Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:6]=1[CH:7]=O>C(O)C>[CH3:1][NH:2][N:3]=[CH:7][C:6]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:5]=1[Cl:4]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CNN
Solvent: CCO
Product: CNN=Cc1ccc(Cl)cc1Cl
Reaction time: 48 h

Procedure:
263 g (5.7 mol) of methylhydrazine were treated with a solution of 200 g (1.14 mol) of 2,4-dichlorobenzaldehyde in 1.2 l of ethanol. After the mixture had been stirred for 48 hours, the small amount of solids present was filtered off and the filtrate was then concentrated. Yield: quantitative.
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:8](=[O:9])[CH2:7][N:6]([CH2:10][CH2:11][N:12]2[CH2:17][C:16](=[O:18])[N:15]([CH2:19][OH:20])[C:14](=[O:21])[CH2:13]2)[CH2:5][C:4]1=[O:22].N1C=CC=CC=1.[C:29](OC(=O)C)(=[O:31])[CH3:30].[C:36](OCC)(=[O:38])[CH3:37]>>[C:29]([O:20][CH2:19][N:15]1[C:14](=[O:21])[CH2:13][N:12]([CH2:11][CH2:10][N:6]2[CH2:7][C:8](=[O:9])[N:3]([CH2:2][O:1][C:36](=[O:38])[CH3:37])[C:4](=[O:22])[CH2:5]2)[CH2:17][C:16]1=[O:18])(=[O:31])[CH3:30]
Reactant: CCOC(C)=O
Reactant: O=C1CN(CCN2CC(=O)N(CO)C(=O)C2)CC(=O)N1CO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCN1C(=O)CN(CCN2CC(=O)N(COC(C)=O)C(=O)C2)CC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.5 %

Procedure:
A mixture of 1,2-bis(4-hydroxymethyl-3,5-dioxopiperazin-1-yl)ethane (1.50 g, 4.8 m mol), pyridine (10 ml) and acetic anhydride (5 ml, 52.9 m mol) was stirred for 12 hours at room temperature. The reaction mixture was diluted with ethyl acetate (20 ml) and the resulting crystals were collected and washed with ethyl acetate and successively with ether and was dried under reduced pressure to give the titled compound (1.34 g; yield 70.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)[N:5]2[N:16]=[C:17]([CH3:19])[CH:18]=[C:4]2[N:3]=1.[I:20]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)[N:5]2[N:16]=[C:17]([CH3:19])[C:18]([I:20])=[C:4]2[N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc2nc(Cl)cc(-c3ccc(F)c(F)c3)n2n1
Solvent: ClCCl
Product: Cc1nn2c(-c3ccc(F)c(F)c3)cc(Cl)nc2c1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
5-Chloro-7-(3,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine (301 mg) is dissolved in CH2Cl2 (50 mL). N-Iodosuccinimide (NIS, 500 mg) is added to the reaction solution. The reaction mixture is stirred at room temperature for about 16 hours. The reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with 1 M NaHCO3 aqueous solution and brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and the target compound (301 mg) is yielded by column chromatography. 1H NMR (CDCl3, 300 MHz) δ 8.04 (m, 1H), 7.78 (m, 1H), 7.38 (q, J=8.7 Hz, 1H), 6.85 (s, 1H), 2.51 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[Na].[K].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[OH:21]>[Cu]>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[O:21][CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)=[O:10]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CC(=O)c1ccccc1Cl
Agent: [Cu]
Agent: [K]
Agent: [Na]
Product: O=C(COc1ccc(Cl)cc1Cl)c1ccccc1

