Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]2[O:14][CH2:15][C@H:16]([CH3:17])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:20])[C:5]([C:18]#[N:19])=[CH:6]3.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][CH2:29][NH2:30])[CH:22]=1>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:30][CH2:29][CH2:28][CH2:27][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)[C:9]2[O:14][CH2:15][C@H:16]([CH3:17])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:20])[C:5]([C:18]#[N:19])=[CH:6]3
Reactant: NCCCc1cccnc1
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Solvent: CS(C)=O
Product: C[C@H]1COc2c(NCCCc3cccnc3)c(F)c(N)c3c(=O)c(C#N)cn1c23
Temperature: 120 °C
Yield: 15.1 %

Procedure:
To a solution of 5 (30 mg, 0.108 mmol) in 5 ml of DMSO, 29.5 mg (0.216 mmol) of 3-(pyridine-3-yl)propan-1-amine were added. The reaction mixture was heated to 120° C. for 3 h. The DMSO was removed under vacuo and the remaining solid was purified by preparative HPLC to give the title compound as a yellow solid (6.4 mg, 15% yield).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:14](Br)[CH:15]=[CH2:16]>CC(C)=O>[CH2:16]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)[CH:15]=[CH2:14]
Reactant: OC1CCNCC1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN1CCC(O)CC1
Temperature: 5 °C

Procedure:
To a 500 mL 3-necked round-bottomed flask, was added 24.0 g of 4-hydroxypiperidine dissolved in 140 mL of acetone. To this mixture was added 40.9 g of powdered anhydrous potassium carbonate. The reaction mixture was cooled to 5° C. with an ice bath. While stirring, 28.7 9 of allyl bromide in 60 mL acetone was added slowly to the reaction mixture. After addition was complete, the reaction mixture was allowed to stir at room temperature for 18 hours. The solid residue was removed by filtration, and acetone was removed from the filtrate using a rotary evaporator yielding 25.0 g of N-allyl(4-hydroxy)piperidine as viscous liquid. To a 500 mL 3-necked round-bottomed flask was added 20 g of N-allyl(4-hydroxy)piperidine dissolved in 75 mL diethyl ether. After cooling to 5° C. with an ice bath, 21.4 g of allyl bromide dissolved in 30 mL of diethyl ether was added slowly. After completion of addition of allyl bromide, the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 24 hours. The solid residue thus formed was collected by filtration and was washed with diethyl ether (2×1.5 L). The washed solid was recrystallized from acetonitrile. After removal of acetonitrile by filtration, the residue was dried under vacuum yielding 22 9 of N,N-diallyl(4-hydroxy)piperidinium bromide as a white solid.
Reaction SMILES: [CH2:1]([N:4]1[CH2:11][CH:10]2[C:6]([C:12]3[S:13][C:14]([F:17])=[CH:15][CH:16]=3)([NH:7][O:8][CH2:9]2)[CH2:5]1)[CH:2]=[CH2:3].[C:18]([N:26]=[C:27]=[S:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[CH2:1]([N:4]1[CH2:11][CH:10]2[C:6]([C:12]3[S:13][C:14]([F:17])=[CH:15][CH:16]=3)([N:7]([C:27]([NH:26][C:18](=[O:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[S:28])[O:8][CH2:9]2)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: C=CCN1CC2CONC2(c2ccc(F)s2)C1
Solvent: C1CCOC1
Product: C=CCN1CC2CON(C(=S)NC(=O)c3ccccc3)C2(c2ccc(F)s2)C1
Temperature: 25 °C
Reaction time: 19 h
Yield: 99.9 %

