Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:14][NH:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[C:11]3[CH:30]=[C:31]([F:35])[C:32]([F:34])=[CH:33][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.[N-:44]=[N+:45]=[N-:46].[Na+]>CC1C=CC=CC=1C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:14][NH:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]4[NH:46][N:45]=[N:44][N:21]=4)=[CH:18][CH:17]=3)[C:11]3[CH:30]=[C:31]([F:35])[C:32]([F:34])=[CH:33][C:10]=3[N:9]=2)=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(NCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(CNc3ccc(-c4nnn[nH]4)cc3)C3CCCCC3)c2cc1F
Temperature: 145 °C

Procedure:
To a suspension of 0.08 g (0.16 mmol) 4-{2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethylamino}-benzonitrile in 2 ml o-xylene were added 0.112 g (0.81 mMol) triethylamine hydrochloride and 0.053 g (0.82 mmol) sodium azide. The resulting mixture was heated to 145° C. After 72 h another 0.112 g (0.81 mMol) triethylamine hydrochloride and 0.053 g (0.82 mMol) sodium azide were added and the temperature of the oil bath was elevated to 160° C. After 24 h the oil bath was removed and the reaction mixture was poured on saturated aqueous ammonium chloride solution. The aqueous phase was extracted three times with ethyl acetate and the combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The resulting light brown solid was dissolved in ethyl acetate. Upon evaporation a suspension formed which was filtered and washed with ethyl acetate. The resulting solid was taken up in 2 ml acetonitrile, heated to reflux and then cooled down to 4° C. The suspension was filtered, the solid washed with acetonitrile and dried under high vacuum. Light brown solid (25%). MS (Turbo Spray): m/z=534.2 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][CH2:11]Br.C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[O:8]1[CH2:11][CH2:10][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: Nc1ccccc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2c(c1)NCCO2
Temperature: 100 °C
Yield: 32.3 %

Procedure:
A mixture of 2-aminophenol (5 g, 45.87 mmol), 1,2-dibromoethane (4.3 g, 22.93 mmol), and K2CO3 (15.8 g, 114.67 mmol) in THF (30 mL) was heated at 100° C. for 16 h. After completion of reaction, water was added and extracted with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The reaction mixture was purified by column chromatography (using 100-200 mesh size silica, the desired product was eluted at 15% EtOAc in hexane) to obtained 1 g of desired product.
Reaction SMILES: FC1C=C(CN)C=NC=1.[O:10]1[CH:14]=[CH:13][N:12]=[C:11]1[CH2:15][NH2:16].[CH:17]1([CH2:20][N:21]2[CH2:25][CH2:24][N:23]([C:26]3[S:27][C:28]([C:32](O)=[O:33])=[C:29]([CH3:31])[N:30]=3)[C:22]2=[O:35])[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][N:21]2[CH2:25][CH2:24][N:23]([C:26]3[S:27][C:28]([C:32]([NH:16][CH2:15][C:11]4[O:10][CH:14]=[CH:13][N:12]=4)=[O:33])=[C:29]([CH3:31])[N:30]=3)[C:22]2=[O:35])[CH2:18][CH2:19]1
Reactant: NCc1ncco1
Reactant: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)NCc1ncco1
Yield: 25 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with oxazol-2-ylmethanamine to react with 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 25% yield: mp 172-174° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CD3OD) δ 7.86 (s, 1H), 7.14-7.10 (m, 1H), 4.61 (s, 2H), 4.12-4.07 (m, 2H), 3.78-3.72 (m, 2H), 3.18 (d, J=7.1 Hz, 2H), 2.53 (s, 3H), 1.03-0.98 (m, 1H), 0.60-0.54 (m, 2H), 0.29-0.24 (m, 2H); MS (ES+) m/z 362.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH2:9].[C:10]([N:18]=[C:19]=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC(C)=O>[C:10]([NH:18][C:19]([NH:9][C:3]1[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=1[Br:1])=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1cc(Br)ccc1Br
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1cc(Br)ccc1Br)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
To a solution of 2,5-dibromo-phenylamine I (2.44 g, 9.72 mmol) in acetone (60 mL) was added benzoylisothiocyanate (1.74 g, 26.0 mL, 10.6 mmol) at room temperature. After 15 min, solid precipitated out. The reaction mixture was continued to stir for 30 min at room temperature. After completion of reaction (TLC monitoring) acetone was distilled off and crude solid filtered with hexane (100 mL) and again washed with hexane (100 mL) to obtain the desired compound as pale-yellow solid (3.9 g, 97%). 1H NMR (DMSO-d6, 400 MHz): δ 7.47 (dd, J=6.4, 6.0 Hz, 1H), 7.53 (m, 2H), 7.66 (s, 1H), 7.70 (m, 1H), 7.99 (m, 1H), 8.01 (s, 1H), 8.17 (d, J=2.4 Hz, 1H), 11.91 (br s, 1H) and 12.63 (br s, 1H).
Reaction SMILES: CN(C)C=O.O[CH2:7][CH2:8][C:9]1[O:13][C:12]([CH3:14])=[N:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[Cl:23][CH2:7][CH2:8][C:9]1[O:13][C:12]([CH3:14])=[N:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(-c2ccccc2)c(CCO)o1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1nc(-c2ccccc2)c(CCCl)o1

