[N:33]=[CH:34][N:35]([C:37]([C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH:36]=4)[C:13]3=[O:29])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: N#Cc1ccc(-c2ccc3c(c2)N(CC24CC5CC(CC(C5)C2)C4)C(=O)C3)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2ccc3c(c2)N(CC24CC5CC(CC(C5)C2)C4)C(=O)C3(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reaction time: 8 h
Yield: 26.5 %

Procedure:
4-(1-Adamantan-1-ylmethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-benzonitrile (191 mg, 0.50 mmol) and 4-chloromethyl-1-trityl-1H-imidazole compound (449 mg, 1.25 mmol) were dissolved in 5 ml of anhydrous THF under an atmosphere of dry N2. To this solution was added 95% KHMDS (220 mg, 1.05 mmol) and the reaction mixture was subsequently stirred overnight. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO3. The DCM layer was dried over Na2SO4, filtered and concentrated under vacuum to give a purple foam which was chromatographed on flash silica gel eluting with a gradient of CHCl3 to CHCl3/MeOH/NH4OH (98/2/0.01) to give 136 mg of the titled compound as a pink oil.
Reaction SMILES: [CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[CH:7]([OH:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[CH3:2].[C:24](Cl)(=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[CH:7]([O:10][C:24](=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16])[CH3:2]
Reactant: CCC1(C)CC(O)C(C)C(C)(CC)N1OC(C)c1ccccc1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(=O)OC1CC(C)(CC)N(OC(C)c2ccccc2)C(C)(CC)C1C
Yield: 936.7 %

Procedure:
In analogy to example 1 were reacted 6,36 g (2 mmol) of 2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-piperidin-4-ol with 4,38 g (2 mmol) of lauroyl chloride and 2.02 g (2 mmol) of triethylamine in toluene to give 9,4 g (94%) dodecanoic acid 2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-piperidin-4-yl ester as yellowish liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].O[NH:29][C:30]([C:32]1[S:33][C:34]([S:37](=[O:40])(=[O:39])[NH2:38])=[CH:35][CH:36]=1)=[NH:31]>>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25]4[O:26][N:31]=[C:30]([C:32]5[S:33][C:34]([S:37]([NH2:38])(=[O:40])=[O:39])=[CH:35][CH:36]=5)[N:29]=4)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:11])[F:10]
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)s1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(-c4nc(-c5ccc(S(N)(=O)=O)s5)no4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) (195 mg, 0.5 mmol) and N-hydroxy-5-sulfamoyl-thiophene-2-carboxamidine (example B.2) (166 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane) as a light yellow solid (50 mg, 17%). MS (ISN) 573.2 [(M−H)−]; mp 324° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])=[CH:8][CH:7]=1)=[N:4][OH:5].CCN(C(C)C)C(C)C.[C:33]1([CH3:43])[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]([F:22])([F:23])[C:3]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:13])=[CH:10][CH:11]=1)=[N:4][O:5][S:39]([C:36]1[CH:37]=[CH:38][C:33]([CH3:43])=[CH:34][CH:35]=1)(=[O:41])=[O:40]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(C(=NO)C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)ON=C(c2ccc(C(C)NC(=O)OC(C)(C)C)cc2)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
tert-Butyl 1-(4-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)phenyl)ethylcarbamate (640 mg, 1.93 mmol) was dissolved in CH2Cl2 (15 ml) together with DIPEA (367 μl, 2.11 mmol) and DMAP (23 mg, 0.19 mmol). The mixture was cooled to 0° C. before slow, portionwise addition of 4-toluenesulfonyl chloride (367 mg, 1.93 mmol). The reaction was allowed to reach room temperature over 2 h, washed with H2O (4*15 ml), dried over MgSO4, filtered and evaporated. The product was purified by flash chromatography using Pet. Ether/EtOAc (3:1) as eluent to give 817 mg (87%) of the title compound as pale solids.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[C:9]([OH:20])=[C:10]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:11]([O:13][CH3:14])=[O:12].C(N(CC)CC)C>ClCCl>[CH3:6][O:7][C:8]1[C:9]([O:20][S:2]([CH3:1])(=[O:4])=[O:3])=[C:10]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:11]([O:13][CH3:14])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(OC)c(OC)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)c(OC)c1OS(C)(=O)=O
Temperature: 25 °C

