Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[C:12]1([CH2:18][CH2:19][CH:20]=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[C:12]1([CH2:18][CH2:19][CH2:20][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]2[CH:11]=[CH:10][N:9]=[CH:8]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCCCCn1ccnc1
Reactant: O=CCCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(CCCNCCCCCn2ccnc2)cc1
Temperature: 5 °C

Procedure:
A mixture of 1-(5-aminopentyl)imidazole (3.48 g), 3-phenylpropionaldehyde (3.08 g), p-toluenesulphonic acid (0.1 g) and toluene (90 ml) was boiled under reflux whilst removing the water formed using a Dean & Stark apparatus under nitrogen for 2 hours. The mixture was evaporated to dryness under reduced pressure to give an oil which was dissolved in IMS (100 ml) and cooled to 5° C. under nitrogen. Sodium borohydride (0.87 g) was added to the solution with stirring. The mixture was allowed to warm to 20° C. and stirred at this temperature for 16 hours. The solvent was removed under reduced pressure. The residue was dissolved in water and acidified to pH 2 with 2M hydrochloric acid. The solution was then basified with 2M sodium hydroxide solution (100 ml) and extracted with ethyl acetate to give an oil. The oil was distilled under high vacuum b.p. 250° C. at 0.04 mbar. The distillate was purified by flash column chromatography on silica using ethyl acetate/methanol/triethylamine (80:10:10) as the mobile phase to give N-(3-phenylpropyl)-5-imidazol-1-ylpentylamine 0.75 hydrate.
Reaction SMILES: [OH:1][CH:2]([CH:6]1[S:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:7]1=[O:19])[C:3]([OH:5])=O.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[NH:28][O:29][C:30](=[O:32])[N:31]=2)=[CH:23][CH:22]=1.IC1C=C(C=CC=1)C(O)=O.FC1(F)CCNCC1>>[OH:1][CH:2]([CH:6]1[S:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:7]1=[O:19])[C:3]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[NH:31][C:30](=[O:32])[O:29][N:28]=2)=[CH:25][CH:26]=1)=[O:5]
Reactant: Cc1ccc(N2CCSC(C(O)C(=O)O)C2=O)cc1
Reactant: Nc1ccc(-c2nc(=O)o[nH]2)cc1
Agent: FC1(F)CCNCC1
Agent: O=C(O)c1cccc(I)c1
Product: Cc1ccc(N2CCSC(C(O)C(=O)Nc3ccc(-c4noc(=O)[nH]4)cc3)C2=O)cc1
Yield: 60.4 %

Procedure:
According to the Step 77-1 in synthetic method for EXAMPLE 77, compound 112-2 (0.55 g) and 3-(4-aminophenyl)-1,2,4-oxadiazol-5(2H)-one (0.52 g) were used instead of 3-iodobenzoic acid and 4,4-difluoropiperidine to obtain compound 112-3 (0.52 g) as a pale yellow amorphous solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[N:15][C:6]2[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:21]([NH:23][CH2:24][CH3:25])=[O:22].[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C>C(#N)CC>[Cl:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:30][CH2:31][N:32]([CH2:2][C:3]2[CH:16]=[N:15][C:6]3[C:7]4[N:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=[O:11])[NH:10][C:5]=3[CH:4]=2)[CH2:33][CH2:34]1)[C:21]([NH:23][CH2:24][CH3:25])=[O:22]
Reactant: O=c1[nH]c2cc(CO)cnc2c2cccn12
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(Cl)c1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)[nH]c(=O)n3cccc43)CC2)c(Cl)c1
Temperature: 95 °C
Reaction time: 6 h
Yield: 66.4 %

Procedure:
To a suspension of 3-(hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (25.00 mg, 0.116 mmol), 3-chloro-N-ethyl-4-(piperazin-1-yl)benzamide (38.9 mg, 0.145 mmol) and (cyanomethyl)trimethylphosphonium iodide (45.2 mg, 0.186 mmol) in Propiononitrile (Volume: 1.0 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.101 mL, 0.581 mmol) at 23° C. The reaction was stirred at 95° C. for 6 hr. The suspension was cooled to 23° C., filtered, rinsed with ACN (3×1 mL) and dried in vacuo to provide 3-chloro-N-ethyl-4-(4-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide (0.0359 g, 0.077 mmol, 66.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.20 Hz, 3 H) 2.53-2.67 (m, 4 H) 2.98-3.14 (m, 4 H) 3.21-3.30 (m, 2 H) 3.65 (s, 2 H) 6.70-6.77 (m, 1 H) 7.08 (dd, J=3.54, 1.52 Hz, 1 H) 7.19 (d, J=8.59 Hz, 1 H) 7.58 (d, J=1.77 Hz, 1 H) 7.68 (dd, J=3.03, 1.52 Hz, 1 H) 7.77 (dd, J=8.34, 2.02 Hz, 1 H) 7.88 (d, J=2.02 Hz, 1 H) 8.37 (d, J=1.77 Hz, 1 H) 8.44 (t, J=5.43 Hz, 1 H) 11.63 (br. s., 1 H). ESI-MS: m/z 465.4 (M+H)+. mp=266.1-271.2° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][C:12](=O)[CH3:13])=[CH:5][CH:4]=1.Cl.[NH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(N(CC)CC)C>CCO>[CH3:13][C:12]1[N:19]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)CN
Reactant: CC(=O)CCC(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)Cn1c(C)ccc1-c1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Yield: 45.9 %