Procedure:
N,N-Dimethylformamide (4.0 ml) was added to a solution of 5-(2-hydroxyethyl)-2-methyl-4-phenyloxazole (10.5 g) in chloroform (100 ml) and, under ice-cooling and stirring, thionyl chloride (11.4 ml) was added dropwise. The mixture was refluxed for 30 minutes and the solvent was distilled off. Then, ice water was added and the mixture was neutralized with sodium hydrogen carbonate and extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off to give an oil of 5-(2-chloroethyl)-2-methyl-4-phenyloxazole, yield 11.0 g (96.5%).
Reaction SMILES: [O:1]=[C:2]1[N:9]2[CH:4]([CH2:5][CH2:6][O:7]C2(C)C)[CH:3]1[CH:12]([CH3:14])[CH3:13].O>C(O)(=O)C>[CH:12]([CH:3]1[CH:4]([CH2:5][CH2:6][OH:7])[NH:9][C:2]1=[O:1])([CH3:14])[CH3:13]
Reactant: CC(C)C1C(=O)N2C1CCOC2(C)C
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C1C(=O)NC1CCO
Temperature: 65 °C

Procedure:
8-oxo-2,2-dimethyl-7α-isopropyl-3-oxa-1-azabicyclo[4.2.0]octane 1.0 g is dissolved in 8 ml of acetic acid and 2 ml H2O is added. The mixture is heated at 65° C. for 1.25 hrs. The acetic acid and H2O are removed under reduced pressure and the residue is taken up in C6H6 and evaporated to give 3-isopropyl-4-(2-hydroxyethyl)azetidinone.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([O-:5])=[O:4].[Ca+2].O[CH:12](CCSC)C([O-])=O.CO.OS(O)(=O)=O>C(Cl)Cl>[OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([O:5][CH3:12])=[O:4]
Reactant: CSCCC(O)C(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(O)CCSC
Temperature: 25 °C
Reaction time: 64 h

Procedure:
Commercial calcium 2-hydroxy-4-(methylthio)-butyrate (20 g, 0.12 mol) was suspended in 250 ml CH2Cl2. CH3OH (15 ml, 0.36 mol) was added and the mixture cooled to 10° C., at which point H2SO4 (3.7 ml, 0.07 mol) was added. An obvious physical change in the slurry was noted. The mixture was heated at reflux for 60 minutes, by which time tlc indicated reaction was nearly complete. As a matter of convenience, the reaction mixture was stirred 64 hours at room temperature, at which time insoluble byproducts were removed by filtration. The filtrate was washed with 150 ml each of saturated NaHCO3 and brine, dried (MgSO4) and stripped to yield title product as an oil; tlc Rf 0.8 (ethyl acetate)0.25 (3:1 hexane:ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:29])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[CH:5][CH:4]=1.C1(C)C=CC=CC=1>C(Cl)(Cl)Cl.Cl.CO>[NH2:21][CH:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:29])[CH2:16][CH2:17]1
Reactant: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
1,1-Dimethylethyl (1-{2-[7-(methyloxy)-2-oxo-1(2H)-quinolinyl]ethyl}-4-piperidinyl)carbamate (2.25 g; 5.61 mmol) was dissolved in a mixture of chloroform (20 ml) and HCl (15 ml) and stirred at rt under argon for 1 hour. The salts were dissolved in MeOH and a small amount of toluene added, all the solvents were then removed. The residues were redissolved in MeOH and stirred with amberlyst ion exchange resin until a neutral pH was reached. The resin was filtered off and the solvent removed and the crude residues were purified by column chromatography on silica gel using a 0-20% 2M NH3:MeOH/DCM gradient, to give the desired product (900 mg; 54%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[OH:15].CC1C=CC(S(O[CH2:27][CH2:28][C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[O:35][CH2:34][CH2:33][C:32]3=[O:39])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:27][CH2:28][C:29]3[CH:30]=[C:31]4[C:36](=[CH:37][CH:38]=3)[O:35][CH2:34][CH2:33][C:32]4=[O:39])[CH2:13][CH2:14]2)=[CH:4][C:3]=1[OH:15]
Reactant: Oc1cc(CC2CCNCC2)ccc1Br
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc3c(c2)C(=O)CCO3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: O=C1CCOc2ccc(CCN3CCC(Cc4ccc(Br)c(O)c4)CC3)cc21
Temperature: 57.5 °C
Reaction time: 6 h