Procedure:
To a stirred solution of 5-allyl-6a-(5-fluoro-2-thienyl)-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole (4.22 g, 16.59 mmol) in tetrahydrofuran (83 mL) is added benzoyl isothiocyanate (2.7 mL, 19.9 mmol). The resulting solution is stirred under nitrogen at room temperature for 19 hours. The solution is concentrated and the residue is purified by silica gel flash chromatography eluting with hexanes/ethyl acetate (two-step gradient from 80:20 to 70:30 to 60:40) to give the title compound (6.92 g, 100%). ES/MS (m/e): 418 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([NH:19][NH2:20])=[O:18])[CH2:11][CH2:10]1.[CH:21]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CCCCCC>C1(C)C=CC=CC=1>[CH:21]1([NH:29][C:30]([NH:20][NH:19][C:17](=[O:18])[CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:14][CH2:13]2)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1ccccc1N1CCN(CCC(=O)NN)CC1
Reactant: O=C=NC1CCCCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COc1ccccc1N1CCN(CCC(=O)NNC(=O)NC2CCCCCCC2)CC1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
To a suspension of 3-[4-(2-methoxyphenyl)piperazino]propanohydrazide D2 (0.30 g, 1.07 mmol) in anhydrous toluene (5 mL), cyclooctyl isocyanate (0.177 g, 1.15 mmol) was added and the mixture was heated at reflux until all solid dissolved. The solution was allowed to cool slowly to room temperature. Hexane was added and the resulting oil was extracted with ethyl acetate, the organic phase was washed with water, dried over MgSO4 and evaporated under reduced pressure to afford 0.40 g (84%) N-cyclooctyl-2-{3-[4-(2-methoxyphenyl)piperazino]propanoyl}-1-hydrazine-carboxamide D3 as a colourless oil.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([F:7])([F:6])[F:5].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:5][C:4]([F:7])([F:6])[CH2:3][CH2:2][S:15][C:12]1[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][CH:11]=1
Reactant: Sc1ccc(Br)cc1
Reactant: FC(F)(F)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)CCSc1ccc(Br)cc1
Temperature: 40 °C
Yield: 95.4 %

Procedure:
3-Bromo-1,1,1-trifluoropropane (640 μl, 6 mmol) was added to a mixture of 4-bromothiophenol (945 mg, 5 mmol) and potassium carbonate (760 mg, 5.5 mmol) in DMF (5 ml) and the reaction mixture heated at 40° C. for 1 hour. The mixture was allowed to cool to ambient temperature and poured into water (50 ml) and extracted with EtOAc (2×30 ml). The extracts were combined, washed with brine (3×30 ml), dried (Chemelut column 1010) and evaporated to give the title compound (1.36 g, 95%) as a pale yellow oil. NMR 2.56 (m, 2H), 3.13 (t, 2H), 7.31 (d, 2H), 7.51 (d, 2H); m/z 285 (M+).
Reaction SMILES: [Br:1][C:2]([CH2:4]Br)=[CH2:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([Mg]Br)=[CH:9][CH:8]=1.Cl>C(OCC)C>[Br:1][C:2](=[CH2:3])[CH2:4][C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: C=C(Br)CBr
Agent: Cl
Solvent: CCOCC
Product: C=C(Br)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A solution of 8 ml (0.0622 mol) of 2,3-dibromopropene in 50 ml diethyl ether was placed under a nitrogen atmosphere by use of a Firestone valve. While cooling in an ice water bath, a solution of 62 ml (0.062 mol) of 1M 4-chlorophenylmagnesium bromide in diethyl ether was added slowly via addition funnel. After stirring for 2 hours while warming to room temperature, the reaction was recooled in an ice bath and 50 ml of 1 N hydrochloric acid was then added via syringe. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO4 and filtered. The solvent was removed from the filtrate in vacuo. The residue was triturated with cold pentanes to yield 12.0 g of 1-(2-bromo-allyl)-4-chloro-benzene as an oil which was used in without further purification.
Reaction SMILES: [CH2:1]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:38]1(=[O:45])[O:44][C:42](=[O:43])[CH2:41][O:40][CH2:39]1>C1(C)C=CC=CC=1>[N:19]([C:42]([CH2:41][O:40][CH2:39][C:38]([OH:45])=[O:44])=[O:43])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: O=C1COCC(=O)O1
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COCC(=O)O
Yield: 87.4 %

