Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[NH2:9])[CH:5]=[CH:6][CH:7]=1.[CH3:15][N:16]=[C:17]=[O:18]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[NH:9][C:17]([NH:16][CH3:15])=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CN(N)c1cccc(Cl)c1
Reactant: CN=C=O
Solvent: CC#N
Product: CNC(=O)NN(CC(=O)OC)c1cccc(Cl)c1

Procedure:
Methyl [1-(3-chlorophenyl)hydrazino]acetate (1.78 g) was dissolved in acetonitrile (20 ml) under nitrogen at room temperature. Methyl isocyanate (1.7 ml) was added to the solution which was then heated at 80° for 2 h. The solvent was removed in vacuo to give an oily residue which solidified on standing. This solid was triturated with ether and filtered to give the title compound (2.0 g), m.p. 121°-122°.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[Br:8][C:9]1[N:14]=[C:13]([CH:15]=O)[CH:12]=[CH:11][CH:10]=1>>[Br:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH2:15][N:4]2[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3]2)[N:14]=1
Reactant: CC1CCCNC1
Reactant: O=Cc1cccc(Br)n1
Product: CC1CCCN(Cc2cccc(Br)n2)C1

Procedure:
16] 3-Methylpiperidine (0.33 mL, 2.8 mmol) was added to a solution of 6-bromo-2-pyridine-carboxaldehyde (350 mg, 1.88 mmol) to give 2-bromo-6-[(3-methylpiperidyl)methyl]pyridine as a white solid.
Reaction SMILES: [C:1]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1C=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[Si](OC)(OC)[O:20][CH2:21][CH2:22][O:23][Si](OC)(OC)OC.[C:35]([O-])(O)=O.[Na+].C(OCC)C>ClCCl.FC(F)(F)S(OC[Si](C)(C)C)(=O)=O.N1C=CC=CC=1>[C:1]([C:2]1[CH:3]=[C:4]([CH:35]2[O:20][CH2:21][CH2:22][O:23]2)[CH:5]=[CH:6][CH:7]=1)(=[O:8])[C:9]1[CH:10]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CO[Si](OC)(OC)OCCO[Si](OC)(OC)OC
Reactant: O=Cc1ccccc1C(=O)c1ccccc1
Reactant: O=C([O-])O
Agent: C[Si](C)(C)COS(=O)(=O)C(F)(F)F
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccccc1)c1cccc(C2OCCO2)c1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
To a stirred solution of benzoylbenzaldehyde (2 g, 10 mmol) and 1,2-bis-(trimethoxysiloxy)ethane (2.3 g, 11 mmol) in dry dichloromethane (30 cm3) under N2 at room temperature was added trimethylsilylmethyl trifluoromethanesulphonate (5 drops). After stirring at 20° C. for 48 hours, pyridine (3 drops) was added followed by saturated NaHCO3 (20 cm3) and diethyl ether (20 cm3). The resulting mixture was stirred for 30 minutes. The ethereal layer was separated off and the aqueous layer extracted twice more with diethyl ether. The combined extracts were washed with water, dried over a mixture of anhydrous Na2CO3 and anhydrous Na2SO4 (1:1) and the solvent removed in vacuo to give 2-(3-benzoylphenyl)-1,3-dioxolane, nD20 1.5890. Yield 2.2 g (91.7%).
Reaction SMILES: C(NCCCN[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH3:21])C.C(OC(N(CCCN(C(OC(C)(C)C)=O)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N:43](C(OC(C)(C)C)=O)[CH2:44][CH2:45][CH2:46][N:47](C(OC(C)(C)C)=O)[CH2:48][CH3:49])CC)=O)(C)(C)C.Cl>CO>[C:41]1([CH2:42][NH:43][CH2:44][CH2:45][CH2:46][NH:47][CH2:48][CH2:49][CH2:8][CH2:9][CH2:10][CH2:11][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][CH2:16][NH:15][CH2:14][C:13]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CCNCCCNCCCCCCCNCCCNCC
Reactant: CCN(CCCN(CCCCCCCN(CCCN(CC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: c1ccc(CNCCCNCCCCCCCCNCCCNCc2ccccc2)cc1
Reaction time: 8 h