Procedure:
A suspension of 2-bromo-5-(piperidin-4-ylmethyl)phenol (RE4) (500 mg, 1.9 mmol), 2-(4-oxo-3,4-dihydro-2H-chromen-6-yl)ethyl 4-methylbenzenesulfonate (RE6) (612 mg, 1.8 mmol) and potassium carbonate (489 mg, 3.5 mmol) in acetonitrile (50 mL) and dimethylformamide (20 mL) was stirred at 55-60° C. for 6 hours. The reaction mixture was cooled to room temperature, and then, water was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained concentrated residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1→chloroform:methanol=20:1) to obtain a semi-purified product of the title compound. A small amount of ethyl acetate was added thereto, and the resulting precipitate was collected by filtration, washed with ethyl acetate, and then dried under reduced pressure to obtain the title compound (5-8) of interest (37 mg, 5%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[O:10])[CH:5]=[N:6][C:7]=1Cl.[OH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CC(N(C)C)=O>[Cl:1][C:2]1[C:7]([O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=2)=[N:6][CH:5]=[C:4]([CH:9]=[O:10])[CH:3]=1
Reactant: O=Cc1cnc(Cl)c(Cl)c1
Reactant: NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc(Oc2ncc(C=O)cc2Cl)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
Combine 5,6-dichloro-pyridine-3-carbaldehyde (1.37 g, 7.80 mmol), 4-hydroxy-benzamide (1.18 g, 8.58 mmol), potassium carbonate (1.62 g, 11.7 mmol) in toluene (10 mL) and DMA (30 mL). Stir the reaction mixture at 100° C. for 1 h. Pour the reaction mixture onto H2O (100 mL) and extract with Et2O (100 mL). Wash the organic layer with H2O (2× 100 mL), dry the organic phase extracts over magnesium sulfate, filter and concentrate to give the title compound (1.09 g, 51%).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.Cl[C:24]1[C:25]2[C:32]([CH3:33])=[C:31]([C:34]([O:36][CH3:37])=[O:35])[S:30][C:26]=2[N:27]=[CH:28][N:29]=1.O.[OH-].[NH4+]>O1CCOCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][CH:5]([O:4][C:3]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:2]=2[NH:1][C:24]2[C:25]3[C:32]([CH3:33])=[C:31]([C:34]([O:36][CH3:37])=[O:35])[S:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:6][CH2:7]1)=[O:12])([CH3:16])([CH3:17])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2N)CC1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCN(C(=O)OC(C)(C)C)CC3)c2c1C
Temperature: 25 °C
Yield: 65.7 %

Procedure:
tert-Butyl 4-(2-amino-5-fluorophenoxy)piperidine-1-carboxylate (0.865 g, 2.8 mmol), methyl 4-chloro-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.675 g, 2.8 mmol) and para-toluene sulfonic acid (0.026 g, 0.14 mmol) were heated at 90° C. in anhydrous 1,4-dioxane (8 mL) for 1.5 hours. The solution was cooled to ambient temperature, diluted with water (2 mL) and adjusted to pH 10 (4:1 water/ammonium hydroxide solution). The precipitate was collected, washed with water and diethyl ether to yield the title compound as yellow solid (0.95 g, 65%).
Reaction SMILES: Br[C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:4][N:5]2[C:10]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:9][C:8]([S:17][CH3:18])=[N:7][C:6]=12.C(=O)([O-])[O-].[Na+].[Na+].[F:31][C:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[CH:34][N:33]=1.C(OCC)(=O)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>[CH:12]1([NH:11][C:10]2[N:5]3[N:4]=[C:3]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:2]([C:36]4[CH:35]=[CH:34][N:33]=[C:32]([F:31])[CH:37]=4)=[C:6]3[N:7]=[C:8]([S:17][CH3:18])[N:9]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CSc1nc(NC2CCCC2)n2nc(-c3ccccc3)c(Br)c2n1
Reactant: OB(O)c1ccnc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1nc(NC2CCCC2)n2nc(-c3ccccc3)c(-c3ccnc(F)c3)c2n1
Temperature: 100 °C
Yield: 33.3 %

