Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH3:22])[CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>ClCCl>[CH3:24][N:2]([CH3:1])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=3[CH3:32])=[CH:17][C:16]=2[CH3:22])[CH2:6][CH2:5][CH2:4]1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Cc1cc(N)ccc1C(=O)N1CCCC(N(C)C)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)C)c3ccccc32)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Dimethylamino-1-(2-methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (H) (1.00 g) is dissolved in dichloromethane (30 ml), and thereto is added triethylamine (0.48 ml) under ice-cooling, and further added dropwise 2-methylbenzoyl chloride (0.44 ml). The mixture is stirred at room temperature for 1 hour. The reaction solution is washed with water, and dried over magnesium sulfate. The solvent is distilled off, and the resulting residue is crystallized by adding thereto ethyl acetate. The precipitated crystal is recrystallized from dichloromethane/ethyl acetate to give 5-dimethylamino-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.92 g) as white powder, m.p. 191°-192° C. HPLC retention time: 7.5 minutes
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]([F:24])([F:23])[C:8]([NH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)=[O:9].[CH2:25]=O>C(O)(=O)C>[F:6][C:7]([F:23])([F:24])[C:8]([N:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH2:25]1)=[O:9]
Reactant: C=O
Reactant: O=C(NCCc1ccc(C(F)(F)F)cc1)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(N1CCc2ccc(C(F)(F)F)cc2C1)C(F)(F)F
Temperature: 0 °C
Reaction time: 18 h

Procedure:
10.0 ml of concentrated sulfuric acid were slowly added dropwise to a solution of 1.77 g (6.2 mmol) of N-trifluoroacetyl-2-(4-trifluoromethylphenyl)ethylamine [prepared from 2-(4-trifluoromethylphenyl)ethylamine and trifluoroacetic anhydride at −5° C.] in 7.5 ml of glacial acetic acid, and, while cooling in ice, 2 ml of formalin solution were added dropwise. After 18 hours at room temperature, the reaction mixture was poured into 130 ml of ice-water and extracted with dichloromethane, and the combined organic phases were washed with sodium bicarbonate solution and then with water. After drying over sodium sulfate, filtration and evaporation, 1.7 g of 2-trifluoroacetyl-7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline were isolated and were converted into 7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline by heating under reflux in ethanol/3N HCl (1:1) and alkaline workup.
Reaction SMILES: [CH:1](=[C:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:26][C:27]1[CH:36]=[CH:35][C:30]2[NH:31][C:32](=[O:34])[O:33][C:29]=2[CH:28]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:1](=[C:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:26][C:27]2[CH:36]=[CH:35][C:30]3[NH:31][C:32](=[O:34])[O:33][C:29]=3[CH:28]=2)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Reactant: O=C(O)C(=O)N1CCC(=Cc2ccccc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2[nH]c(=O)oc2c1)C(=O)N1CCC(=Cc2ccccc2)CC1