Procedure:
In a round bottomed flask, charged with 1-(4-(trifluoromethyl)phenyl)pentane-1,4-dione (3.18 g, 13.02 mmol) in EtOH (Ratio: 2, Volume: 13 mL) and ethyl 2-aminoacetate hydrochloride (1.818 g, 13.02 mmol) was added ethyl 2-aminoacetate hydrochloride (1.818 g, 13.02 mmol) and triethylamine (10.53 mL, 76 mmol). The reaction mixture was heated at 70° C. for 15.5 h (˜50% of SM remained by TLC and LCMS). The reaction was then concentrated and the residue was treated with water and extracted with DCM (3×). The organic layer was dried with MgSO4. The crude product was added to a 120 g ISCO silica gel column and was purified with a gradient of 0% to 50% EtOAc/hexanes. The product was obtained as a light yellow oil (1.8 g, 5.98 mmol, 45.9% yield). 1H NMR (CDCl3/400 MHz) δ (ppm) 7.62 (d, 2H), 7.42 (d, 2H), 6.23 (d, 1H), 6.05-6.02 (m, 1H), 4.55 (s, 2H), 4.25 (q, 2H), 2.24 (s, 3H), 1.28 (t, 3H). MS m/z: 312.22 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[CH:11][N:10]=1)[CH3:8].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[N:1]1([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[CH:11][N:10]=2)[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CC(Br)c1ccc(-c2ccc([N+](=O)[O-])cc2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(c1ccc(-c2ccc([N+](=O)[O-])cc2)cn1)n1ccnc1
Temperature: 50 °C

Procedure:
To a stirred solution of 1H-imidazole (13 mg, 0.19 mmol) in DMF (2 mL) was added 2-(1-bromoethyl)-5-(4-nitrophenyl)pyridine (50 mg, 0.1 mmol) and K2CO3. The reaction was heated at 50° C. for about 1 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution (10 mL), organic layer was dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 100-200μ) using 2% methanol in DCM eluent to afford 2-(1-(1H-imidazol-1-yl)ethyl)-5-(4-nitrophenyl)pyridine as off white solid (50 mg, 58% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.97 (s, 1H), 8.31 (d, 2H), 8.22 (dd, 1H), 8.01 (d, 2H), 7.82 (s, 1H), 7.30 (t, 2H), 6.91 (s, 1H), 5.71-5.65 (m, 1H), 1.84 (d, 3H), LC-MS m/z calcd for [M+H]+ 295.11. found 295.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[Br:18]P(Br)Br>C(OCC)C>[Br:18][CH2:10][C:9]#[C:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCC#Cc1cccc(F)c1
Solvent: c1ccncc1
Solvent: CCOCC
Product: Fc1cccc(C#CCBr)c1
Temperature: -2.5 °C
Reaction time: 3 h
Yield: 126 %

Procedure:
3-(3-Fluoro-phenyl)-prop-2-yn-1-ol (0.750 g, 0.005 mol) was taken in diethyl ether (10 ml) containing catalytic amount of pyridine (0.05 ml). The reaction mixture was then cooled to −5-0° C. Tribromo phosphine (0.26 ml, 0.003 mol) was added slowly at −5-0° C. and stirred at the same temperature for 3 hrs. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over Na2SO4, and evaporated under vacuum to get 1-(3-bromo-prop-1-ynyl)-3-fluoro benzene (0.805 gm, 76%).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([OH:22])=[O:21].[K].I([O-])(=O)(=O)=[O:26].[Na+].Cl>O.ClCCl>[CH3:1][C:2]1([CH3:23])[S:6](=[O:26])[C@@H:5]2[C@H:7]([NH:10][C:11]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([OH:22])=[O:21]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: Cl
Agent: [K]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC1(C)[C@H](C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2S1=O
Reaction time: 3 h

