Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].C(=O)(O)[O-].[Na+].O.C(O[C:20]([CH3:23])([CH3:22])[CH3:21])(=O)C>C(OCC)(=O)C.Cl(O)(=O)(=O)=O>[O:1]=[C:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([O:8][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:7]
Reactant: CC(=O)CCCC(=O)O
Reactant: CC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)CCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 65 h
Yield: 85 %

Procedure:
To a solution of 5-oxohexanoic acid (25 g, 192 mmol) in t-butyl acetate (600 mL) was added perchloric acid (500 μL, 8.31 mmol) and the resulting pale yellow solution was allowed to stir at room temp, with a drying tube in place, for 65 h. The reaction was diluted with ethyl acetate (400 mL) and then quenched with a mixture of sodium bicarbonate (50 g, 595 mmol) and water (100 mL). The organic layer was extracted with saturated aqueous sodium bicarbonate (5×150 mL), water (1×100 mL), brine (1×75 mL), dried over sodium sulfate, and filtered. The solvent was removed in vacuo to give the title compound (30.55 g, 85%) as a light oil. 1H NMR (500 MHz, chloroform-d) δ 2.50 (t, J=7.2 Hz, 2H), 2.25 (t, J=7.3 Hz, 2H), 2.16 (s, 3H), 1.89-1.83 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].F[C:15]1[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([CH3:21])[CH:20]=1>CN(C)C(=O)C>[N+:22]([C:18]1[CH:17]=[CH:16][C:15]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:20][C:19]=1[CH3:21])([O-:24])=[O:23]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 20 °C

Procedure:
14.1 g (150 mmol) of phenol were dissolved in 120 ml of anhydrous N,N-dimethylacetamide, while stirring, 20.6 g (150 mmol) of finely powdered potassium carbonate were added and the mixture was stirred at 70°-80° C. for 30 minutes. After cooling to 20° C., 23.25 g (18.3 ml, 150 mmol) of 5-fluoro-2-nitrotoluene were added dropwise, the mixture was heated at 135°-140° C. for 2 hours and, after cooling, concentrated in vacuo, the residue was introduced into ice and the crystalline product was filtered off with suction, washed with water and dried, 30 g, melting point 43°-46° C.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.C(=O)=O.C[O:21][C:22]([C:24]1[C:25]([CH2:41][CH2:42][O:43][CH3:44])=[N:26][C:27]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)=[N:28][C:29]=1[CH3:30])=O>O1CCCC1>[CH3:44][O:43][CH2:42][CH2:41][C:25]1[C:24]([CH2:22][OH:21])=[C:29]([CH3:30])[N:28]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[N:26]=1
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C)c1C(=O)OC
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COCCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C)c1CO
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 103.6 %

Procedure:
A 1.2 M solution of DIBALH in toluene (34.6 ml, 41.5 mmol) was added dropwise to a dry-ice cooled solution of 4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid methyl ester (4.9 g, 13.8 mmol) in tetrahydrofuran (50 ml). The reaction mixture was stirred for 15 min at −70° C., the dry-ice bath was removed and the reaction temperature was allowed to come to RT. The reaction mixture was stirred for 2 h at RT. Under ice-cooling 6 N aqueous HCl (10 ml) was carefully added. After 4 min ether was added, the layers were separated and the organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure to give 4.67 g (14.3 mmol, quant.) of crystalline [4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol.
Reaction SMILES: [H-].[Al+3].[Na+].[H-].[H-].[H-].[Cl-].[Mg+2].[Cl-].[CH2:10]([N:17]1[CH2:22][CH:21]=[C:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH:19]([CH2:30][OH:31])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>C1COCC1.O>[CH2:10]([N:17]1[CH2:22][CH2:21][C@@H:20]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[C@H:19]([CH2:30][OH:31])[CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OCC1CN(Cc2ccccc2)CC=C1c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OC[C@@H]1CN(Cc2ccccc2)CC[C@H]1c1ccc(F)cc1
Temperature: 50 °C
Yield: 81.1 %