Procedure:
N,N'-Bis[3-(ethylamino)propyl]-1,7-heptanediamine Treat 3,7,15,19-tetra(t-butoxycarbonyl)-3,7,15,19-tetraazaheneicosane (1.68 gm, 0.0024 mol) with HCl in methanol (50 ml, 1.0N) and stir overnight. Filter the mixture and recrystallize the title compound from methanol/water (20:80, v/v) to yield 0.5 gm of the title compound. Rf is 0.39 on silica gel plates eluted with 40% ammonia (concentrated) in methanol; mp 322-23° C. with degradation.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][N:8]([C:14]3[C:18](=O)[CH2:17][CH2:16][CH:15]=3)[C:7]=2[CH:20]=1)#[N:2].Cl.[CH3:22][O:23][NH2:24]>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][N:8]([C:14]3[C:18](=[N:24][O:23][CH3:22])[CH2:17][CH2:16][CH:15]=3)[C:7]=2[CH:20]=1)#[N:2]
Reactant: CON
Reactant: CC1(C)CN(C2=CCCC2=O)c2cc(C#N)ccc2O1
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CCC=C1N1CC(C)(C)Oc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
In 3 ml of pyridine was dissolved 0.3 g of 6-cyano-3,4-dihydro-2,2-dimethyl-4-(5-oxo-1-cyclopenten-1-yl)-2H-1,4-benzoxazine followed by addition of 0.26 g of methoxyamine hydrochloride. The mixture was stirred at room temperature overnight and the solvent was then distilled off under reduced pressure. The residue was poured in water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled Off under reduced pressure. Finally the residue was washed with ethanol-ether to give 0.26 g of 6-cyano-3,4-dihydro-4-(5-methoxyimino-1-cyclopenten-1-yl)-2,2-dimethyl-2H-1,4-benzoxazine.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH2:9])=[N:7][OH:8])=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[C:19][CH2:20][CH2:21][C:22](O)=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O1CCOCC1>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:9]=[C:22]([CH2:21][CH2:20][C:19]#[C:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[O:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCC#Cc1ccccn1
Reactant: NC(=NO)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Product: Fc1ccc(-c2noc(CCC#Cc3ccccn3)n2)cc1
Temperature: 100 °C
Yield: 25.1 %

Procedure:
A mixture of commercially available 4-fluoro-N′-hydroxybenzamidine (220 mg, 1.4 mmol), 5-(pyridin-2-yl)pent-4-ynoic acid (330 mg, 1.4 mmol), HOBT (210 mg, 1.4 mmol) and EDCI.HCl (400 mg, 2.1 mmol) in dioxane (4.5mL) was stirred at R.T for 7H, The reaction mixture was then heated at 100° C. for 36 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM. The organic layer was washed with water, 1N NaOH and water. The organic layer was dried over Na2SO4, filtred and evaporated. Purification by flash chromatography (prepacked 10 g silicagel column, DCM/MeOH: 99/1 as eluent) to afford 103 mg of 2-(4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine (Yield: 25%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18](Br)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].C(N(CC)CC)C.[C:33]([C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=1)#[CH:34]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([C:34]#[C:33][C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:42])([F:43])[F:44])=[CH:37][CH:36]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(Br)c2)Cc2ccccc2C1
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(C#Cc3ccc(C(F)(F)F)cc3)c2)Cc2ccccc2C1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
300 mg (0.74 mmol) of the compound of step 1 and 90.1 mg (0.89 mmol) of triethylamine were dissolved in 10 ml of dry toluene. 171.5 mg (148 μmol) of tetrakis(triphenylphosphine)palladium(0) and 14.1 mg (74 μmol) of copper(I) iodide were added, and the mixture was stirred for 30 min. Subsequently 126.2 mg (0.74 mmol) of 1-ethynyl-4-trifluoromethyl-benzene were added and the mixture was heated to 100° C. for 10 h. The mixture was filtered, the solvent was evaporated and the residue was purified by preparative RP HPLC (water/ACN gradient) to give 40 mg of the title compound.
Reaction SMILES: [O:1]([CH2:19][C:20]1([CH2:28][N:29]2[CH:33]=[C:32]([CH2:34][O:35][CH2:36][O:37][CH3:38])[N:31]=[C:30]2[N+:39]([O-:41])=[O:40])[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22][CH2:21]1)[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:26][C:23]1([CH3:27])[O:22][CH2:21][C:20]([CH2:19][OH:1])([CH2:28][N:29]2[CH:33]=[C:32]([CH2:34][O:35][CH2:36][O:37][CH3:38])[N:31]=[C:30]2[N+:39]([O-:41])=[O:40])[CH2:25][O:24]1
Reactant: COCOCc1cn(CC2(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)COC(C)(C)OC2)c([N+](=O)[O-])n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COCOCc1cn(CC2(CO)COC(C)(C)OC2)c([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.3 %