Procedure:
Methanesulfonyl chloride (634 μl, 0.008 mol) was added dropwise to an ice-cooled solution of methyl 3,4-dimethoxy-2-hydroxybenzoate (1.58 g, 0.0075 mol) and triethylamine (1.27 ml, 0.009 mol) in dichloromethane (30 ml) and the reaction then allowed to warm to room temperature, with stirring. The reaction mixture was washed with water (2×25 ml) and the organic layer dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with a solvent gradient of diethyl ether:hexane (60:40 to 100:0, v/v) to give the subtitle compound as a colourless oil that crystallised on standing (1.94 g, 90%). MS m/z 308 (MNH4)+.
Reaction SMILES: ClC1C=C2C(C)(C)/C(=C\C=C(/C3C=CC=C(CCCCC(O[N:70]4[C:74](=[O:75])[CH2:73][CH2:72][C:71]4=[O:76])=O)C=3)\C=C\C3C(C)(C)C4C5C=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C=5C=CC=4[N+]=3CCCCS([O-])(=O)=O)/N=C2N(CCCCS([O-])(=O)=O)C=1.[Na+:77].[Na+].[Na+].[C:80]([CH2:83][CH2:84]/[C:85](/[CH:110]=[CH:111]/[C:112]1[C:113]([CH3:130])([CH3:129])[C:114]2[C:115]([N:128]=1)=[N+:116]([CH2:121][CH2:122][CH2:123][S:124]([O-:127])(=[O:126])=[O:125])[CH:117]=[C:118]([Cl:120])[CH:119]=2)=[CH:86]\[CH:87]=[C:88]1\[N:89]([CH2:103][CH2:104][CH2:105][S:106]([O-:109])(=[O:108])=[O:107])[C:90]2[C:95]([C:96]\1([CH3:98])[CH3:97])=[CH:94][C:93]([S:99]([O-:102])(=[O:101])=[O:100])=[CH:92][CH:91]=2)([OH:82])=[O:81].[Na+].[Na+]>>[Cl:120][C:118]1[CH:119]=[C:114]2[C:113]([CH3:130])([CH3:129])[C:112](/[CH:111]=[CH:110]/[C:85](/[CH2:84][CH2:83][C:80]([O:82][N:70]3[C:74](=[O:75])[CH2:73][CH2:72][C:71]3=[O:76])=[O:81])=[CH:86]/[CH:87]=[C:88]3/[N:89]([CH2:103][CH2:104][CH2:105][S:106]([O-:109])(=[O:107])=[O:108])[C:90]4[C:95]([C:96]/3([CH3:97])[CH3:98])=[CH:94][C:93]([S:99]([O-:102])(=[O:100])=[O:101])=[CH:92][CH:91]=4)=[N:128][C:115]2=[N+:116]([CH2:121][CH2:122][CH2:123][S:124]([O-:127])(=[O:126])=[O:125])[CH:117]=1.[Na+:77].[Na+:77]
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)CCC(=O)O)=Nc2c1cc(Cl)c[n+]2CCCS(=O)(=O)[O-]
Reactant: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C(/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C)c1cccc(CCCCC(=O)ON2C(=O)CCC2=O)c1
Agent: [Na+]
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)CCC(=O)ON2C(=O)CCC2=O)=Nc2c1cc(Cl)c[n+]2CCCS(=O)(=O)[O-]

Procedure:
Compound 36 is prepared analogously to compound 29 (Example 38), except that compound 19 is used as a starting material.
Reaction SMILES: C(O[C:5]1[O:6][CH2:7][C:8](=[O:16])[C:9]=1[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])(C)C.C(OC(C)C)(=O)CC(OC(C)C)=O.ClCC(Cl)=O.[NH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C(O)C>[O:39]1[CH2:40][CH2:41][N:36]([NH:35][C:5]2[O:6][CH2:7][C:8](=[O:16])[C:9]=2[C:10]([O:12][CH:13]([CH3:14])[CH3:15])=[O:11])[CH2:37][CH2:38]1
Reactant: NN1CCOCC1
Reactant: CC(C)OC(=O)C1=C(OC(C)C)OCC1=O
Agent: CC(C)OC(=O)CC(=O)OC(C)C
Agent: O=C(Cl)CCl
Solvent: CCO
Product: CC(C)OC(=O)C1=C(NN2CCOCC2)OCC1=O
Reaction time: 18 h

Procedure:
To a solution of isopropyl 2-isopropoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (12.2 g, 53.6 mmol), which similarly prepared according to the procedure described in the Example 74, Third step using diisopropyl malonate and chloroacetyl chloride, in ethanol (45 mL), 4-aminomorpholine (5.7 mL, 59.2 mmol) was added at ambient temperature. The mixture was stirred for 18 h. The solvent was removed under reduced pressure, and the crude product was suspended in methyl tert-butyl ether, then the precipitate was collected by filtration, washed with methyl tert-butyl ether and hexane then dried to afford isopropyl 2-(morpholinoamino)-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (11.2 g, y. 75%).
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:12]([C:13]2[O:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:11][CH:10]=[C:9]([NH2:26])[N:8]=1.[OH-].[Na+].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36]Cl)[N:31]=1>CN(C)C=O>[Cl:29][C:30]1[N:31]=[C:32]([CH2:36][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][C:15]3[CH:14]=[C:13]([C:12]4[C:7]([NH2:6])=[N:8][C:9]([NH2:26])=[CH:10][CH:11]=4)[O:17][N:16]=3)=[CH:20][CH:21]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: ClCc1cccc(Cl)n1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4cccc(Cl)n4)cc3)no2)c(N)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (21.2 μL, 0.11 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. An N,N-dimethylformamide (1 mL) solution of 2-chloro-6-chloromethyl-pyridine (34.3 mg, 0.21 mmol) described in Manufacturing Example 52-1-2 was added to a suspension of this solid in N,N-dimethylformamide (1 mL), which was stirred for 1 hour at 60° C. This reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate=1:2), and then further purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (15.9 mg, 37%) as a trifluoroacetic acid salt.