Procedure:
Sodium aluminium hydride in THF (2.0 ml of a 1M solution) was carefully added to substantially anhydrous magnesium chloride (0.19 g, 1.5% H2O) under nitrogen. The mixture was stirred and heated to 50° C. and then a solution of (+)-1-benzyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (0.60 g) in THF (1.7 ml) was added dropwise over approximately 2 minutes. The reaction mixture was stirred and boiled under reflux for 4 hours. The mixture was cooled to ambient temperature and then stirred in an ice/water bath whilst water (0.1 ml) then 5M sodium hydroxide solution (0.1 ml) and water (0.1 ml) were added. The suspension was diluted with THF (5 ml) and the mixture filtered. The residue was washed with THF (3×5 ml) and the combined filtrate and washings were evaporated under reduced pressure to give a yellow oil (0.49 g). This oil was analysed by GLC, Chiral HPLC and 1H nmr using the conditions described above. Starting material 13.2% was still present in the product as analysed by GLC. The amount of desfluoro compound as determined by HPLC was less than 0.1%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7]C(=O)[C:5]2=[O:15].[OH:16]O.Cl>[OH-].[Na+]>[NH2:7][C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[C:5]([OH:15])=[O:16]
Reactant: OO
Reactant: O=C1Nc2c(cc(F)cc2[N+](=O)[O-])C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1c(C(=O)O)cc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.17 %

Procedure:
To a slurry of 5-fluoro-7-nitro-1H-indole-2,3-dione (3 g, 14.2 mmol) in aqueous 5N NaOH solution (30 mL) was added slowly an aq. solution of 33% hydrogen peroxide (3 mL) at 0° C. After completion of the addition, the reaction mixture was stirred at room temperature for 4 h. After completion of the reaction, the reaction mixture was acidified with 2N HCl and the resulting precipitate was filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as yellow solid (2 g, 70.17%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[S:16]1[CH:20]=[CH:19][N:18]=[C:17]1[C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>CO>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([C:17]3[S:16][CH:20]=[CH:19][N:18]=3)=[CH:28][CH:27]=2)[CH:8]=1
Reactant: COC(=O)CCc1cccc(CN)c1
Reactant: O=Cc1ccc(-c2nccs2)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CNCc2ccc(-c3nccs3)cc2)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, of Preparation 44, and 4-thiazol-2-yl-benzaldehyde, of Preparation 25, using the method described in Example 1, Step A, except the imine was formed in MeOH at reflux over 2 h. 1H NMR (400 MHz, CDCl3) δ 7.93 (d, 2H), 7.85 (d, 1H), 7.43 (d, 2H), 7.31 (d, 1H), 7.28-7.09 (m, 4H), 3.84 (s, 2H), 3.79 (s, 2H), 3.66 (s, 3H), 2.94 (t, 2H), 2.63 (t, 2H); MS 367 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:20][C@H:19]3[C@H:16]([CH2:17][C@H:18]3O)[CH2:15]1)=[N:9][C:8]([O:22][CH3:23])=[CH:7][CH:6]=2.CCOC(/N=N/C(OCC)=O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:55]1(=[O:65])[NH:59][C:58](=[O:60])[C:57]2=[CH:61][CH:62]=[CH:63][CH:64]=[C:56]12>C1COCC1.C1COCC1.O1CCOCC1>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:20][C@H:19]3[C@H:16]([CH2:17][C@@H:18]3[N:59]3[C:55](=[O:65])[C:56]4[C:57](=[CH:61][CH:62]=[CH:63][CH:64]=4)[C:58]3=[O:60])[CH2:15]1)=[N:9][C:8]([O:22][CH3:23])=[CH:7][CH:6]=2
Reactant: COc1ccc2ncc(F)c(CCN3C[C@H]4C[C@@H](O)[C@H]4C3)c2n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1ccc2ncc(F)c(CCN3C[C@H]4C[C@H](N5C(=O)c6ccccc6C5=O)[C@H]4C3)c2n1
Reaction time: 12 h
Yield: 42 %