Procedure:
A mixture of 49 mg (0.2 mmol) of (4-benzylidene-piperidine-1-yl)-oxo-acetic acid, 33 μl (0.24 mmol) of triethylamine, 30 mg (0.2 mmol) of 6-amino-3H-benzoxazol-2-one [J. Chem. Soc., 321. (1938)] 79.6 mg (0.21 mmol) of HBTU [O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (Advanced Chem. Tech.)]and 1 ml of dimethylformamide is stirred at room temperature for 24 h. The reaction mixture is purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. The quality and the quantity of the product are determined by HPLC-MS method as described above. k′=9.66.
Reaction SMILES: [Br:1][CH2:2][C@H:3]1[CH2:7][C:6]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:5]=2[O:4]1.[Br:13]Br>C(O)(=O)C.CO>[Br:13][C:11]1[C:5]2[O:4][C@@H:3]([CH2:2][Br:1])[CH2:7][C:6]=2[CH:8]=[C:9]([F:12])[CH:10]=1
Reactant: Fc1ccc2c(c1)C[C@H](CBr)O2
Reactant: BrBr
Solvent: CO
Solvent: CC(=O)O
Product: Fc1cc(Br)c2c(c1)C[C@H](CBr)O2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (R)-2-bromomethyl-5-fluoro-2,3-dihydro-benzofuran (3.20 g, 14 mmol) in acetic acid was added bromine (2.2 ml, 42 mmol) and the reaction mixture was allowed to stir at room temperature for 12 h. The solvent was removed in vacuo and the residue dissolved in dichloromethane and washed with saturated aqueous sodium sulfite. The solvent was removed in vacuo and purification by flash column chromatography (silica, ethyl acetate:hexanes 1:19) afforded 3.16 g (74%) of as a light yellow oil. HRMS EI m/e 307.8846 (M)+, Calc'd. 307.8848. [α]D25=+24.8 (c 1% in methanol).
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[C:17]([Cl:23])[CH:16]=1>CN(C)C=O.C1C=CC=CC=1>[Cl:23][C:17]1[CH:16]=[C:15]([Cl:14])[CH:20]=[CH:19][C:18]=1[CH2:21][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)Cc1ccccc1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(Cl)cc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 30 parts of methyl benzeneacetate, 6.8 parts of sodium hydride dispersion 78%, 135 parts of N,N-dimethylformamide and 180 parts of benzene is stirred for 1 hour at room temperature, while nitrogen gas is introduced. Another 90 parts of benzene is added. Then there is added dropwise, during a 30 minutes-period, a solution of 43.4 parts of 1,3-dichloro-4-(chloromethyl)benzene in 45 parts of N,N-dimethylformamide. Upon completion, stirring is continued for 30 minutes at room temperature. The reaction mixture is poured onto water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed with water, dried, filtered and evaporated. The residue is distilled, yielding 26.5 parts of methyl 2,4-dichloro-α-phenylbenzenepropanoate; bp. 140°-145° C at 0.05 mm. pressure.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[H-].[Na+].Cl[C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1.O>O1CCCC1>[CH2:1]([O:7][C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-hexen-1-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl) pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [F:1][C:2]([F:12])([C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)[C:3]([F:6])([F:5])[F:4].[CH2:13]=[O:14]>CC(C)=O>[F:12][C:2]([F:1])([C:7]1[CH:11]=[CH:10][N:9]([CH2:13][OH:14])[N:8]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: C=O
Reactant: FC(F)(F)C(F)(F)c1cc[nH]n1
Solvent: CC(C)=O
Product: OCn1ccc(C(F)(F)C(F)(F)F)n1
Temperature: 130 °C
Reaction time: 5 h
Yield: 91.7 %

Procedure:
The mixture of 1.86 g of 3-(pentafluoroethyl)-1H-pyrazole and 0.60 g of paraformaldehyde was stirred at 130° C. for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added. The mixture was filtered. The filtrate was concentrated under reduced pressure to obtain 1.98 g of 3-(pentafluoroethyl)-1H-pyrazole-1-ylmethanol.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[C:9]([CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>O>[C:9]([CH:13]1[CH2:17][CH2:16][N:15]([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=2)[CH2:14]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: Nc1cccc(F)n1
Reactant: CC(C)(C)C1CCNC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)C1CCN(c2cccc(N)n2)C1
Temperature: 150 °C
Yield: 55.2 %

Procedure:
A suspension of 6-fluoropyridin-2-amine (500 mg, 4.46 mmol), 3-tert-butylpyrrolidine (730 mg, 4.46 mmol) in water (0.5 mL) and triethylamine (0.9 g, 8.92 mmol) was heated to 150° C. in a microwave oven for 30 minutes. The reaction mixture was purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH=20:1) to give 6-(3-tert-butylpyrrolidin-1-yl)pyridin-2-amine (540 mg, 55%) as a brown oil. LC-MS: [M+H]+, 220, tR=1.228 min.
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][CH:13]=C)[C:10]2[N:9]=[C:8]([C:15]#[N:16])[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1.I([O-])(=O)(=O)=[O:18].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[O:1]=[C:2]1[N:11]([CH2:12][CH:13]=[O:18])[C:10]2[N:9]=[C:8]([C:15]#[N:16])[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCn1c(=O)ccc2ccc(C#N)nc21
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc2ccc(=O)n(CC=O)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.9 %

Procedure:
7-Oxo-8-(2-propen-1-yl)-7,8-dihydro-1,8-naphthyridine-2-carbonitrile (374 mg, 1.773 mmol) was dissolved in 1,4-dioxane (10 ml) and water (10 ml). Sodium periodate (948 mg, 4.433 mmol) was added, followed by osmium tetroxide (0.38 ml of 4% aqueous solution). The mixture stirred at rt for 1 h, water (40 ml) was added the mixture was stirred for a further 1 h. The reaction was concentrated to about 50 ml and extracted with 20% MeOH/DCM (3×100 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give 7-oxo-8-(2-oxoethyl)-7,8-dihydro-1,8-naphthyridine-2-carbonitrile as an impure brown solid (423 mg, 112%).
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[O:19]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:27]=2)[C:5](=[O:7])[CH2:4][CH2:3]1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1cccc(Oc2ccccc2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available 3-phenoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.92 min.; [M+H]+: 404.17 g/mol.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[C:10]=2[C:9]2[CH:8]=[C:7]([CH3:20])[CH:6]=[CH:5][C:4]1=2)[CH3:2].CC1C=C2C(=CC=1)NC1C2=CC=C2C=CC=CC2=1>>[CH2:1]([N:3]1[C:15]2[C:10](=[CH:11][CH:19]=[C:18]3[CH:17]=[CH:16][CH:12]=[CH:13][C:14]3=2)[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([CH3:20])[CH:8]=2)[CH3:2]
Reactant: CCn1c2ccc(C)cc2c2c3ccccc3ccc21
Agent: Cc1ccc2[nH]c3c4ccccc4ccc3c2c1
Product: CCn1c2ccc(C)cc2c2ccc3ccccc3c21
Yield: 76.2 %