Procedure:
Penicillin G, potassium salt (349.9 g) was dissolved in 3 liters of water. Sodium periodate (194 g) was added and the mixture was stirred for three hours. Dichloromethane (500 ml) was added and the pH of the water layer was adjusted to 2.3 with 6 N hydrochloric acid with vigorous stirring. The aqueous layer was separated and extracted with four 400 ml portions of dichloromethane. The combined extract was washed with aqueous sodium bisulfite to remove any iodine color, dried over sodium sulfate, filtered, and evaporated. The solid residue was empasted with 400 ml of ethyl acetate and allowed to stand at 0° C. overnight. The solid was isolated by filtration and dried in vacuo to afford 322 g of penicillin G sulfoxide.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH:23]([C:26]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([CH3:35])[CH3:34])[C:27]=1[NH2:28])([CH3:25])[CH3:24].[Br:36][CH2:37][C:38](O)=[O:39]>CN(C)C=O>[Br:36][CH2:37][C:38]([NH:28][C:27]1[C:26]([CH:23]([CH3:25])[CH3:24])=[CH:32][CH:31]=[CH:30][C:29]=1[CH:33]([CH3:35])[CH3:34])=[O:39]
Reactant: O=C(O)CBr
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.3 %

Procedure:
1-(3′-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC) (2.1 g, 11 mmols) and 1-hydroxybenzotriazole (HOBt) (1.49 g, 11 mmols) were added to an N,N-dimethylformamide (DMF) (30 ml) solution of 2,6-diisopropylaniline (1.97 g, 10 mmols) and bromoacetic acid (2.08 g, 15 mmols), and stirred at room temperature for 12 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through silica gel column chromatography (developer: hexane/acetone=5/1), and the resulting crystals were recrystallized from ether-hexane to obtain 1.26 g (42%) of 2-bromo-N-(2,6-diisopropylphenyl)acetamide as colorless needle-like crystals.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:27])[CH2:15][CH2:16][CH2:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.C(N(CC)CC)C.[C:52]1([CH2:58][CH2:59][CH2:60][CH2:61][CH:62]=[O:63])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>C(Cl)Cl>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:27])[CH:15]([CH2:16][CH2:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:62]([OH:63])[CH2:61][CH2:60][CH2:59][CH2:58][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCCCc1ccccc1
Reactant: O=C(CCCS(=O)(=O)c1ccccc1)N1C(=O)OCC1Cc1ccccc1
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OCC(Cc2ccccc2)N1C(=O)C(CCS(=O)(=O)c1ccccc1)C(O)CCCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 141 %

Procedure:
A solution containing (-)-4-benzyl-3-(4-phenylsulfonylbutanoyl)oxazolidin-2-one (2 g, 5.16 mmol) in anhydrous CH2Cl2 (20 mL) is cooled to 0° C. Di-n-butylboron triflate (1 M in CH2Cl2, 6 mL, 6.03 mmol) is added by syringe over 15 minutes followed by the addition of triethylamine (0.68 g, 6.76 mmol). The clear yellow solution is then cooled to -78° C. Freshly distilled 5-phenylpentanal (0.92 g, 5.72 mmol) in anhydrous CH2Cl2 (2 mL) is added dropwise to the reaction mixture. After 30 min, the reaction mixture is warmed to 0° C. and maintained at this temperature for 1 hour. The reaction mixture is quenched by the slow addition of 3:1 MeOH/pH 7 phosphate buffer (30 mL) followed by 2:1 MeOH/30% H2O2 (30 mL) being careful to keep the temperature below 5° C. After the addition is complete, the reaction is maintained an additional hour at 0° C. then concentrated to half-volume in vacuo. The mixture is then diluted with diethyl ether (100 mL) and water (100 mL) and the layers are separated. The organic phase is washed with 5% NaHCO3 (3×50 mL), aqueous NaHSO3 (3×50 mL), water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product is combined with the crude material obtained from four additional reactions performed on identical scale and purified by silica gel chromatography (CH2Cl2 /diethyl ether, 19:1→9:1) to provide 4 g (35%) of (-)-4-benzyl-3-[3-hydroxy-7-phenyl-2-(2-phenylsulfonylethyl)-heptanoyl]-oxazolidin-2-one as a colorless, viscous oil which is homogeneous by TLC analysis [CH2Cl2 /diethyl ether, 19:1, Rf (oxazolidinone)=0.45, Rf (aldol product)=0.40]. [α]23D -20° (c 7.5, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.42-1.58 (m, 6H), 2.06 (m, 1H), 2.20 (m, 1H), 2.24 (d, J=4 Hz, 1H), 2.58 (t, J=7.5 Hz, 2H), 2.69 (dd, J=13.3, 9.9 Hz, 1H), 3.24 (m, 3H), 3.86 (m, 1H), 3.98 (quint. J=4.2 Hz, 1H), 4.16 (m, 2H), 4.65 (m, 1H), 7.18-7.52 (m, 10H), 7.59 (m, 2H), 7.68 (m, 1H), 7.90 (m, 2H) ppm. Mass spectrum (FAB) m/z 550 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.C(N(CC)CC)C.[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[S:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:13])([CH3:14])[C:6]=2[CH:15]=1)(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: CN1C(=O)OC(C)(C)c2cc(N)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)OC(C)(C)c2cc(NS(=O)(=O)c3cccc(Cl)c3Cl)ccc21
Reaction time: 0.17 h
Yield: 4.9 %