Procedure:
86 mg (0.15 mmol equivalents) of 5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-5-[(4-methoxymethoxymethyl-2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane was dissolved in 1.0 mL of tetrahydrofuran, 0.17 mL (1 mol/L solution, 0.17 mmol equivalents) of a solution of tetrabutylammonium fluoride in tetrahydrofuran was added thereto, and the mixture was stirred at room temperature (25° C.) for 10 minutes. After completion of the reaction, the solvent was removed by distillation, and the obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=1/1) to give 47 mg (0.14 mmol equivalents) of 2,2-dimethyl-5-hydroxymethyl-5-{(4-methoxymethoxymethyl-2-nitro-1H-imidazol-1-yl)methyl}-1,3-dioxane.
Reaction SMILES: [CH:1]1([NH:5][CH2:6][C:7]2[N:8]=[CH:9][C:10]([NH:13]C(=O)OC(C)(C)C)=[N:11][CH:12]=2)[CH2:4][CH2:3][CH2:2]1.FC(F)(F)CO>>[CH:1]1([NH:5][CH2:6][C:7]2[N:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)Nc1cnc(CNC2CCC2)cn1
Solvent: OCC(F)(F)F
Product: Nc1cnc(CNC2CCC2)cn1
Temperature: 150 °C
Yield: 94.3 %

Procedure:
In a 15 mL microwave tube was dissolved tert-butyl 5-((cyclobutylamino)methyl)pyrazin-2-ylcarbamate (330 mg, 1.19 mmol, Eq: 1.00) in 2,2,2-trifluoroethanol (119 mg, 12 ml, 1.19 mmol, Eq: 1.00) and the resulting mixture was heated in seal tube at 150° C. for 3 hrs. The crude reaction mixture was concentrated in vacuo, treated with MeOH and re-concentrated to remove residual trifluoroethanol. The material was azeotroped with toluene to afford 200 mg (95%) of the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.ClC1C=C(C=CC=1)C(OO)=[O:15]>C(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3]1[C:4]([CH3:9])=[N+:5]([O-:15])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ncccc1CCl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1c(CCl)ccc[n+]1[O-]
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3-chloromethyl-2-methylpyridine from Step 2 above (0.50 g; 3.5 mmol) in CHCl3 (40 mL) was added m-chloroperoxybenzoic acid (1.1 g of 55:45 mCPBA:mCBA; 3.5 mmol). After 1.5 h, TLC analysis indicated complete conversion to a lower Rf product. The solution was extracted with equal volumes of saturated aqueous NaHCO3 and water, dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 97:3 CH2Cl2 :MeOH as eluant. 3-Chloromethyl-2-methylpyridine N-oxide was obtained as a solid (TLC: Rf =0.30 (97:3 CH2Cl2 :MeOH); FAB MS m/z 158 (M+ +H)).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].Br[CH2:6][C:7]1[N:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][CH:8]=1>CN(C=O)C.CO.[Pd]>[NH2:1][CH2:6][C:7]1[N:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][CH:8]=1
Reactant: N#Cc1cccc(CBr)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Pd]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1cccc(CN)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.4 %