Procedure:
Using the procedure outlined in 34A, 8-methyl-11H-benzo[a]carbazole gave a 76.2% yield of 11-ethyl-8-methyl-11H-benzo[a]carbazole, mp 111°-114°, (CH2Cl2 /petroleum ether), (C,H,N)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[S:12]([C:15]1[CH:20]=[CH:19][C:18](F)=[CH:17][CH:16]=1)(=[O:14])=[O:13].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CS(C)=O>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[S:12]([C:15]1[CH:20]=[CH:19][C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: C1CNCCN1
Reactant: Cn1cc(S(=O)(=O)c2ccc(F)cc2)c2cc(Br)ccc21
Solvent: O
Solvent: CS(C)=O
Product: Cn1cc(S(=O)(=O)c2ccc(N3CCNCC3)cc2)c2cc(Br)ccc21
Temperature: 120 °C
Yield: 81.8 %

Procedure:
The 5-Bromo-3-(4-fluoro-benzenesulfonyl)-1-methyl-1H-indole (0.30 g, 0.85 mmol) was mixed with piperazine (0.34 g, 4 mmole) and methyl sulfoxide (3 mL). The mixture was heated at 120° C. in a sealed tube for 3 hours. The mixture was diluted with 10 mL water and the resultant precipitate was collected by filtration, washed with water, and recrystallized from chloroform/benzene to provide 5-Bromo-1-methyl-3-(4-piperazin-1yl-benzenesulfonyl)-1H-indole (0.302 g, 0.695 mmol), M+H 436.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([OH:10])=[O:9].C(Cl)(Cl)Cl.O.[CH2:19](O)[CH3:20]>S(=O)(=O)(O)O>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([O:10][CH2:19][CH3:20])=[O:9]
Reactant: CCO
Reactant: O=C(O)COc1cccc(CO)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1cccc(CO)c1
Reaction time: 72 h

Procedure:
A solution of 3-(hydroxymethyl)phenoxyacetic acid (3.18 g.) in ethanol (30 ml.) was treated with concentrated sulphuric acid (10 drops) and allowed to stand for 3 days. Chloroform (100 ml.) and water (50 ml.) were then added. The organic phase was separated, washed sequentially with saturated aqueous sodium hydrogen carbonate solution (2×50 ml.), water (50 ml.) and saturated brine (50 ml.) and then dried (MgSO4) The dried solution was evaporated and the residue purified by flash column chromatography, eluting with petrol (40°-60° )/ ethyl acetate (60:40 v/v) to give ethyl 3-(hydroxymethyl)phenoxyacetate (2.6 g.) as a colourless oil, NMR: 1.25 (3H,t), 2.8 (1H,br s), 4.25 (2H,q), 4.6 (4H,s) and 6.6-7.4 (4H,m)ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]([C:12](=[O:29])[NH:13][C:14]1[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=1[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[CH2:31](N(CC)CC)C.C(N[C@@H](C(O)=O)C(C)C)(OC(C)(C)C)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]([C:12](=[O:29])[NH:13][C:14]1[CH:19]=[C:18]([CH3:31])[CH:17]=[CH:16][C:15]=1[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)Nc1cc(Br)ccc1NCc1ccccc1
Reactant: CCN(CC)CC
Agent: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(NCc2ccccc2)c(NC(=O)C(NC(=O)OC(C)(C)C)C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [1-(2-benzylamino-5-bromo-phenylcarbamoyl)-2-methyl-propyl]-carbamic acid tert-butyl ester (250 mg, 0.9 mmol) and triethylamine (0.19 ml, 1.35 mmol) in dry DMF (5 ml), was added Boc-D-valine (290 mg, 1.35 mmol) followed by TBTU (290 mg, 0.9 mmol,). The reaction mixture was stirred at room temperature overnight. Ethyl acetate was added. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered, and the filtrated was concentrated in vacuo. The crude material was purified by flash chromatography to yield [1-(2-Benzylamino-5-methyl-phenylcarbamoyl)-2-methyl-propyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1.C([O-])([O-])=[O:13].[K+].[K+].CS(C)=O.OO>O>[F:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C:10]([NH2:11])=[O:13])[CH:5]=[N:6][CH:7]=1
Reactant: N#CCOc1cncc(F)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)COc1cncc(F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60.1 %