Procedure:
A solution of dioctadecylamine (2.0 g, 3.8 mmol) and diglycolic anhydride (0.44 g, 3.8 mmol) was refluxed in toluene (50 mL) for 48 h. The solvent was then evaporated and the crude product recrystallized form CHCl3 to give (C18H37)2NCOCH2OCH2COOH as a white solid (2.12 g, 87%), mp 80–81° C. 1H-NMR (300 MHz, δ, CDCl3): 0.87 (6H, t, J=6.9 Hz), 1.25 (64H, m), 1.55 (4H, bs), 3.07 (2H, t, J=7.8 Hz), 3.34 (2H, t, J=7.8 Hz), 4.21 (2H, s), 4.38 (2H, s). 13C-NMR (75 MHz, δ, CDCl3): 14.2, 22.8, 26.9, 27.0, 27.5, 28.7, 29.4, 29.5, 29.6, 29.7, 29.8, 32.0, 47.0, 71.4, 73.2, 171.0, 172.2. IR (KBr, cm−1): 1748 (CO), 1602 (CO).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:10]([F:11])=[C:9]([NH:12]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:8]=[C:7]([CH:32](OCC)[O:33]CC)[N:6]=2)[CH2:3][CH2:2]1.OS(O)(=O)=O.CC#N>O>[NH2:12][C:9]1[C:10]([F:11])=[C:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:6]=[C:7]([CH:32]=[O:33])[CH:8]=1
Reactant: CCOC(OCC)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(CC2CC2)n1
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Product: Nc1cc(C=O)nc(CC2CC2)c1F
Yield: 89.7 %

Procedure:
Using the procedure for Example 12, 2-(cyclopropylmethyl)-6-(diethoxymethyl)-3-fluoro-N-tritylpyridin-4-amine (4.34 g, 8.5 mmol), conc H2SO4 (1 mL), CH3CN (35 mL) and H2O (35 mL) gave 4-amino-6-(cyclopropylmethyl)-5-fluoropicolinaldehyde (1.48 g, 88%) as an off-white solid: mp 99-100° C.; 1H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 7.25 (d, J=6.7 Hz, 1H), 4.40 (br s, 2H), 2.76 (dd, J=7.0, 2.9 Hz, 2H), 1.17 (m, 1H), 0.50 (m, 2H), 0.29 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 193.10, 149.43 (d, J=15.4 Hz), 148.84 (d, J=253.6 Hz), 148.73 (d, J=5.4 Hz), 141.49 (d, J=12.6 Hz), 107.76 (d, J=3.8 Hz), 36.25 (d, J=1.8 Hz), 10.16 (d, J=1.5 Hz), 4.56; 19F NMR (376 MHz CDCl3) δ −144.19. HRMS-ESI (m/z) [M+H]+ calcd for C10H11FN2O, 194.0855. found, 194.0857.
Reaction SMILES: [NH2:1][CH:2]1[C:7]([C:8](=[O:13])[C:9]([F:12])([F:11])[CH3:10])=[CH:6][CH:5]=[CH:4][N:3]1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.S(=O)(=O)(O)O>CCOC(C)=O.CCCCCC>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]2[NH:3][C:2]3[N:1]=[CH:4][CH:5]=[CH:6][C:7]=3[C:8]([OH:13])([C:9]([F:11])([F:12])[CH3:10])[C:19]=2[CH:18]=1
Reactant: CC(F)(F)C(=O)C1=CC=CN(c2ccc(Cl)cc2)C1N
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(F)(F)C1(O)c2cc(Cl)ccc2Nc2ncccc21
Temperature: 25 °C
Reaction time: 47.5 h
Yield: 91.1 %

Procedure:
Method JJ: 2-Amino-N-(4-chlorophenyl)-3-(2,2-difluoropropionyl)pyridine (35) (190 mg, 0.640 mmol) was treated with conc. sulfuric acid (1 mL). The resulting red homogeneous solution was stirred at room temperature for 47.5 h. The reaction was quenched with saturated aqueous Na2CO3 (15 mL), and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Flash chromatography (50% EtOAc-hexane) provided 37 (173 mg, 91% yield) as an off-white solid (m.p. 188-190° C.).
Reaction SMILES: C1COCC1.[NH2:6][C:7]1[C:12]2=[C:13]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:30]=4[F:39])=[O:27])=[C:21]([F:40])[CH:20]=3)[C:14]([CH2:16][O:17][CH3:18])=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1.[Br:41]N1C(C)(C)C(=O)N(Br)C1=O.[O-]S([O-])=O.[Na+].[Na+]>CCOC(C)=O>[NH2:6][C:7]1[C:12]2=[C:13]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[CH:31][C:30]=4[F:39])=[O:27])=[C:21]([F:40])[CH:20]=3)[C:14]([CH2:16][O:17][CH3:18])=[C:15]([Br:41])[N:11]2[N:10]=[CH:9][N:8]=1
Reactant: COCc1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)c(F)c1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn2c1Br
Temperature: -40 °C
Reaction time: 1 h
Yield: 107 %

