Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13][CH2:12][N:11](C(OCC)=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[BrH:27]>O>[OH2:7].[BrH:27].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:25][CH:26]=1.[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:25][CH:26]=1.[BrH:27]
Reactant: CCOC(=O)N1CCC(C(=O)c2ccc(F)cc2)(c2ccccc2)CC1
Agent: Br
Solvent: O
Product: O=C(c1ccc(F)cc1)C1(c2ccccc2)CCNCC1
Temperature: 25 °C

Procedure:
A mixture of 14 parts of ethyl 4-(4-fluorobenzoyl)-4-phenyl-1-piperidinecarboxylate and 150 parts of a hydrobromic acid solution 48% in water was stirred and refluxed for 30 minutes. The reaction mixture was diluted with 100 parts of water and the whole was stirred while the mixture was allowed to cool to room temperature. The precipitated product was filtered off (filtrate I was set aside), washed with methylbenzene and stirred in 2-propanone. It was filtered off again (filtrate II was set aside) and dried, yielding a first fraction of 4.3 parts of (4-fluorophenyl) (4-phenyl-4-piperidinyl)methanone hydrobromide hemihydrate.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:41]=[CH:42][CH:43]=1)[CH2:6][NH:7][C:8](=[O:40])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:36]=[N+:37]=[N-:38])[CH:30]=2)[CH:10]=1.[CH2:46]([OH:50])[CH2:47][C:48]#[CH:49]>CS(C)=O.N.O.[Cu]I>[OH:50][CH2:46][CH2:47][C:48]1[N:38]=[N:37][N:36]([CH2:35][C:31]2[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=2)[C:28]([NH:27][C:16]2[CH:17]=[CH:18][C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:20][C:15]=2[C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][N:12]=2)[C:8]([NH:7][CH2:6][C:5]2[CH:41]=[CH:42][CH:43]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:4]=2)=[O:40])=[O:39])[CH:49]=1
Reactant: [N-]=[N+]=NCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: C#CCCO
Agent: [Cu]I
Agent: N
Solvent: O
Solvent: CS(C)=O
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(Cn3cc(CCO)nn3)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(3-(azidomethyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (55 mg, 0.09 mmol, 1.00 equiv, 95%) in DMSO (3 mL), but-3-yn-1-ol (19 mg, 0.27 mmol, 3.00 equiv), and copper(I) iodide (0.84 mg, 0.05 equiv). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 10 mL of 10% NH3.H2O. The resulting solution was extracted with 5×30 mL of ethyl acetate and the organic layers combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product (60 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 10 mg (14%) of a yellow to green solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.48 (s, 1H), 9.55-9.58 (t, J=6 Hz, 1H), 8.93 (s, 1H), 8.36 (s, 2H), 7.96 (s, 1H), 7.85-7.96 (s, 1H), 7.71-7.77 (m, 3H) 7.64 (s, 1H), 7.55-7.60 (m, 5H), 7.44 (s, 1H), 5.67 (s, 2H), 4.63 (t, 2H), 3.58-3.61 (t, 2H), 3.40 (s, 4H), 2.75-2.77 (t, J=9 Hz, 2H), 1.61-1.78 (d, 6H). MS (ES, m/z): 684 [M+H]+.
Reaction SMILES: [I:1][C:2]1[C:3](O)=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:13]([O-:16])([O-])=O.[K+].[K+].BrC[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C)C=O.C(OCC)(=O)C>[C:26]([Si:23]([CH3:25])([CH3:24])[O:22][CH2:21][CH2:13][O:16][C:5]1[C:4]([O:10][CH3:11])=[CH:3][C:2]([I:1])=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C=O)cc(I)c1O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(I)cc(C=O)c1OCCO[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Yield: 95.8 %

Procedure:
To a solution of 5-iodovanillin (10 g, 35.9 mmol) (Aldrich) in N,N-dimethylformamide (150 mL) was added anhydrous K2CO3 (14.9 g, 108 mmol), and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (10.3 g, 43 mmol, Aldrich). The reaction mixture was heated at 60° C. for 18 h. The crude was cooled to room temperature, diluted with ethyl acetate, washed with water, brine. The organic layer was separated, dried over MgSO4, concentrated, and purified by chromatography to give 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-3-methoxy-benzaldehyde as a yellow oil (Yield 15 g, 96%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.COCC(O)C.[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:12][C:4]1[CH:3]=[C:2]([N:22]2[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1cc(Cl)c2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: COCC(C)O
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2n1
Reaction time: 48 h