Procedure:
8—Bromo-N-cyclopentyl-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine (0.20 g, 0.50 mmol) was dissolved in N,N-dimthylformamide. To this solution was added dichlorobis(triphenylphosphine)palladium (II] (70 mg, 0.2 equiv), anhydrous sodium carbonate (105 mg, 2 equiv), 2-fluoro-4-pyridinylboronic acid (91 mg, 1.3 equiv) and a few drops of water. The reaction mixture was heated at 100° C. for 12 hours, at which time no starting material remained in the reaction mixture. Ethyl acetate and water were added to the reaction mixture. The phases were separated and the organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (ethyl acetate:hexane 1:1) gave 70 mg (33%) of N-cyclopentyl-8-(2-fluoro-4pyridinyl)-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine as a white foam. 1H-NMR (CDCl3): δ 8.10 (d, 1H), 7.60 (m, 2H), 7.52 (m, 3H), 7.37 (m, 1H), 7.29 (s, 1H), 6.55 (d, 1H), 4.63 (m, 1H), 2.66 (s, 3H), 2.3–2.1 (m, 2H), 2.0–1.6 (m, 6H);F-NMR (CDCl3): δ −69.01; MS m/z 421 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]O.[ClH:6].[NH2:7][CH2:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13]>>[ClH:6].[NH2:7][CH2:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([O:14][CH2:4][CH2:3][O:2][CH3:1])=[O:13]
Reactant: NCC(=O)CCC(=O)O
Reactant: COCCO
Agent: Cl
Product: COCCOC(=O)CCC(=O)CN
Reaction time: 1 h

Procedure:
From 2-methoxyethanol (5.0 g; 66 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol) at 70° C. The reaction was complete after 1 h. The yield was 1.25 g (93%) of yellowish oil.
Reaction SMILES: [C:1]([C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)#[N:2].[N+:8]([O-])([OH:10])=[O:9]>C(OC(=O)C)(=O)C>[N+:8]([C:6]1[CH:7]=[C:3]([C:1]#[N:2])[S:4][CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: N#Cc1cccs1
Solvent: CC(=O)OC(C)=O
Product: N#Cc1cc([N+](=O)[O-])cs1