Procedure:
To a solution of THF (500 mL) was added 1-{4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea (2.29 g, 4.65 mmol). The solution was cooled to −40° C. and then 1,3-dibromo-5,5-dimethylhydantoin (665 mg, 2.33 mmol) was added in two batches 20 min apart. The reaction was stirred at −40° C. for 1 h and then allowed to warm to rt over the following 2 h. Aq saturated Na2SO3 was added to the reaction followed by EtOAc. The layers were separated and the aqueous layer was back extracted with EtOAc. The organic layer was washed with 1 N NaOH and water, dried (Na2SO4), filtered and evaporated to yield 2.83 g crude (107%) of the desired product. MS [M+H]+=571; LCMS RT=3.54.
Reaction SMILES: CO.[C:3]([C:5]1[C:10]([F:11])=[C:9]([F:12])[C:8]([OH:13])=[C:7]([F:14])[C:6]=1[F:15])#[N:4].[C:16](Cl)(=[O:20])[C:17]([CH3:19])=[CH2:18].O>[Na]>[C:16]([O:13][C:8]1[C:7]([F:14])=[C:6]([F:15])[C:5]([C:3]#[N:4])=[C:10]([F:11])[C:9]=1[F:12])(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: C=C(C)C(=O)Cl
Reactant: N#Cc1c(F)c(F)c(O)c(F)c1F
Agent: [Na]
Solvent: O
Solvent: CO
Product: C=C(C)C(=O)Oc1c(F)c(F)c(C#N)c(F)c1F
Yield: 33.2 %

Procedure:
In 50 ml of methanol having 0.94 g (0.0236 mol) of sodium hydroide dissolved therein, 3.0 g (0.0157 mol) of 4-cyano-2,3,5,6-tetrafluorophenol was dissolved. The resultant solution was kept with ice at 0° C. To the cooled solution, 1.80 g (0.0173 mol) of methacrylic acid chloride as slowly added dropwise. After completion of this dropwise addition, the resultant mixture was stirred at the same temperature for two hours. It was then mixed with 50 ml of pure water and adjusted to pH 10 by addition of an aqueous 20% sodium hydroide solution. As the result, white crystals occurred. The white crystals were filtered, washed with cold water, and then dried to obtain 1.35 g of 4-cyano-2,3,5,6-tetrafluorophenyl methacrylate (purity 98% and yield 32 mol % based on 4-cyano-2,3,5,6-tetrafluorophenol). The analyses obtained of this novel substance for the determination of its chemical structure were the same as those of Example 2.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][NH:11][CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:15]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)(=[O:18])[CH:16]=[CH2:17].Cl>>[CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][N:11]([CH2:17][CH2:16][C:15]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18])[CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: CC1=C2CCNCC2c2ccccc21
Reactant: C=CC(=O)N1CCCCC1
Agent: Cl
Product: CC1=C2CCN(CCC(=O)N3CCCCC3)CC2c2ccccc21

Procedure:
1,3,4,9b-Tetrahydro-5-methyl-2H-indeno[1,2-c]pyridine and acrylic acid piperidide are reacted in accordance with the process described in Example 6. Reaction period nine hours. M.P. of the hydrochloride of the title compound 219°-221° from ethanol (decomp.).
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.[N:11]([O-])=[O:12].[Na+]>Cl.O>[N:11]([N:4]1[CH2:3][CH2:2][S:1][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]1=2)=[O:12]
Reactant: O=N[O-]
Reactant: c1ccc2c(c1)NCCS2
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NN1CCSc2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 69.9 %