Procedure:
Hitherto this compound has been prepared by reacting o-chloroacetophenone with the sodium or potassium salt of 2,4-dichlorophenol at a temperature of at least 120° C. in the presence of a copper catalyst to produce 2-(2,4-dichlorophenoxy)acetophenone. This is then reacted with sulphur and morpholine to afford a thioacetmorpholide which is thereafter hydrolysed.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[OH:12].C([O-])([O-])=O.[K+].[K+].CS(C)=O.Br[CH2:25][CH:26]1[CH2:28][CH2:27]1>C1(C)C=CC=CC=1>[CH:26]1([CH2:25][O:12][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=2[O:3][CH:2]([F:13])[F:1])[CH:8]=[O:9])[CH2:28][CH2:27]1
Reactant: BrCC1CC1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
55 g of 4-(difluoromethoxy)-3-hydroxybenzaldehyde, 42.42 g of K2CO3 (1.05 eq), 4.86 g of KI (0.1 eq) and 220 mL of dimethylsulphoxide (DMSO) were loaded in a reactor. The mixture was heated at 70° C. and kept for 1 h. A mixture previously prepared of 42.65 g of bromomethyl cyclopropane (1.08 eq) and 110 mL of DMSO was added for 1 hour. The reaction was kept for 3 h at 70° C., and then cooled at room temperature. Once the temperature was reached, 375 mL of toluene was added. The suspension was filtered to remove the remaining K2CO3, and then it was cooled at 0-5° C., and 375 mL of deionised water were loaded. The phases were separated and the organic phase was washed twice with 55 mL of deionised water. The solvent was removed at reduced pressure, obtaining 70 g (yield 99%) of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzaldehyde as a viscous yellowish fluid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[CH2:20][CH2:21][OH:22]>CN(C=O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:20][CH2:21][O:22][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[N:3]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: COc1cccc(CCO)c1
Reactant: Clc1cncc(OC2CCNCC2)n1
Solvent: CN(C)C=O
Product: COc1cccc(CCOc2cncc(OC3CCNCC3)n2)c1
Reaction time: 16 h

Procedure:
A solution of the product obtained in Step 2 above (0.043 g, 0.20 mmol) in DMF (1.1 mL) was added to a mixture of 3-methoxyphenethyl alcohol (0.061 g, 0.40 mmol) and K-t-BuO (1.0 M in tert-butanol; 0.4 mL, 0.40 mmol) in DMF (0.8 mL). The reaction mixture was vortexed for 16 h at 50° C. under nitrogen, quenched with water (0.1 mL) and concentrated in vacuo. The residue was partitioned between water (2 mL) and 4 ethyl acetate (4 mL) and poured through a hydromatrix column, which was eluted with ethyl acetate/Et3N (95:5). Solvents were evaporated off and the residue was dissolved in methanol/water (50 mL) and loaded onto a conditioned weak cation exchange SPE column (1 g, Amberlyst CG-50 I). The column was washed with water (10 mL) and methanol (10 mL). The compound was eluted with aqueous 2.0 M NH3 in methanol (20 m) and concentrated in vacuo. The residue was analysed for identity and purity by LC-UV/MS. Yield: 8 mg (12%). HRMS m/z calcd for C18H23N3O3 (M)+ 329.1739, found 329.1743.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Cl:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19].C(O)(=O)C>CCCCCC.CO>[Cl:8][C:9]1[C:14]([C:15]([O:17][CH3:1])=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COC(=O)c1cccc([N+](=O)[O-])c1Cl

Procedure:
A solution of trimethylsilyldiazomethane in hexane (2 M) was added dropwise to a solution of 2.01 g 2-chloro-3-carboxy-nitrobenzene in 20 mL methanol at room temperature until no further gas evolution occurred. Acetic acid was then added to quench excess trimethylsilyldiazomethane. The reaction mixture was evaporated under vacuum and the residue was dried in an oven overnight. The 2-chloro-3-methoxycarbonylnitrobenzene obtained was pure enough for the following reaction.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C12CC3CC(CC(C3)C1)C2.O=O.[OH:26]N1C(=O)C2=CC=CC=C2C1=O>>[C:9]12([OH:26])[CH2:8][CH:7]3[CH2:6][CH:11]([CH2:12][CH:13]([CH2:5]3)[CH2:1]1)[CH2:10]2.[C:1]1(=[O:26])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: C1C2CC3CC1CC(C2)C3
Agent: O=O
Product: O=C1C=CC=C2C1=Cc1ccccc12
Product: OC12CC3CC(CC(C3)C1)C2

Procedure:
In page 762 of the "Lecture Draft II" (1994) of 67th Spring Annual Meeting of Chemical Society of Japan, it is reported that oxidation of an alcohol such as benzyl alcohol or benzhydrol with air using vanadomolybdophosphoriate and N-hydroxyphthalimide provides a ketone such as acetophenone or benzophenone in a high yield, and that oxidation of fluorene or adamantane with oxygen using N-hydroxyphthalimide gives a corresponding adamantanol or fluorenone.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([Cl:15])=[CH:7][C:6]=1[Cl:16])=[O:4].[CH2:17]([NH:24][C:25]([NH:27][CH3:28])=[S:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[BrH:1].[CH2:17]([N:24]=[C:25]1[N:27]([CH3:28])[C:3]([C:5]2[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([Cl:15])=[CH:7][C:6]=2[Cl:16])([OH:4])[CH2:2][S:26]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CNC(=S)NCc1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)c(Cl)cc1Cl
Product: Br
Product: CN1C(=NCc2ccccc2)SCC1(O)c1cc(S(N)(=O)=O)c(Cl)cc1Cl