Procedure:
4-Chloro-2-methylquinoline (5 g, 28 mmol) was mixed with 1-methoxy-2-propanol, tert-butyl piperazine-1-carboxylate was added (5.74 g, 30.8 mmol) and the mixture was refluxed for 4.5 hours after which the product started to precipitate. The mixture was concentrated under reduced pressure and left at room temperature for 48 hours. The product was separated by filtration, washed with ethylacetate and dried at 50° C. 4.382 g of a solid were obtained (13.38 mmol, 48%). MS (APCI): m/z=327.9 [M+1]+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6](C2C=CC=CC=2C)[C:5]=1[OH:18])[CH:2]=[CH2:3].[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)C(OO)=O.C(=O)([O-])[O-:31].[K+].[K+]>>[Cl:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:22][C:21]=1[C:6]1[C:5]2[O:18][CH:2]([CH2:3][OH:31])[CH2:1][C:4]=2[CH:9]=[CH:8][C:7]=1[F:10]
Reactant: O=C([O-])[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1ccc(F)c(-c2ccccc2C)c1O
Agent: [K+]
Product: OCC1Cc2ccc(F)c(-c3ccccc3Cl)c2O1
Yield: 55.1 %

Procedure:
Treatment of 1-bromo-2-chlorobenzene (5.63 g, 29.4 mmol) with (2-fluoro-6-methyoxyphenyl)boronic acid (5.0 g, 29.42 mol) generally according to the procedure described for Intermediate 37 afforded 2.0 g (29%) of 6-fluoro-2′-chlorobiphenyl-2-yl methyl ether. Treatment of 6-fluoro-2′-chlorobiphenyl-2-yl methyl ether with hydrogen bromide (50 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 395 afforded a brown oil. The oil was reacted with sodium hydride (0.34 g, 14.35 mmol) and allyl bromide (1.74 g, 14.35 mmol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 to provide 3-allyl-6-chloro-2′-chlorobiphenyl-2-ol. Treatment of 3-allyl-6-fluoro-2′-methylbiphenyl-2-ol (1.2 g, 4.56 mmol) with m-chloroperoxybenzoic acid (2.36 g, 13.68 mmol, 77%) and potassium carbonate (1.575 g, 11.4 mmol) generally according to the procedure described for Intermediate 9 afforded 0.7 g (55%) of (±)-[7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment (±)-[7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanol (1.5 g, 5.81 mmol) with p-toluenesulfonyl chloride (1.66 g, 8.71 mol) generally according to the procedure described for Intermediate 10 gave 0.9 g (82%) of (±)-[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.50 g, 1.15 mmol) with sodium azide (0.4 g, 6.15 mmol) generally according to the procedure described for Intermediate 98 afforded 0.35 g, (99%) of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran (0.35 g, 1.15 mmol) in tetrahydrofuran (10 mL) with polymer-supported triphenylphosphine (0.60 g, 2.3 mmol) generally according to the procedure described for Example 154 provided 0.170 g (47%) of (±)-{[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 248-250° C.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.CC1C=CC(S(O[CH2:21][C@@:22]2([CH3:25])[CH2:24][O:23]2)(=O)=O)=CC=1.C(OCC)(=O)C.C1CCN2C(=NCCC2)CC1>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]([CH2:21][C@:22]2([CH3:25])[CH2:24][O:23]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@]2(C)CO2)cc1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Yield: 67.8 %

Procedure:
2-Chloro-4-nitro-1H-imidazole (1.51 g, 10.17 mmol) and (R)-2-methyloxiran-2-ylmethyl 4-methylbenzene sulfonate (3.70 g, 15.25 mmol) were suspended in acetonitrile (150 ml). Benzyl(triethyl)ammonium chloride (0.23, 1.02 mmol) was added to this suspension, and the resulting mixture was stirred under reflux for 10 hours. After the reaction mixture was allowed to return to room temperature, ethyl acetate was added to the solution. The resulting mixture was washed with an aqueous sodium hydrogencarbonate, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure and dissolved in ethyl acetate (40 ml). DBU (1.57 ml, 10.17 mmol) was added to the solution with cooling on ice-bath, and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=7/3) to afford (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole (1.50 g, yield 68%) as a light yellow oil.
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:25][O:26]C1C=CN=C(CN)C=1>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[C:23]([O:26][CH3:25])[CH:22]=[CH:21][N:20]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Reactant: COc1ccnc(CN)c1
Agent: Cl
Product: COc1ccnc(CNc2nc(C)c(C)c(NC3CCCCC3)n2)c1