Procedure:
3,4-Dihydro-2H-benzo[1,4]thiazine (1.2 g, 7.94 mmol) was dissolved in 3N HCl at 0° C., and the reaction mixture stirred for 5 min. at 0° C. A solution of sodium nitrite (548 mg, 7.94 mmol) in water was added at the same temperature, and the reaction mixture stirred at 0° C. for 1 h. After completion of reaction water was added and extracted with DCM. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure, to provide 1 g desired product.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:8]=1CO.N1C(C)=CC=CC=1C.[CH2:25](Cl)[Cl:26]>>[CH3:16][O:15][C:14]1[CH:13]=[C:12]([CH:11]=[CH:8][C:7]=1[O:6][CH3:5])[CH2:25][Cl:26]
Reactant: ClCCl
Reactant: COc1cccc(CO)c1OC
Solvent: O=S(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: COc1ccc(CCl)cc1OC
Reaction time: 0.5 h

Procedure:
Thionyl chloride (288 g) is added over 1.5 hour to a stirred solution of 2,3-dimethoxybenzyl alcohol (400 g) and 2,6-lutidine in methylene chloride (2 l). The reaction mixture is then stirred for 30 minutes after which it is washed with 2 N hydrochloric acid (7×1 l) and then with water. The organic layer is separated, dried (MgSO4) and evaporated to give a residue, which upon distillation yields 3,4-dimethoxybenzyl chloride (375 g), b.p. 145°-150° C. at 20-25 nm (waterpump vacuum). The material solidifies on standing.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:19])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]2.[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:1]/[N:2]=[C:3](\[NH2:19])/[CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NC(CCCOc1ccc2c(c1)CCC(=O)N2)=NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N/C(CCCOc1ccc2c(c1)CCC(=O)N2)=N\OC(=O)c1ccc(Cl)cc1
Temperature: 110 °C
Yield: 22.9 %

Procedure:
To a stirred solution of N′-hydroxy-4-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)butanimidamide (0.100 g, 0.37 mmol) in dry toluene (2 mL) at room temperature, p-chlorobenzoyl chloride (0.066 g, 0.37 mmol) and potassium carbonate (0.061 g) were added. The reaction mixture was heated to 110° C. overnight in a sealed tube. Solids were filtered, then water was added to the filtrate and stirred for few minutes. The solid precipitate which formed was filtered and dried to yield (Z)—N′-((4-chlorobenzoyl)oxy)-4-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)butanimidamide (0.034 g; 22%). 1H NMR: 400 MHZ, DMSO-d6: δ 2.00 (t, J=6.80 Hz, 2H), 2.29 (t, J=7.60 Hz, 2H), 2.40 (t, J=7.20 Hz, 2H), 2.83 (t, J=7.60 Hz, 2H), 3.97 (t, J=6.40 Hz, 2H), 6.60 (s, 2H), 6.76 (s, 2H), 6.82 (s, 1H), 7.58 (d, J=8.40 Hz, 2H), 8.13 (d, J=8.40 Hz, 2H), 9.90 (s, 1H).
Reaction SMILES: C([Mg]Br)C.[Cl:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[O:9][CH2:10][C:11]#[CH:12].[C-]#N.Br[CH2:19][C:20]#[C:21][CH2:22][C:23]#[CH:24]>CCOCC.O1CCCC1>[Cl:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[O:9][CH2:10][C:11]#[C:12][CH2:19][C:20]#[C:21][CH2:22][C:23]#[CH:24]
Reactant: C#CCOc1cccc(Cl)c1
Reactant: C#CCC#CCBr
Agent: CC[Mg]Br
Agent: [C-]#N
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CCC#CCC#CCOc1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
21.76 ml (9.8 g, 0.735 mmol) of a 3.38N solution of ethylmagnesium bromide in ether was added dropwise, under argon to a cold (0°-5° C.) solution of 11.66 g (0.7 mol) of 3-(m-chlorophenoxy)-1-propyne [I. Iway, et al., Chem. Pharm. Bull., 11, 1042 (1963)] in 80 ml of anhydrous tetrahydrofuran. The rate was monitoredto maintain a temperature of 0° C. Thereafter, the reaction mixture was stirred for 1 hour further at 0°-5° C. Then, 31.35 mg ofcuprous cyanide were added and the mixtured stirred 20 minutes more. Then asolution of 5.5 g (0.035 mol) of 1-bromo-2,5-hexadiyne in 20 ml of anhydrous tetrahydrofuran was added dropwise to the mixture as the temperature was maintained at between 0°-5° C. Then the reaction was stirred at room temperature for 3 additional hours and quenched with 200 ml of 1N sulfuric acid and ice. After extraction with ether (3×200 ml), the combined organic extracts were concentrated invacuo to a small volume, and washed several times with EDTA and water, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on 350 g of silica gel, using hexane as eluant, and the product crystallized from methylene chloride-hexane, to yield 9-(m-chlorophenoxy)-1,4,7-nonatriyne, as an oil. The product was stored in dry ice.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2[CH:22]=[CH:23][CH:24]=[N:25]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CC1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:25][CH:24]1[CH2:22][CH2:23]1)=[O:7]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cccc(Br)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-Bromo-benzoic acid (2.5518 g, 12.7 mmol) and HATU (5.2230 g, 13.7 mmol) were dissolved in DMF (40 mL). DIEA (4.644 mL, 26.7 mmol) was added, and the mixture was allowed to stir at room temperature for 15 minutes. Then cyclopropylamine (0.88 mL, 12.7 mmol) was added, and the reaction was stirred at ambient temperature overnight. The solvent was removed, and the crude was purified via silica gel chromatography to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:16][OH:17])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])=[CH:4][CH:3]=1.Cl.Cl[CH2:20][CH2:21][NH2:22].[OH-].[K+]>CN(C)C=O>[ClH:1].[NH2:22][CH2:21][CH2:20][O:17][N:16]=[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15]
Reactant: NCCCl
Reactant: N#CCCCCCC(=NO)c1ccc(Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#CCCCCCC(=NOCCN)c1ccc(Cl)cc1
Temperature: 10 °C