Procedure:
was obtained in a manner analogous to the method described in Example 10 from 3.5 g of 2-bromo-2',4'-dichloro-5'-sulfamoylacetophenone and 1.8 g of 1-benzyl-3-methyl-thiourea. Mp. 173° C (decomposition).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl.Cl.[CH3:23][O:24][NH2:25].C(OCC)(=O)C>O.O1CCCC1>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[N:25][O:24][CH3:23])[C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(C(=O)C(=O)O)cc1
Reactant: CON
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCCOc1ccc(C(=NOC)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
A solution of 4-octyloxyphenylglyoxylic acid (0.935 g) in a mixture of water (9 ml) and tetrahydrofuran (18 ml) and adjusted to pH 3.5-4 with 1N hydrochloric acid and methoxyamine hydrochloride (0.337 g) was added thereto at room temperature. The mixture was stirred for 2 hours at room temperature maintaining pH 3.5~4 with 1N hydrochloric acid. The reaction mixture was added to ethyl acetate. The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 2-(4-octyloxyphenyl)-2-methoxyiminoacetic acid (0.57 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6](I)[CH:5]=1.[C:13]1([O:19][CH2:20][C:21]#[CH:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][C:21]([CH2:20][O:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:22]2)=[O:12]
Reactant: COC(=O)c1ccc(N)c(I)c1
Reactant: C#CCOc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2[nH]c(COc3ccccc3)cc2c1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
Resin bound 4-amino-3-iodo-benzoic acid methyl ester was suspended in DMF and treated with 15.6 g of phenyl propargylether, 60 ml of triethylamine and catalytic amounts of CuI and bis(triphenylphosphine)palladium(II) chloride. The resin was shaken for 6 h at 50° C. and washed subsequently with DMF, isopropanol/water and diethylether.
Reaction SMILES: [NH:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].[P:10]([OH:13])([OH:12])[OH:11].P(=O)(O)(O)O.[CH2:19]=O>>[P:10]([CH2:19][N:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4])([OH:13])([OH:12])=[O:11]
Reactant: OP(O)O
Reactant: C=O
Reactant: O=C(O)CNCC(=O)O
Agent: O=P(O)(O)O
Product: O=C(O)CN(CC(=O)O)CP(=O)(O)O
Temperature: 140 °C
Yield: 61.2 %

Procedure:
In a three-necked round-bottom flask equipped with a mechanical stirrer, 33.28 g (0.25 mol) of iminodiacetic acid (IDA) were mixed with 20.5 g (0.25 mol, 1 eq.) of phosphorous acid and 122.5 g (1.25 mol, 5 eq.) of phosphoric acid. The reaction mixture was heated to 140° C. 20.68 ml of 36.6 wt.-% aqueous solution of formaldehyde (1.1 eq.) were then added over 60 min. During the addition, the temperature of the reaction mixture decreased from 140° C. to 125° C. At the end of the formaldehyde addition the reaction mixture was kept at reflux for 30 min. The precipitate formed by cooling the reaction mixture was isolated by filtration and washed with fresh water. After drying the precipitate was analysed by 1H and 31P NMR and identified as 81.3% pure N-(phosphonomethyl)iminodiacetic acid (PMIDA, 28 g, 61.2% yield).
Reaction SMILES: Br[CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1C=O)=O.[Br:19][C:20]1[CH:21]=[CH:22][C:23]([NH2:26])=[N:24][CH:25]=1.O.CN([CH:31]=[O:32])C>>[Br:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:3]([C:5]3[CH:6]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[C:2]([C:13]3[CH:14]=[CH:15][C:16]([CH:31]=[O:32])=[CH:17][CH:18]=3)[N:26]=2)[CH:25]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CN(C)C=O
Reactant: O=Cc1ccccc1C(=O)C(Br)c1ccccc1
Solvent: O
Product: O=Cc1ccc(-c2nc3ccc(Br)cn3c2-c2ccccc2)cc1
Temperature: 100 °C