Procedure:
To a solution of 2-cyanothiophene (10.9 g; 0.1 mol) in 25 ml of acetic anhydride (t=10° C.) are added 9 ml of fuming nitric acid (d=1.49 g/ml).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10](=O)[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CCO.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:1]([O:5][C:6]([N:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][CH:10]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: Nc1ccccc1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: CCO
Solvent: O
Product: CC(CN(CC(=O)O)C(=O)OC(C)(C)C)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of [tert-Butoxycarbonyl-(2-oxo-propyl)-amino]-acetic acid (1 eq), aniline (1.2 eq) and Ti(OiPr)4(1.25 eq) was stirred at RT for 30 min under N2 flow. The mixture was diluted with dry EtOH (0.8 M) and NaBH3(CN) (0.67 eq) was added. The reaction mixture was stirred for 24 h, after which water was added and the resulting white, inorganic precipitate was filtered, and washed with EtOH. The filtrate was concentrated under reduced pressure and the resulting crude was diluted with EtOAc. The solution was extracted with 1N NaOH and the aqueous phase was washed with EtOAc twice. The aqueous phase was acidified to pH 1 by addition of conc. HCl at 0° C. and washed with EtOAc. The pH of the collected aqueous phase was adjusted to pH 3-4 and product extracted with EtOAc (5×). The collected organic phases were dried (Na2SO4), filtered and evaporated to provide LL1 as a transparent oil. MS (ES) C16H24N2O4 requires: 308 found: 309 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([O-])(=O)C.[Na+].C1(C)C=CC=CC=1.[CH2:23]=[C:24]1[O:28][C:26](=[O:27])[CH2:25]1>O>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([F:10])[C:2]=1[NH:1][C:26](=[O:27])[CH2:25][C:24](=[O:28])[CH3:23])#[N:5]
Reactant: N#Cc1cccc(F)c1N
Reactant: C=C1CC(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)CC(=O)Nc1c(F)cccc1C#N
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a mixture of 2-amino-3-fluorobenzonitrile (41.9 g), sodium acetate (30.3 g) and toluene (200 mL) was added diketene (28.2 mL) over 10 min at 0° C. The reaction mixture was stirred at room temperature for 7 hr. To the reaction mixture were added toluene (150 mL) and diketene (4.7 mL) at room temperature, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether/ethanol to give the title compound (48.64 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])([O-:3])=[O:2].[H-].[Na+].[CH2:22](Br)[C:23]#[CH:24].C1(C)C=CC=CC=1>CN(C=O)C.CCOC(C)=O>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:24][C:23]#[CH:22])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(NCCOCCO)c([N+](=O)[O-])c1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCOCCOCCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
2-(2-(2,4-dinitrophenylamino)ethoxy)ethanol (s-1b) (100 mg, 0.369 mmol, 1.0 equiv.) was dissolved in 0.81 mL of DMF and slowly added to a slurry of NaH (17.71 mg, 0.738 mmol, 2.0 equiv.) in 0.81 mL of DMF in a flame dried flask pre-cooled to 0° C. An 80% solution of propargyl bromide in toluene (0.0490 □L, 0.443 mmol, 1.2 equiv.) was added slowly. The ice bath was then removed and the reaction was allowed to stir at room temperature for an additional 2 hours. The reaction was then re-cooled to 0° C., quenched with saturated NH4Cl, and then extracted with diethyl ether (3×50 mL). The organic layers were combined, dried with Na2SO4, concentrated under reduced pressure, and chromatographed (silica gel, 3×25 cm, 0% EtOAc in hexanes, then 10% EtOAc in hexanes, then 20% EtOAc in hexanes, then 30% EtOAc in hexanes) to yield 2,4-dinitro-N-(2-(2-(prop-2-ynyloxy)ethoxy)ethyl)aniline (s-2b) as a dark yellow solid (50 mg, 45% yield). IR (thin film) 3360 (m), 3285 (m), 3107 (w), 2872 (m), 1621 (s), 1588 (m), 1524 (m), 1425 (w), 1335 (s), 1305 (m), 1133 (m), 1101 (m), 920 (w), 832 (w); 1H NMR (500 MHz, CDCl3) δ 9.15 (d, J=2.6 Hz, 1H), 8.81 (bs, 1H), 8.27 (dd, J=9.4, 2.3 Hz, 1H), 6.96 (d, J=9.5 Hz, 1H), 4.21 (d, J=2.3 Hz, 2H), 3.84 (t, J=5.2 Hz, 2H), 3.74 (m, 4H), 3.61 (q, J=5.2 Hz, 2H), 2.44 (t, J=2.3 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 148.6, 136.3, 130.7, 130.4, 124.4, 114.2, 79.6, 74.9, 70.7, 69.3, 68.9, 58.7, 43.4. HRMS (ES+) calc'd for C13H15N3O6 (M+H) m/z 310.0994 Found 310.1033.
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]1[CH2:18][C:17](=[O:19])[NH:16][C:14]1=[O:15])=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].ON1C(=O)CCC1=O.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([O:37]O)=[O:36])[CH:30]=1>C(Cl)Cl.CCOCC>[C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]1[CH2:18][C:17](=[O:19])[NH:16][C:14]1=[O:15])=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Cl:28][C:29]1[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=1)[C:35]([OH:37])=[O:36]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Agent: O=C1CCC(=O)N1O
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In still another alternative synthesis of (10), N-hydroxysuccinimide (230 mg, 2 mmol) was added to a solution of compound (8) (248 mg, 1 mmol) in CH2Cl2 (10 mL) was added and the reaction mixture cooled to 0° C. m-Chloroperbenzoic acid (670 mg, 3 mmol, commercial grade: 77% in water) was added over a period of 10 min and the mixture allowed to stir at room temperature for 16 h. The reaction mixture was diluted with ether (50 mL) and washed with water (2×10 mL), saturated sodium bicarbonate solution (10 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (10) together with m-chlorobenzoic acid. The crude product mixture was purified by column chromatography on silica gel, eluting with 4:6 EtOAc:hexane. Residual m-chlorobenzoic acid was removed by repeated crystallizations from a mixture of tert-butyl methyl ether and hexane which resulted in analytically pure product (30 mg, 11%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:32]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:32][CH2:11][CH2:10][CH2:9][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: OCCCc1cc(Cl)ccc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClCCCc1cc(Cl)ccc1Cl
Reaction time: 2.5 h
Yield: 93.3 %

Procedure:
Compound 66-2 (1.73 g) was dissolved in methylene chloride (20 ml), triphenylphosphine (2.43 g) and N-chlorosuccinimide (1.24 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 2.5 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.76 g) as a colorless oil.