Procedure:
To a solution of (±)-(1S,5R,6R)-3-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-azabicyclo[3.2.0]heptan-6-ol (230 mg, 0.73 mmol) in THF (2 mL) as added DEAD (0.11 mL, 0.76 mmol), followed by dropwise addition of a preformed solution of PPh3 (190 mg, 0.72 mmol) and phthalimide-(107 mg, 0.73 mmol) in THF-dioxane (4 mL, 1:1). The resulting solution was heated at reflux. After 12 h, the solution was concentrated and the residue purified via a column chromatography (silica, 1% MeOH in DCM (1% NH4OH)) yielding the title compound (137 mg, 42%) as a yellow oil: LC/MS (ES) m/e 448 (M+H)+.
Reaction SMILES: [Na].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].[O-]CC.[Na+].Br[CH:16]([CH3:20])[C:17](=[O:19])[CH3:18]>C(O)C>[CH2:9]([O:8][C:2]([CH:3]([CH:16]([CH3:20])[C:17](=[O:19])[CH3:18])[C:4](=[O:5])[CH3:6])=[O:7])[CH3:10]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(=O)C(C)Br
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C(C)=O)C(C)C(C)=O
Reaction time: 0.5 h

Procedure:
7.3 G.; 0.317 mol of sodium was dissolved in 125 ml. of absolute ethanol. 87.0 G. (0.669 mol) of ethyl acetoacetate were added to the resulting solution of sodium ethoxide in the cold. The reaction was heated to reflux and 48.6 g. (0.322 mol) of freshly distilled 3-bromo-2-butanone were added dropwise with stirring over a period of 30 min. Refluxing was continued until the mixture tested neutral to pH paper (~1.5 hrs.). The precipitated sodium bromide was filtered off the cold solution and most of the ethanol was removed on an evaporator. The mixture was filtered again and distilled. The 3-ethoxycarbonyl-4-methylhexane-2,4-dione fraction which boiled at 131°-137° C./18 mm. was collected.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.Cl[C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([O:21][CH3:22])[N:14]=1>>[CH3:22][O:21][C:15]1[N:16]=[C:17]([O:19][CH3:20])[N:18]=[C:13]([CH:7]2[C:6]3[C:10](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[NH:9][C:8]2=[O:11])[N:14]=1
Reactant: COc1nc(Cl)nc(OC)n1
Reactant: O=C1Cc2cccc(Cl)c2N1
Product: COc1nc(OC)nc(C2C(=O)Nc3c(Cl)cccc32)n1

Procedure:
7-Chloro-1,3-dihydro-2H-indol-2-one (101.5 g) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (152 g) are reacted analogously to Example 1 Variant A. This gives the title compound as solid in an HPLC purity of 99% area (181.9 g, 97% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](OC(=O)C)(=[O:10])[CH3:9]>C(Cl)Cl>[C:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:10])[CH3:9]
Reactant: Nc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1