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using [(4-methoxypyridin-2-yl)methyl]amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-grey solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.07 (d, J=11.01 Hz, 3H), 1.23 (d, J=11.01 Hz, 2H), 1.47 (d, J=9.94 Hz, 2H), 1.60 (s, 3H), 1.88 (s, 3H), 2.25 (s, 3H), 4.73 (d, J=5.37 Hz, 2H), 7.22-7.29 (m, 2H), 7.59 (d, J=7.79 Hz, 1H), 8.53-8.56 (m, 2H), 12.88 (bs, 1H); MS (ESI) m/z 342.7 (M+1)+.
Reaction SMILES: B(F)(F)F.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O.[OH-].[NH4+:16].FC(F)(F)C(O[C:22](=O)[C:23](F)(F)F)=O>>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:12]([CH:22]=[CH:23][N:16]=[CH:10]2)=[CH:13][CH:14]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: [NH4+]
Reactant: COc1cccc(C=O)c1
Agent: FB(F)F
Agent: [OH-]
Product: COc1ccc2ccncc2c1
Temperature: 0 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
To a solution of BF3.AcOH complex (33.78 g, 0.180 mol) in triflouoracetic anhydride (40 ml) at 0° C. was added a solution of the imine prepared from 3-methoxybenzaldehyde and aminoethanaldiethylacetal (Tetrahedron, 1971, 27, 1253) (15.06 g, 0.0599 mol) in trifluoroacetic anhydride (40 ml), maintaining the temperature below 10° C. After 48 hours, the mixture was poured into ice-water (300 ml), the solution made basic with concentrated ammonium hydroxide and extracted with dichloromethane. The organic phase was then extracted with aqueous hydrochloric acid solution (5N, 2×400 ml). The combined aqueous was made basic with concentrated ammonium hydroxide solution and extracted with dichloromethane. The organic phase was dried (MgSO4), filtered, the solvent removed under reduced pressure and the residue purified on silica, eluting with a solvent gradient of 98:2 to 95:5 dichloromethane:methanol, to give the title compound, (6.85 g, 72%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]=1[C:4]#[N:5].O=[C:22]([CH3:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:1]=[C:22]([CH3:29])[C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: N#Cc1c(N)cccc1OCCCOc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCCCOc3ccccc3)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-(3-phenoxypropoxy)benzonitrile (Example 33b) and ethyl 3-oxobutanoate as a yellow solid (47%). 1H NR (400 MHz, DMSO-d6) δ 1.33 (t, J=8.0 Hz, 3H), 2.34 (m, 2H), 2.57 (s, 3H), 4.19 (t, J=4.0 Hz, 2H), 4.33 (q, J=8.0 Hz, 2H), 4.37 (t, J=4.0 Hz, 2H), 6.91-6.97 (m, 4H), 7.24-7.29 (m, 3H), 7.53 (t, J=8.0 Hz, 1H), 8.17 (s, 2H). MS 381 (MH+).
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([C:11]2[CH:12]=[C:13]([C:17](=[O:19])[CH3:18])[CH:14]=[N:15][CH:16]=2)[CH:2]=1.[C:20]([N:28]=C=O)(=[O:27])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(Cl)Cl>[C:17]([C:13]1[CH:12]=[C:11]([C:3]2[CH:4]=[C:5]3[C:10](=[N:1][CH:2]=2)[N:9]([C:20]([NH2:28])=[O:27])[CH2:8][CH2:7][CH2:6]3)[CH:16]=[N:15][CH:14]=1)(=[O:19])[CH3:18]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: CC(=O)c1cncc(-c2cnc3c(c2)CCCN3)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)c1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Temperature: 50 °C
Yield: 50.6 %