Procedure:
3.3 mMol (2-Bromo-2-phenyl-ethanoyl)-benzaldehyde and 1.2 equivalents of 5-Bromo-pyridin-2-ylamine are dissolved in 10 ml DMF. The reaction mixture is heated at 100° C. for 18 hours. The reaction mixture is cooled and water is added. It is then extracted with ethyl acetate. The organic layer is dried and concentrated. The crude is purified by column chromatography to yield the desired compound.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O:14]CC)C.[CH2:17]1C[O:20][CH2:19][CH2:18]1>>[C:1]([O-:10])(=[O:14])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:19]([O:20][C:1](=[O:10])[CH:2]=[CH2:3])[CH2:18][CH3:17]
Reactant: C1CCOC1
Reactant: CCOCC
Reactant: O=C(Cl)C=Cc1ccccc1
Product: C=CC(=O)OCCC
Product: O=C([O-])C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The cinnamoyl chloride (5 g, 33.7 mmol), 3-hydroxy propyl acrylate (35.0 mmol), and TEA (105 mmol) were dissolved in THF and stirred at the room temperature for 24 hours. After completion of the stirring, diethylether was added to form a precipitate, which was then filtered out. A column chromatography using a developing solvent (EA:hexane=1:4) was carried out to yield a titled product, cinnamate-propyl-acrylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][NH2:42])[CH:36]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:27]([NH:42][CH2:41][C:37]2[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=2)=[O:33])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCc1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)NCc4cccnc4)cc3)c2cc1OC
Yield: 93 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in toluene (5 ml) with heat, after the addition of triethylamine (1 ml), triphosgene (56 mg) was added, and the admixture was refluxed with heat for 2 minutes. 3-Pyridylmethylamine (0.05 ml) was added to the reaction mixture, and the admixture was refluxed with heat for 12 minutes After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 71 mg of the title compound (yield: 93%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:9]Br>C(Cl)Cl>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2](=[O:1])[NH:3][CH:4]=1
Reactant: Cc1cccnc1O
Reactant: BrBr
Solvent: ClCCl
Product: Cc1cc(Br)c[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-hydroxy-3-methylpyridine (0.500 g, 4.58 mmol, Acros Organics) in DCM (15 mL) was slowly added bromine (0.282 mL, 5.50 mmol). After addition, the mixture was stirred at rt for 18 h. The mixture was cooled to 0° C. and was quenched with saturated aqueous NaHCO3 (5 mL). The mixture was then extracted with EtOAc (3×20 mL). The combined organic layer were dried over MgSO4 and concentrated. The residue was then dissolved in MeOH (20 mL) and silica gel was added. The mixture was concentrated and dried in vacuo. The resulting mixture was then purified by silica gel flash column chromatography (solid loading, 0%-100% EtOAc/hexane) to afford the title compound as a light pink solid. MS (ESI, positive ion) m/z: 188, 190 (M+H).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][C:12]1=[O:18]>>[CH3:7][N:6]1[C:2]([N:14]2[CH2:15][CH2:16][CH2:17][NH:11][C:12](=[O:18])[CH2:13]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: O=C1CNCCCN1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Product: Cn1ncc([N+](=O)[O-])c1N1CCCNC(=O)C1
Yield: 92 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 1,4-diazepan-2-one gave 4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepan-2-one as an off-white solid (0.27 g, 92%). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 6.10 (s, 1H), 3.95-3.86 (m, 2H), 3.80 (s, 3H), 3.51-3.44 (m, 2H), 3.43-3.37 (m, 2H), 2.04-1.97 (m, 2H)
Reaction SMILES: CC(C)([O-])C.[Na+].C([Li])CCC.[C:12]1([CH:18]2[S:23][CH2:22][CH2:21][CH2:20][S:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Br[CH2:25][C:26]1[CH:30]=[CH:29][O:28][CH:27]=1>CCCCCC.C1COCC1>[C:12]1([C:18]2([CH2:25][C:26]3[CH:30]=[CH:29][O:28][CH:27]=3)[S:19][CH2:20][CH2:21][CH2:22][S:23]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(C2SCCCS2)cc1
Reactant: BrCc1ccoc1
Agent: CC(C)(C)[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1ccc(C2(Cc3ccoc3)SCCCS2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred suspension of sodium tert-butoxide (5.16 g, 54 mmol) in dry hexane (120 mL) was added n-butyl lithium (34 mL, 51 mmol) at 0° C. and stirred for 1 h at 0° C., and then for 1 h at room temperature. The mixture was cooled to −78° C., and transferred to a preformed mixture of 2-phenyl-[1,3]dithiane (10.0 g, 51 mmol) dissolved in dry THF (120 mL) at −78° C., and n-butyl lithium (34 mL, 51 mmol) and kept for 15 min. A dark brown colored solution was observed. After stirring for 1 h at −78° C., 3-bromomethyl-furan (Danso-Danquah R. E. and Scott A. I. Tetrahedron, 1993, 49, 8195-8210; New D. G. et al, J. Org. Chem., 1996, 61, 1578-1598) (10.7 g, 66 mmol) was added via canula. After 30 min., the reaction mixture was quenched with water and warmed to ambient temperature. The reaction mixture was extracted with diethyl ether, and the organic extracts were dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography using 0.2-0.5% ethyl acetate in hexane as eluent. Yield: 5.6 g, 32%.
Reaction SMILES: Br[C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[Cl:12][C:13]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:14]=1[O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[Cl:12][C:13]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:14]=1[O:15][CH:16]1[CH2:17][CH2:18][N:19]([C:2]2[C:3](=[O:11])[N:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=2)[CH2:20][CH2:21]1.[CH2:14]([OH:15])[CH2:13][CH2:25][CH3:24]
Reactant: Cn1nc(Br)c(=O)n(C)c1=O
Reactant: Fc1ccc(Cl)c(OC2CCNCC2)c1
Product: CCCCO
Product: Cn1nc(N2CCC(Oc3cc(F)ccc3Cl)CC2)c(=O)n(C)c1=O
Yield: 77 %