Procedure:
To a mixture of 2-((5-fluoropyridin-3-yl)oxy)acetonitrile (0.55 g, 3.62 mmol), K2CO3 (0.60 g, 4.34 mmol) and DMSO (0.55 mL) in H2O (8 mL) was added H2O2 (0.55 mL, 30%) dropwise in an ice bath and the mixture was stirred at rt for 5 min. It was then concentrated in vacuo and the residue was purified by a silica gel column chromatography (EtOAc) to give the title compound as a white solid (0.37 g, 60%).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:15])=[N:11][C:12]=2[Cl:14])[N:7]=[C:6]1Cl)[C:2]#[C:3][CH3:4].C([O-])(=[O:19])C.[Na+].C(=O)(O)[O-].[Na+].Cl>CS(C)=O.O>[CH2:1]([N:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:15])=[N:11][C:12]=2[Cl:14])[NH:7][C:6]1=[O:19])[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(Cl)nc2nc(Cl)nc(Cl)c21
Reactant: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC#CCn1c(=O)[nH]c2nc(Cl)nc(Cl)c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.7 %

Procedure:
7-(2-Butynyl)-2,6,8-trichloro-7H-purine (1.0 g) was dissolved in dimethylsulfoxide (20 mL), and then sodium acetate (595 mg) and sodium bicarbonate (366 mg) were added to the mixture. This reaction solution was stirred at room temperature for 12 hours, and then 1 N of aqueous hydrochloric acid solution (5.0 mL) and 80 mL of water were added. This reaction solution was stirred at room temperature for one hour, and then a white precipitate was collected by filtration. The white solid obtained was washed with water and t-butyl methyl ether to give the title compound (800 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.CO>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4ccc(F)cc4)c3C2=O)C(=O)N1
Yield: 75.9 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and 4-fluorobenzoyl chloride (0.95 mL, 8.0 mmol) in THF (40 mL) was heated to reflux for 15 h. To the mixture was added methanol (5 mL) to give a suspension. The suspension was filtered and washed with ether (2×10 mL) then methanol (5 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4-fluoro-benzamide as a yellow solid (1.2 g, 77% yield): mp, 283-285° C.; 1H NMR (DMSO-d6) δ 2.06-2.10 (m, 1H, CHH), 2.48-2.65 (m, 2H, CH2), 2.83-2.97 (m, 1H, CHH), 5.18 (dd, J=5.4, 12.6 Hz, 1H, NCH), 7.42-7.49 (m, 2H, Ar), 7.69 (d, J=7.2, Hz, 1H, Ar), 7.91 (t, J=8.2 Hz, 1H, Ar), 8.03-8.08 (m, 2H, Ar), 8.54 (d, J=8.3 Hz, 1H, Ar), 10.41 (s, 1H, NH), 11.15 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.10, 30.98, 49.29, 115.96 (d, JC-F=22 Hz); 118.03, 118.67, 128.09 (d, JC-F=235 Hz), 130.12, 131.49, 136.18, 136.75, 162.70, 164.08, 166.56, 168.22, 169.29, 172.27; Anal Calcd for C20H14N3O5F+0.2H2O: C, 60.21; H, 3.64; N, 10.53; F, 4.76; H2O, 0.90. Found: C, 60.17; H, 3.55; N, 10.47; F, 4.90; H2O, 0.95.
Reaction SMILES: [CH2:1]([O:3][NH:4][C:5](=[C:8]1[C:13](=[O:14])[CH:12]=[C:11]([CH2:15][CH3:16])[O:10][C:9]1=[O:17])[CH2:6][CH3:7])[CH3:2].C(Cl)(Cl)Cl.CC(C)=[O:24]>O.[Hg]>[CH2:1]([O:3][NH:4][C:5]([CH:8]1[C:13](=[O:14])[CH:12]=[C:11]([CH2:15][CH3:16])[O:10][C:9]1=[O:17])([OH:24])[CH2:6][CH3:7])[CH3:2]
Reactant: CC(C)=O
Reactant: CCONC(CC)=C1C(=O)C=C(CC)OC1=O
Agent: [Hg]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCONC(O)(CC)C1C(=O)C=C(CC)OC1=O