Procedure:
1-[5-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yl]-ethanone (50 mg, 0.20 mmol) and benzoyl isocyanate (48 mg, 0.30 mmol) are dissolved in 2.0 mL of DCM. The mixture is heated at 50° C. for 16 hrs. Then the solvent is removed in vacuum and the residue is dissolved in 2.0 mL of EtOH. K2CO3 (46 mg, 0.34 mmol) is added and the mixture is heated at 80° C. for 45 min. The solvent is removed and the residue is partitioned between water (35 mL) and EtOAc (75 mL). The aqueous layer is separated and extracted with DCM (2×30 mL). The organic layers are combined and concentrated to give the crude product. EtOAc (2 mL) is added to the crude and the white solid formed is filtered, rinsed with more EtOAc (2×3 mL) and dried to give 30 mg of the titled product.
Reaction SMILES: [N:1]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]=S.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:12][CH:11]=1.CC(C)N=C=NC(C)C.[NH:32]1[CH:36]=[C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:34]=[N:33]1>C(Cl)Cl>[CH2:40]([O:39][C:37]([C:35]1[CH:36]=[N:32][N:33]([C:2]([NH:1][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[O:17])=[CH:12][CH:11]=2)[CH:34]=1)=[O:38])[CH3:41]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: CCOC(=O)N=C=S
Reactant: Nc1ccc(C(=O)N2CCCC2)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CCOC(=O)NC(=Nc1ccc(C(=O)N2CCCC2)cc1)n1cc(C(=O)OCC)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
Ethyl isothiocyanatoformate (0.60 mL, 5.1 mmol) was added to a suspension of (4-amino-phenyl)-pyrrolidin-1-yl-methanone (0.873 g, 4.59 mmol) in DCM (15 mL) and the reaction mixture was stirred at room temperature for 1 h. DIC (1.01 mL, 5.05 mmol) was then added, followed by ethyl pyrazole-4-carboxylate (0.707 g, 5.05 mmol). Stirring was continued for 18 h, at which point the reaction mixture was concentrated. Diethyl ether (25 mL) was added to the residue and the resulting suspension was cooled to 0° C. and filtered. The filtrate was concentrated and the residue was purified by FCC (2-100% EtOAc/hexanes) to yield the titled compound (1.502 g, 77% yield). MS (ESI/Cl): mass calcd. for C21H25N5O5, 427.2; m/z found, 428.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[Cl:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[N:30]=[CH:31][C:32]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[N:33]2>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:41]2[CH2:42][CH2:43][N:38]([C:32]3[CH:31]=[N:30][C:29]4[C:34](=[CH:35][CH:36]=[CH:37][C:28]=4[Cl:27])[N:33]=3)[CH2:39][CH2:40]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: Clc1cccc2nc(N3CCNCC3)cnc12
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3cnc4c(Cl)cccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 5-chloro-2-piperazin-1-yl-quinoxaline Melting point: 74° C. C32H31ClF3N5O (M=594.08) Calc.: molecular peak (M+H)+: 594/596. Found: molecular peak (M+H)+: 594/596.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-:6].[Na+].[N+:8]([C:11]([N+:15]([O-:17])=[O:16])([CH3:14])[CH2:12]O)([O-:10])=[O:9].S(=O)(=O)(O)O>O>[N+:8]([C:11]([N+:15]([O-:17])=[O:16])([CH3:14])[CH2:12][N:1]([CH2:12][C:11]([N+:8]([O-:10])=[O:9])([N+:15]([O-:16])=[O:6])[CH3:14])[CH2:2][C:3]([OH:5])=[O:4])([O-:10])=[O:9]
Reactant: [OH-]
Reactant: CC(CO)([N+](=O)[O-])[N+](=O)[O-]
Reactant: NCC(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(CN(CC(=O)O)CC(C)([N+](=O)[O-])[N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Reaction time: 8 h

Procedure:
A solution of 7.5 g. (0.1 mole) of glycine, 4.0 g. (0.1 mole) of sodium hydroxide and 50 ml. of water was mixed with 15.0 g. (0.1 mole) of 2,2-dinitropropanol. The temperature rose to 42° and the yellow solution formed was allowed to stand overnight. Upon addition of dilute sulfuric acid a viscous, colorless oil separated and solidified on standing. The product 15.6 g. (92.0%) was collected and recrystallized from methanol-water to give white crystals, m.p. 123°-124°.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][C:25]([OH:27])=O.[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1)([O-:30])=[O:29]>C1COCC1.CN(C=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][C:25]([N:40]1[CH2:41][CH2:42][N:37]([C:34]2[CH:33]=[CH:32][C:31]([N+:28]([O-:30])=[O:29])=[CH:36][CH:35]=2)[CH2:38][CH2:39]1)=[O:27]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: COc1ccc2[nH]cc(CC(=O)O)c2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CC(=O)N3CCN(c4ccc([N+](=O)[O-])cc4)CC3)c2c1
Reaction time: 1 h
Yield: 91 %