Procedure:
Acetanilide is prepared by the method of Example 5 using 5.0 mls (0.05 mole) of aniline, 7.5 grams of 3A molecular sieves and 6.6 g (0.065 mole) of acetic anhydride in 100 mls of methylene chloride. The crude product (6.23 grams; 86% of theoretical) is recrystallized from toluene to obtain pure acetanilide, m.p. 112°-114° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[CH:14][N:15]2[C:20]=1[C:19](=[O:21])[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]([CH:29]([NH:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:30][CH3:31])=[N:16]2)=[O:11].[CH3:44][C:45]1[CH:53]=[CH:52][C:48]([C:49](Cl)=[O:50])=[CH:47][CH:46]=1>C(Cl)Cl>[CH3:8][O:9][C:10]([C:12]1[CH:13]=[CH:14][N:15]2[C:20]=1[C:19](=[O:21])[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]([CH:29]([N:32]([CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[C:49](=[O:50])[C:48]1[CH:52]=[CH:53][C:45]([CH3:44])=[CH:46][CH:47]=1)[CH2:30][CH3:31])=[N:16]2)=[O:11]
Reactant: CCC(NCCCNC(=O)OC(C)(C)C)c1nn2ccc(C(=O)OC)c2c(=O)n1Cc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(c1nn2ccc(C(=O)OC)c2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
Triethylamine (0.011 mL, 0.079 mmol) was added to a solution of 3-benzyl-2-[1-(3-tert-butoxycarbonylamino-propylamino)-propyl]-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-5-carboxylic acid methyl ester (0.013 g, 0.026 mmol) and 4-methyl-benzoyl chloride (0.01 mL, 0.079 mmol) in CH2Cl2 (0.50 mL) at 0 C. The reaction mixture was stirred at 0° C. for 4 h, quenched with saturated NaHCO3 (3 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 8/1 to 1/1 hexane/EtOAc to afford the title compound (0.015 g, 94%) as a solid: 1H NMR (CDCl3) δ 7.02–7.32 (m, 11H), 5.95 (m, 3H), 4.85 (m, 1H), 3.86 (s, 3H), 3.25 (m, 2H), 2.65 (m, 2H), 2.32 (s, 3H), 2.00 (m, 1H), 1.80 (m, 1H), 1.60 (m, 1H), 1.32 (s, 9H), 0.85 (m, 1H), 0.65 (m, 3H); MS (ESI+) 616 (M++H); HRMS (ESI+) calculated: 616.3135 (M++H). found: 616.3110 (M++H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:10](I)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]2[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1)#[CH:15].CN.C(O)C>CC(N(C)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.[Cu]I.O>[OH:1][C:2]1[CH:12]=[CH:11][C:10]([C:15]#[C:14][C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH:25][C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=3)(=[O:23])=[O:24])=[CH:20][CH:21]=2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C#Cc1ccc(S(=O)(=O)Nc2ncccc2C)cc1
Reactant: CCOC(=O)c1cc(I)ccc1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CN
Solvent: CC(=O)N(C)C
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Nc3ncccc3C)cc2)ccc1O
Yield: 77.9 %

Procedure:
Dichlorobis(triphenylphosphine)palladium (0.07 g, 0.1 mmol) and copper(I)iodide (0.04 g, 0.2 mmol) were added to a solution of ethyl 2-hydroxy-5-iodobenzoate (14.9 g, 50 mmol) and 4-ethynyl-N-(3-methyl-2-pyridinyl)benzenesulfonamide (14.3 g, 50 mmol) in methylamine (10 g, 0.1 mol) and dimethylacetamide (60 ml) at 65° C. Hot ethanol was added after 1 h and then hot water (100 ml) with stirring. The solid was filtered off after cooling in the refrigerator and recrystallized from formic acid and water to yield 17.0 g (77%) product.
Reaction SMILES: C1(CC(CC(=O)NCCC2C=CC=CC=2)C(N(C(=O)[C@H](CC2N=CNC=2)N)N)=O)C2C(=CC=CC=2)C=CC=1.Cl.N(OCCC(C)C)=O.[C:48]1([CH2:58][CH:59]([CH2:75][C:76](=[O:86])[NH:77][CH2:78][CH2:79][C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)[C:60]([NH:62][C@H:63]([C:70]([N:72]=[N+]=[N-])=[O:71])[CH2:64][C:65]2[N:69]=[CH:68][NH:67][CH:66]=2)=[O:61])[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:51]=[CH:50][CH:49]=1.[N-]=[N+]=[N-].N[C@@H:91]([CH2:102][CH:103]([CH3:105])[CH3:104])[CH:92]([OH:101])[C:93]([O:95][CH2:96][CH2:97][CH:98]([CH3:100])[CH3:99])=[O:94]>CN(C)C=O.C(N(CC)CC)C>[C:48]1([CH2:58][CH:59]([CH2:75][C:76](=[O:86])[NH:77][CH2:78][CH2:79][C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)[C:60]([NH:62][C@H:63]([C:70]([NH:72][C@@H:91]([CH2:102][CH:103]([CH3:105])[CH3:104])[CH:92]([OH:101])[C:93]([O:95][CH2:96][CH2:97][CH:98]([CH3:99])[CH3:100])=[O:94])=[O:71])[CH2:64][C:65]2[N:69]=[CH:68][NH:67][CH:66]=2)=[O:61])[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:51]=[CH:50][CH:49]=1
Reactant: CC(C)CCOC(=O)C(O)[C@@H](N)CC(C)C
Reactant: [N-]=[N+]=NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC(=O)NCCc1ccccc1)Cc1cccc2ccccc12
Agent: CC(C)CCON=O
Agent: Cl
Agent: N[C@@H](Cc1c[nH]cn1)C(=O)N(N)C(=O)C(CC(=O)NCCc1ccccc1)Cc1cccc2ccccc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CCOC(=O)C(O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC(=O)NCCc1ccccc1)Cc1cccc2ccccc12
Reaction time: 16 h