Procedure:
5.0 mmol. (1.25 gr) of 4'-chloro-6-cyanocaprophenone oxime, melting point 58°-59° C, 5.2 mmol (0.60 gr) of 2-chloroethylaminehydrochloride and 0.7 gr of KOH powder were sequentially added to 12.5 ml of dimethyl-formamide (DMF) while stirring at 10° C.
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH3:32])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH3:33])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:34](NN)(=O)CC>>[CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH2:32][CH3:34])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:12][CH2:13][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:15][CH2:16]3)=[O:10])=[C:7]([CH3:33])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Reactant: CCC(=O)NN
Product: CCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 152 and using propionohydrazide instead of acetohydrazide. m/z (ES+) 454 (M+H)+. 1H NMR (400 MHz, Chloroform-d) δ 7.75-7.43 (m, 3H), 7.40-7.17 (m, 3H), 5.18-4.81 (m, 1H), 4.30-3.91 (m, 1H), 3.84-3.55 (m, 1H), 3.21-2.99 (m, 1H), 2.92-2.69 (m, 4H), 2.40 and 2.32 (2 singlets, amide rotamers, ArCH3, 3H), 2.25-1.84 (m, 7H), 1.83-1.42 (m, 3H), 1.32 (t, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17]CC)=O.[C:20]1([NH:26][NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(N(CC)CC)C>[N+:12]([C:9]1[CH:8]=[CH:7][C:6]2[NH:5][CH:4]=[C:3]3[C:15](=[O:17])[N:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:27]=[C:2]3[C:11]=2[CH:10]=1)([O-:14])=[O:13]
Reactant: CCOC(=O)c1cnc2ccc([N+](=O)[O-])cc2c1Cl
Reactant: NNc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1c2c[nH]c3ccc([N+](=O)[O-])cc3c-2nn1-c1ccccc1
Temperature: 135 °C
Yield: 85 %

Procedure:
In a vial were added 4a, phenyl hydrazine and triethylamine. The vial was sealed and heated to 135° C. for 12 hours. The product was collected by filtration and was washed with methanol in 85% yield. 1H-NMR (DMSO-d6) δ (ppm): 7.19 (1H, tt, J=7.32, 1.22 Hz), 7.42 (2H, t, J=7.56 Hz), 7.84 (1H, d, J=9.03 Hz), 8.16 (2H, dd, J=8.30, 1.22 Hz), 8.82 (1H, s), 8.89 (1H, d, J=2.44 Hz). m/z 307.3 (MH+).