Procedure:
Sodium azide (0.280 g, 4.32 mmol) was added to a solution of 6-bromomethyl-pyridine-2-carbonitrile (0.610 g, 2.88 mmol) in DMF (12 ml) and the resulting pale yellow solution was stirred at rt for 16 h. Standard basic workup gave the crude product as a tan solid in quantitative yield (0.501 g). The crude solid was dissolved in MeOH (15 ml), treated with 10% Pd/C (0.050 g) and placed under 40 psi H2 on a Parr shaker for 30 minutes (Note: it is imperative that this reduction is stopped at 30 minutes or reduction of the nitrile also occurs). The mixture was filtered through Celite®, the cake was washed with MeOH and the combined filtrate was concentrated under reduced pressure to give a yellow oil. Purification by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 83:15:2, v/v/v) afforded 6-aminomethyl-pyridine-2-carbonitrile (0.178 g, 46%) as a white crystalline solid. 1H NMR (CDCl3) δ 1.96 (br s, 2H), 4.02 (s, 2H), 7.53 (d, 1H, J=9.0 Hz), 7.59 (d, 1H, J=9.0 Hz), 7.80 (t, 1H, J=9.0 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][C@@H:15]([O:14][S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])[CH2:16]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C

Procedure:
A solution of 4-nitrobenzenesulfonyl chloride (4.44 g) in methylene chloride (50 ml) was added to a stirred solution of tert-butyl 3-(R)-hydroxypyrrolidine-1-carboxylate (3.75 g) and pyridine (2.5 ml) in methylene chloride (30 ml) at 10° C. and the mixture allowed to warm to ambient temperature with stirring. The reaction mixture was poured into saturated sodium bicarbonate solution. The organic layer was separated, washed with brine and dried over sodium sulfate. The solution was evaporated under vacuum to give tert-butyl3-(R)-[(4-nitrophenyl)sulfonyloxy]pyrrolidine-1-carboxylate as a yellow crystalline solid. (4.37 g, 59%); 1H NMR Spectrum: (CDCl3) 1.43 (s, 9H), 1.80-2.40 (m, 2H), 3.30-3.65 (m, 4H), 5.20 (hs, 1H), 8.10 (d, 2H), 8.42 (d, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:35])[C:15](=[O:34])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[NH:23][C:24](=[O:33])[C:25]4[C:30]([CH:31]=3)=[C:29]([CH3:32])[CH:28]=[CH:27][CH:26]=4)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[CH3:35][N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:15](=[O:34])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[NH:23][C:24](=[O:33])[C:25]3[C:30]([CH:31]=2)=[C:29]([CH3:32])[CH:28]=[CH:27][CH:26]=3)=[CH:18][CH:17]=1
Reactant: Cc1cccc2c(=O)[nH]c(-c3ccc(C(=O)N(C)C4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2c(=O)[nH]c(-c3ccc(C(=O)N(C)C4CCNCC4)cc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.5 %

Procedure:
To 4-{methyl-[4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzoyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (21 mg, 0.044 mmol) was added 2:1 CH2Cl2/TFA (1 mL) and the reaction mixture stirred at RT for 1 h. The solvent was removed in vacuo, re-dissolved in MeOH and passed through an SCX-2 cartridge (1 g). The column was washed with MeOH (4× column volumes), the desired product eluted from the cartridge with 0.5M NH3/MeOH (4× column volumes) and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC-MS to obtain N-methyl-4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-N-piperidin-4-yl-benzamide as a white solid (2.4 mg, 14%).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=2[O:19][CH3:20])[C:6]2[CH:21]=[CH:22][CH:23]=[CH:24][C:5]=2[N:4]([CH3:25])[C:3]1=[O:26].[CH3:27][C:28]1[CH:29]=[C:30]([N:34]=[C:35]=[O:36])[CH:31]=[CH:32][CH:33]=1>>[CH3:25][N:4]1[C:5]2[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=2[C:7]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=2[O:19][CH3:20])=[N:8][CH:2]([NH:1][C:35]([NH:34][C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([CH3:27])[CH:29]=2)=[O:36])[C:3]1=[O:26]
Reactant: Cc1cccc(N=C=O)c1
Reactant: COc1cc(OC)c(C2=NC(N)C(=O)N(C)c3ccccc32)c(OC)c1
Product: COc1cc(OC)c(C2=NC(NC(=O)Nc3cccc(C)c3)C(=O)N(C)c3ccccc32)c(OC)c1
Yield: 94 %