Procedure:
To a suspension of 200 mg of N-[(+)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidine hydrazide in 5 ml of N,N-dimethylformamide were added successively dropwise 0.25 ml of a dry 5.1N-hydrogen chloride in N,N-dimethyformamide solution and 0.07 ml of isoamyl nitrite with stirring at -20° C. After disappearance of hydrazide compound, the reaction mixture was cooled to -30° C., and neutralized by adding 0.2 ml of triethylamine to prepare a solution of N-[(+)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)-propionyl]-L-histidine azide. The azide solution prepared was added dropwise to 110 mg of isoamyl (2RS,3S)-3-amino-2-hydroxy-5-methylhexanoate and 0.1 ml of triethylamine in 2 ml of dry N,N-dimethylformamide under ice-cooling, and the mixture was stirred for 16 hours. The reaction mixture was evaporated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The pressure was purified by silica gel column chromatography (eluent: chloroform/ethanol=10/1 by volume) to obtain 52 mg of isoamyl (2RS,3S)-3-{N-[(+)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidyl}amino-2-hydroxy-5-methylhexanoate as a white powder.
Reaction SMILES: Cl.N[OH:3].[OH-].[Na+].C[N:7]([CH:9]=[N:10][C:11]([C:13]1[N:14]=[CH:15][C:16]2[NH:17][C:18]3[C:23]([C:24]=2[CH:25]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:12])C>O.C(O)(=O)C>[OH:3][NH:7][CH:9]=[N:10][C:11]([C:13]1[N:14]=[CH:15][C:16]2[NH:17][C:18]3[C:23]([C:24]=2[CH:25]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:12]
Reactant: NO
Reactant: CN(C)C=NC(=O)c1cc2c(cn1)[nH]c1ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(N=CNO)c1cc2c(cn1)[nH]c1ccccc12
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
A mixture of 0.35 g of hydroxylamine hydrochloride, 1.5 ml of water, 1.0 ml of 5 N sodium hydroxide, 3.5 ml of acetic acid and 1.1 g of N-[(dimethylamino)methylene]-beta-carboline-3-carboxamide is allowed to stand for 1/2 h at room temperature. After adding 3 ml of water, the white precipitate is filtered off and washed with water. 1.0 g of N-[(hydroxyamino)methylene]-beta-carboline-3-carboxamide with a m.p. of 235°-240° C. is obtained.
Reaction SMILES: [C:1]([CH:3]1[CH2:5][CH:4]1[C:6]([O:8]CC)=O)#[N:2].[OH-].[Na+].Cl.S(Cl)(Cl)=O.Cl.[CH3:19][NH:20][O:21][CH3:22].C(N(CC)CC)C>O.ClCCl.CO>[C:1]([CH:3]1[CH2:5][CH:4]1[C:6]([N:20]([O:21][CH3:22])[CH3:19])=[O:8])#[N:2]
Reactant: CCOC(=O)C1CC1C#N
Reactant: CNOC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CON(C)C(=O)C1CC1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6.50 g (46.7 mmol) of the compound from Example 72A were introduced into 20 ml of methanol at RT, 46.7 ml (46.7 mmol) of a 1N aqueous sodium hydroxide solution were added, and the mixture was stirred at RT for 2 h. Concentrated hydrochloric acid was then added until the pH was 2, the mixture was extracted with diethyl ether, and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was taken up in 8.5 ml (117 mmol) of thionyl chloride and stirred at 65° C. for 4 h. Cooling was followed by concentration, and the residue was twice taken up in diethyl ether and again concentrated each time. The residue was introduced into 17 ml of dichloromethane, 3.43 g (35.1 mmol) of N,O-dimethylhydroxylamine hydrochloride and 9.8 ml (70.3 mmol) of