Procedure:
The compound 30 (solid) is prepared from the triazine 1b and from the intermediate 8b according to the synthesis method 1 in n-butanol (yield: 77%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[F:32][C:33]1[CH:57]=[CH:56][CH:55]=[CH:54][C:34]=1[O:35][C:36]1[N:41]=[C:40]2[O:42][C:43]([C:45]3[CH:50]=[C:49]([CH3:51])[C:48]([OH:52])=[C:47]([CH3:53])[CH:46]=3)=[N:44][C:39]2=[CH:38][CH:37]=1.O[C:59]([CH3:68])([CH3:67])[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61]>O1CCCC1.C(N(CC)CC)C>[F:32][C:33]1[CH:57]=[CH:56][CH:55]=[CH:54][C:34]=1[O:35][C:36]1[N:41]=[C:40]2[O:42][C:43]([C:45]3[CH:50]=[C:49]([CH3:51])[C:48]([O:52][C:59]([CH3:68])([CH3:67])[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])=[C:47]([CH3:53])[CH:46]=3)=[N:44][C:39]2=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)O
Reactant: Cc1cc(-c2nc3ccc(Oc4ccccc4F)nc3o2)cc(C)c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(-c2nc3ccc(Oc4ccccc4F)nc3o2)cc(C)c1OC(C)(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
With ice cooling, 72 mg of triphenylphosphine were dissolved in 1 ml of dry tetrahydrofuran, and 47 mg of diethyl azodicarboxylate were added. After 15 min, 80 mg of 4-[5-(2-fluorophenoxy)oxazolo[5,4-b]pyridin-2-yl]-2,6-dimethylphenol were added, followed by 32 μl of triethylamine and 44 mg of tert-butyl alpha-hydroxyisobutyrate. The reaction mixture was then stirred at room temperature for 16 hours, and another 72 mg of triphenylphosphine and 47 mg of diethyl azodicarboxylate were added with ice cooling. After a further 4 h at room temperature, the reaction was concentrated and purified by preparative HPLC. This gave 60 mg (53%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N:14]2[CH2:15][CH:16]([CH2:17][OH:18])[O:19][CH:20]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(CC(C)NCC(O)CO)cc1OC
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(CC(C)N2CC(CO)OC2c2ccccc2)cc1OC

Procedure:
A mixture of 3-[3-(3,4-dimethoxyphenyl)-2-propylamino]-1,2-propanediol (14.3 g., 0.053 m.), benzaldehyde (12.7 g., 0.12 m.) and benzoic acid (0.3 g.) in toluene (45 ml.) is refluxed for 3 hours, collecting the water formed in a Dean-Stark trap. After washing with saturated NaHCO3 solution and with H2O (2×), the solvent is distilled under reduced pressure. Excess benzaldehyde is distilled at 100° C. at 0.1 mm. The residue, (II) (16.88 g., 89%) is used without further purification in the next step.