Procedure:
By condensing 3-amino-1,3-dihydro-1-methyl-5-(2,4,6-trimethoxyphenyl)-1,4-benzodiazepin-2-one with 3-methylphenyl isocyanate, 1,3-dihydro-1-methyl-3-(3-methylphenylureido)-5-(2,4,6-trimethoxyphenyl)-1,4-benzodiazepin-2-one is obtained; m.p.=240° C., Yield=94%.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([C:13]([OH:15])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[CH2:17]([NH2:20])[CH2:18][NH2:19].C(Cl)Cl>CN1CCCC1=O.CO>[NH2:19][CH2:18][CH2:17][NH:20][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([C:13]([OH:15])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: NCCN
Reactant: Cn1cc(C(=O)O)c(=O)c2ccc(Cl)cc21
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: ClCCl
Product: Cn1cc(C(=O)O)c(=O)c2ccc(NCCN)cc21
Temperature: 130 °C
Yield: 30.3 %

Procedure:
To a solution of 7-chloro-1-methyl-4-oxo-1,4-dihydro-3-quinoline carboxylic acid (1.5 g, prepared according to H. Agui and T. Nakagome, J. Heterocycl. Chem., (1979), 16(7), 1353–60) in 1-methyl-2-pyrrolidinone (15 mL), was added ethylenediamine (1.9 g). The mixture was heated at 130° C. for 24 hours. The reaction mixture was cooled and poured into DCM (20 mL). The precipitate obtained was dispersed in MeOH, filtered giving the title compound (500 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[C:9]([O:11]C)=O)[CH:2]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:18][CH2:19][NH:20][CH3:21].[H-].[Na+].COCCOCCOC>O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:18][CH2:19][N:20]([CH3:21])[C:9](=[O:11])/[CH:8]=[CH:7]/[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)/C=C/c1cccnc1
Reactant: CNCCc1ccc(OC)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: COc1ccc(CCN(C)C(=O)/C=C/c2cccnc2)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.6 %

Procedure:
A mixture of methyl trans-3-(3-pyridyl)acrylate (326 mg), 3,4-dimethoxy-N-methylphenethylamine (390 mg), 60% sodium hydride (80 mg) and diethylene glycol dimethyl ether (2 ml) was stirred at room temperature for 24 hours. Water was added to the reaction mixture, extracted with ethyl acetate, washed with water and dried over magnesium sulfate. After the solvent was distilled out under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol=50:1) and recrystallized to yield the titled compound (278 mg, 43%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18]Cl)[CH3:12]>>[CH2:11]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[CH3:1])[CH3:12]
Reactant: Cc1nc2ccccc2[nH]1
Reactant: CCOCCOCCCl
Product: CCOCCOCCn1c(C)nc2ccccc21
Yield: 84 %

Procedure:
1-[2-(2-Ethoxyethoxy)ethyl]-2-methyl-1H-benzimidazole was synthesized as in Synthesis Example 1 except that an equimolar amount of 2-methylbenzimidazole was used instead of benzimidazole and an equimolar amount of 2-chloroethyl 2-ethoxyethyl ether was used instead of 2-chloroethyl methyl ether. Yield 84%.
Reaction SMILES: [O:1]1[C:3]2[CH2:4][CH2:5][CH2:6][C:2]1=2.[F:7][C:8]1[CH:13]=[C:12]([SH:14])[CH:11]=[CH:10][C:9]=1[CH:15]([CH3:20])[C:16]([O:18]C)=[O:17]>ClCCl>[F:7][C:8]1[CH:13]=[C:12]([S:14][C@H:2]2[CH2:6][CH2:5][CH2:4][C@@H:3]2[OH:1])[CH:11]=[CH:10][C:9]=1[CH:15]([CH3:20])[C:16]([OH:18])=[O:17]
Reactant: COC(=O)C(C)c1ccc(S)cc1F
Reactant: C1CC2=C(C1)O2
Solvent: ClCCl
Product: CC(C(=O)O)c1ccc(S[C@H]2CCC[C@@H]2O)cc1F
Temperature: 25 °C
Reaction time: 39 h
Yield: 83.9 %