Procedure:
In a 100 ml flask, 1.62 g (10 mmoles) of 1,1′-carbonyl-diimidazole is added to a solution of 2.05 g (10 mmoles) of 5-methoxyindole-3-acetic acid in 10 ml of THF. After one hour of agitation at ambient temperature, a solution of 1-(4-nitrophenyl)piperazine in 10 ml of DMF is added dropwise. Agitation is continued for 15 hours. The reaction medium is then concentrated under vacuum and the evaporation residue is precipitated from 50 ml of an ethyl acetate/water mixture (1/1). After filtration, the solid is rinsed successively with 50 ml of water, 50 ml of ethyl acetate and 50 ml of dichloromethane. After drying under vacuum, a yellow powder is obtained with a yield of 91%. Melting point: 239-240° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:18]=[CH:17][C:11]([CH:12]([OH:16])C(O)=O)=[CH:10][CH:9]=1.CI.[C:21]([O:24][CH2:25]C)(=[O:23])[CH3:22]>CN(C=O)C.O>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][O:16][CH2:22][C:21]([O:24][CH3:25])=[O:23])=[CH:17][CH:18]=1
Reactant: CCOC(C)=O
Reactant: O=C(O)C(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
Cesium carbonate (6.5 g) was added to a solution of 4-fluoromandelic acid (CAS #395-33-5, 1.7 g) and methyl iodide (1.9 mL) in DMF (15 ml), and the reaction solution was stirred at room temperature for 11 hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.22 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12]C(=O)[O:10][C:8](=O)[C:7]=12.[NH:14]([CH2:16][C:17]([OH:19])=[O:18])[CH3:15].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O>[I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:12])[C:7]=1[C:8]([N:14]([CH3:15])[CH2:16][C:17]([OH:19])=[O:18])=[O:10]
Reactant: CNCC(=O)O
Reactant: O=c1[nH]c2cccc(I)c2c(=O)o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CC(=O)O)C(=O)c1c(N)cccc1I

Procedure:
A suspension of 8.7 g (0.03 mol) of 6-iodoisatoic acid anhydride, 2.95 g (0.033 mol) of sarcosine and 4.2 g of potassium carbonate in 50 ml of dimethylformamide is heated to 50° for 30 minutes. After cooling, the mixture is diluted with 400 ml of water, adjusted to pH 1-2 with 2 N hydrochloric acid and extracted several times with chloroform/isopropanol (4:1). After evaporation of the solvent and recrystallization of the residue from methylene chloride/hexane, there is obtained N-(6-iodoanthraniloyl)-N-methylglycine of melting point 147°-149°.
Reaction SMILES: Br[CH:2]([OH:4])[CH3:3].Cl[S:6]([N:9]=[C:10]=[O:11])(=[O:8])=[O:7].[CH:12]1([NH2:15])[CH2:14][CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[CH:12]1([NH:15][S:6]([N:9]2[CH2:3][CH2:2][O:4][C:10]2=[O:11])(=[O:8])=[O:7])[CH2:14][CH2:13]1
Reactant: CC(O)Br
Reactant: NC1CC1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OCCN1S(=O)(=O)NC1CC1
Yield: 48 %

Procedure:
To a solution of bromoethanol (1 g, 8.06 mmol) in DCM was added chloro sulfonyl isocyanate (1.13 g, 8.06 mmol) in DCM and this solution added over 2 min, dropwise, to cyclopropyl amine (0.552 g, 0.009 mmol) and triethylamine (1 ml, 0.007 mmol) in DCM and stirred at RT for 1 h. The mixture was quenched with 0.2 M HCl solution and extracted with DCM (3×150 ml). The combined organic layer was washed with water, brine and dried over sodium sulphate. The solvent was distilled off to afford the product in 48% yield (0.8 g). 1H NMR (400 MHz, DMSO-d6): δ 8.15-8.14 (d, 1H), 4.42 (t, 2H), 3.70 (t, 2H), 2.35 (m, 1H), 0.58-0.53 (m, 4H).