triethylamine were added, and the mixture was stirred at RT overnight. Water was added, the phases were separated, two extractions with dichloromethane were carried out, and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: dichloromethane/methanol 9/1) to result in 1.72 g (24% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[C:49](/[CH:51]=[CH:52]/[C:53]([O:55][CH3:56])=[O:54])[CH:48]=[CH:47][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41](=[O:44])[O:42][CH3:43])=[CH:35][C:34]=2[O:45][CH3:46])[CH:22]=1)[CH2:18]O.[Br:57]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3]1[CH:50]=[C:49](/[CH:51]=[CH:52]/[C:53]([O:55][CH3:56])=[O:54])[CH:48]=[CH:47][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41](=[O:44])[O:42][CH3:43])=[CH:35][C:34]=2[O:45][CH3:46])[CH:22]=1)[CH2:18][Br:57]
Reactant: COC(=O)/C=C/c1ccc(OCCCCCCCCOc2cc(CO)cc(OCCCCCCCCOc3ccc(/C=C/C(=O)OC)cc3OC)c2)c(OC)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc(OCCCCCCCCOc2cc(CBr)cc(OCCCCCCCCOc3ccc(/C=C/C(=O)OC)cc3OC)c2)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
2.39 g (3.08 mmol) of 3,5-bis[(8-{2-methoxy-4-[(1E)-3-methoxy-3-oxo-1-propenyl]phenoxy}octyl)oxy]benzyl alcohol, 1,14 g (3.42 mmol) tetrabromomethane were dissolved in 25 ml dichloromethane. The solution was subsequently cooled to 0° C. and a solution of 0.86 g (3.29 mmol) triphenylphosphine in 20 ml dichloromethane was added dropwise thereto over a period of 1 hour. The mixture was subsequently allowed to react for 20 h at 25° C. and reduced in volume by evaporation. Chromatography of the residue on 120 g silica gel using first toluene:ethyl acetate (19:1) then (4:1) as eluant yielded 1.94 g (78%) 3,5-bis[(8-{2-methoxy-4-[(1E)-3-methoxy-3-oxo-1-propenyl]phenoxy}octyl)oxy]benzyl bromide as colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[CH:8][N:9]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:10](=[O:11])[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:3]1.[Br:23]Br>CN(C=O)C>[Br:23][C:3]1[N:2]([CH3:1])[C:6]2[N:7]=[CH:8][N:9]([CH2:12][C:13]([F:15])([F:16])[F:14])[C:10](=[O:11])[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: BrBr
Reactant: Cn1cc(-c2ccccn2)c2c(=O)n(CC(F)(F)F)cnc21
Solvent: CN(C)C=O
Product: Cn1c(Br)c(-c2ccccn2)c2c(=O)n(CC(F)(F)F)cnc21
Reaction time: 0.08 h
Yield: 69.5 %

Procedure:
To a stirred solution of 7-methyl-5-(pyridin-2-yl)-3-(2,2,2-trifluoroethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (53.6 mg, 0.174 mmol) in anhydrous DMF (1.8 ml) at 0° C. was added bromine (9.85 μl, 0.191 mmol) and the mixture stirred for 5 min. Further bromine (9.85 μl, 0.191 mmol) was added and the mixture stirred for 5 min. The mixture was partitioned between ethyl acetate (5 ml) and an aqueous mixture (3:1:4, water, saturated sodium hydrogen carbonate (aq) solution and 20% w/w sodium thiosulfate (aq) solution, 20 ml). The aqueous phase was separated and extracted with ethyl acetate (3×5 ml). The combined ethyl acetate fractions were washed with brine/water (1:1, 4×5 ml), dried (anhydrous sodium sulfate), filtered and reduced in vacuo. The resulting residue was purified by silica gel chromatography (0-5% methanol in ethyl acetate) to afford the title compound (46.8 mg, 70%). LCMS RT=0.74 min, [M+H+(79Br)]=387.0, [M+H+(81Br)]=389.0.