Procedure:
To an aqueous solution (19 mL) of borax (0.1 g, 0.26 mmol), 1,2-epoxycyclopentene (0.8 mL, 9.3 mmol) and compound (9) (1.60 g, 7.5 mmol) were sequentially added. The mixture was stirred at room temperature for 39 hours and dichloromethane (50 mL) was added thereto. The organic layer was washed with water and dried (over sodium sulfate). The solvent was distilled off, and the residue was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (8:1) solution followed by conventional hydrolysis to give 1.79 g (84%) of compound (16) of interest as yellow oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]([O:20]C)=O)[C:15]([OH:22])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.[Cl-].[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH3+:33])=[C:28]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:27]=1>C(O)C>[O:23]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]([NH:33][CH2:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][C:28]=2[S:34]([CH3:37])(=[O:36])=[O:35])=[O:20])[C:15]([OH:22])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2
Reactant: COC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1O
Reactant: CS(=O)(=O)c1cc(F)ccc1C[NH3+]
Agent: [Cl-]
Solvent: CCO
Product: CS(=O)(=O)c1cc(F)ccc1CNC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a slurry of methyl 5-(1,1-dioxido-1,2-thiazinan-2-yl)-8-hydroxy-1,6-naphthyridine-7-carboxylate (2.11 g, 6.26 mmol) in ethanol (30 mL) in a pressure flask was added 1-[4-fluoro-2-(methylsulfonyl)phenyl]methanaminium chloride followed by N,N,N-diisopropylethylamine (2.17 mL, 12.52 mmol). The pressure flask was purged with nitrogen and closed. The reaction was heated to 80 degrees C. for 16 hours. The reaction containing residual solids was cooled and determined to be incomplete by LCMS analysis. Added degassed DMF (10 mL) to solubilize the remaining solids, resealed the pressure tube and reheated to 80 degrees C. overnight. The reaction was cooled, transferred to a round bottom flask and reduced to a small volume in vacuo. The residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The organic layer was washed with water, dried over Na2SO4, filtered and reduced to a small volume in vacuo. The residue was crystallized via the addition of 5 mL of methanol. The crystals were filtered and dried in vacuo to afford the title compound.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH:11]1[CH2:16][CH2:15][C:14]2([CH2:21][CH:20](O)[C:19]3[CH:23]=[C:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[CH:26][C:18]=3[O:17]2)[CH2:13][CH2:12]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+].CCOC(C)=O>C1(C)C=CC=CC=1>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH:11]1[CH2:16][CH2:15][C:14]2([CH:21]=[CH:20][C:19]3[CH:23]=[C:24]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])[CH:25]=[CH:26][C:18]=3[O:17]2)[CH2:13][CH2:12]1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(O)CC1(CCC(N3CCc4ccccc4C3)CC1)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)Nc1ccc2c(c1)C=CC1(CCC(N3CCc4ccccc4C3)CC1)O2
Temperature: 25 °C

Procedure:
To a stirred suspension of the alcohol from example 2 above (310 mg, 0.7 mmol) in toluene (8 ml )was added p-toluene sulfonic acid (200 mg). This was boiled without a condenser until the reaction mixture was a gum. It was then cooled to r.t., sat. NaHCO3 (1 00 ml ) and EtOAc (1 00 ml ) were added. The biphasic mixture was stirred at r.t until all of the gummy solid dissolved. The layers were separated and the organic phase was dried over Na2SO4 and evaporated under reduced pressure to give 166 mg of a pale yellow oil, 55.8%.1H NMR (CDCl3)δ7.28-6.79 (m, 7H), 6.30 (d, J=1OHz, 1H), 5.55 (d, J=10 Hz, 1H), 3.83 (s, 2H), 2.91 (s, 7H), 2.62-2.48 (m, 1H), 2.20 (d, J=12 Hz, 2H), 2.00-1.82 (m, 4H), 1.45 (dt, J=13 Hz, J=4 Hz, 2H).