Procedure:
After 1g of 3-(1-ethoxyaminopropylidene)-6-ethyl-3,4-dihydro-2H-pyrane-2,4-dione was dissolved in 50ml of acetone containing 5% of water, it was irradiated with high-pressure mercury arc for a day. Chloroform was added to the residue after the distillation of acetone and the insoluble crystal was obtained by filtration of chloroform solution containing the residue. The crude product was recrystallized from the mixture of benzene and petroleum ether, and thereby 0.6g of 3-(1-ethoxyamino-1-hydroxypropyl)-6-ethyl-3,4-dihydro-2H-pyrane-2,4-dione having a melting point of 63° to 64°C as a white plate was obtained.
Reaction SMILES: C([O:8][C:9]1[C:17]2[C:16](=[O:18])[NH:15][N:14]=[C:13]([CH3:19])[C:12]=2[N:11]2[CH2:20][CH2:21][N:22]([CH3:25])[C:23](=[O:24])[C:10]=12)C1C=CC=CC=1.[H-].[Na+].[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH2:32]Cl.Br>CN(C=O)C.C(O)(=O)C>[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH2:32][N:15]1[C:16](=[O:18])[C:17]2[C:9]([OH:8])=[C:10]3[C:23](=[O:24])[N:22]([CH3:25])[CH2:21][CH2:20][N:11]3[C:12]=2[C:13]([CH3:19])=[N:14]1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: Cc1n[nH]c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1nn(Cc2ccc(Cl)c(Cl)c2)c(=O)c2c(O)c3n(c12)CCN(C)C3=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10-(benzyloxy)-4,8-dimethyl-7,8-dihydropyrazino[1′,2′:1,5]-pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.05 g, 0.15 mmol) in DMF (1 mL) was treated with sodium hydride (5 mg, 0.17 mmol). The resultant mixture was stirred at room temperature for 5 minutes. After bubbling ceased, 3,4-dichlorobenzyl chloride (0.02 mL, 0.16 mmol) was added and the reaction mixture was stirred at room temperature for overnight. The reaction was then treated with 33% HBr solution in acetic acid (2 mL) and stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. The residue was treated with water and the solid precipitated was collected by filtration to provide the titled compound as white solid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([NH:26][C@H:27]([C:31]([OH:33])=[O:32])[CH:28]([CH3:30])[CH3:29])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].O[CH2:35][CH2:36][C@@H:37]([CH2:50][O:51][C:52](=[O:70])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[CH2:38][N:39]1[CH:47]=[N:46][C:45]2[C:44](=[O:48])[NH:43][C:42]([NH2:49])=[N:41][C:40]1=2>C1COCC1.CN(C)C1C=CN=CC=1>[CH2:19]([O:18][C:16]([NH:26][C@H:27]([C:31]([O:33][CH2:35][CH2:36][C@@H:37]([CH2:50][O:51][C:52](=[O:70])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[CH2:38][N:39]1[CH:47]=[N:46][C:45]2[C:44](=[O:48])[NH:43][C:42]([NH2:49])=[N:41][C:40]1=2)=[O:32])[CH:28]([CH3:29])[CH3:30])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCO)Cn1cnc2c(=O)[nH]c(N)nc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCOC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)Cn1cnc2c(=O)[nH]c(N)nc21
Temperature: 20 °C

Procedure:
A solution of dicyclohexylcarbodiimide (1500 g, 7.27 moles) in THF (7 L) was added to a reactor containing a mixture of N-carbobenzyloxy-L-valine (3630 g, 14.5 moles) in THF (20 L). The resulting mixture was stirred at 20±5° C. for 1–2 hours. The product of Example 30, step e) (2500 g, 4.81 moles) and 4-dimethylaminopyridine (59 g, 0.48 moles) were charged to a second reactor. To this second reactor was filtered the THF mixture from the first reactor, followed with a rinse of THF (15 L). The resulting mixture was stirred at 20±5° C. for 1–3 hours. Water (600 mL) was added and the solution was concentrated under vacuum at not more than 45° C. The residual oil was taken up in ethyl acetate (14 L) and filtered. The filtrate was washed successively with 10% aqueous sodium bicarbonate (2×14 L) and 10% brine (14 L). The organic phase was concentrated under vacuum and the residue was dissolved in methanol (10 kg) at 50–60° C. The warm solution was added gradually to a mixture of acetonitrile (30 kg) and water (13 kg) at ambient temperature. The mixture was stirred 1 hour at 15° C., then filtered to isolate the crude product, which was dried at 40° C. under vacuum to provide the desired product as a white solid (3.9 kg).