Procedure:
To a stirred solution of 6-amino-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (0.15 g, 0.73 mmol) in methylene chloride (5 mL) at 0° C. was added triethylamine (0.15 mL, 1.07 mmol). After 10 minutes, 2,3-dichlorobenzenesulfonyl chloride (0.27 g, 1.10 mmol) was added. The solution was stirred for 5 hours, then partitioned between ammonium chloride solution (sat.) and methylene chloride. The organic layer was dried over magnesium sulfate and concentrated. Flash silica gel column separation with 30% ethyl acetate/hexane followed by trituration with ether gave 2,3-dichloro-N-(1,4,4-trimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)benzenesulfonamide as an off-white solid (0.015 g, 5%). 1H NMR (DMSO-d6): δ 10.17 (s, 1H), 8.02 (dd, J=7.9, 1.4 Hz, 1H), 7.93 (dd, J=8.1, 1.4 Hz, 1H), 7.56 (t, J=8.0 Hz, 1H), 7.03 (m, 3H), 3.20 (s, 3H), 1.48 (s, 6H). MS (ESI) m/z 415/417/419 ([M+H]+); MS (ESI) m/z 413/415/417 ([M−H]−).
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]#[N:22])=[CH:11][CH:10]=2)[C:6](=[O:23])[N:5]([CH2:24][CH2:25][CH3:26])[C:4](=[O:27])[CH:3]=1.[CH2:28]([SH:31])[CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:7]2[C:2]([S:31][CH2:28][CH2:29][CH3:30])=[CH:3][C:4](=[O:27])[N:5]([CH2:24][CH2:25][CH3:26])[C:6]2=[O:23])=[CH:10][CH:11]=1)#[N:22]
Reactant: CCCS
Reactant: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3C#N)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCSc1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A mixture of 6-chloro-1-(2'-cyanobiphenyl-4-yl)methyl-3-propylpyrimidine-2,4(1H,3H)-dione (0.7 g), propylmercaptan (0.2 ml) and potassium carbonate (0.51 g) in acetonitrile (12 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness and then the residue was extracted with methylene chloride-water. The organic layer was washed with water, dried, and evaporated to dryness to give colorless syrups (0.77 g, 100%).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:16]=[CH:15][S:14][N:13]=1)SC)#[N:2].[NH2:17][CH2:18][CH2:19]SCC1C=CSN=1.C(N)C>>[C:1]([NH:3][C:4]([NH:17][CH2:18][CH3:19])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:16]=[CH:15][S:14][N:13]=1)#[N:2]
Reactant: NCCSCc1ccsn1
Reactant: CSC(=NCCSCc1ccsn1)NC#N
Agent: CCN
Product: CCNC(=NCCSCc1ccsn1)NC#N

Procedure:
Reacting N-cyano-N'-[2-(3-isothiazolylmethylthio)ethyl]-S-methylisothiourea, prepared from 3-[(2-aminoethyl)thiomethyl]isothiazole by the procedure of EXample 3(c) (i), with ethylamine by the procedure of Example 4 gives N-cyano-N'-ethyl-N"-[2-(3-isothiazolylmethylthio)ethyl]guanidine.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([C:13](=[O:14])[CH2:12][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([NH2:10])=[O:9])[CH:20]=[CH:19][CH:18]=1
Reactant: NC(=O)c1ccccc1O
Reactant: COc1cccc(C(=O)CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(C(=O)COc2ccccc2C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
To a suspension of 5 g (36.5 mmol) of salicylamide in 60 mL of N,N-dimethylformamide, 8.36 g (36.5 mmol) of 2-bromo-1-(3-methoxy-phenyl)-ethanone and 7.57 g (54.7 mmol) of potassium carbonate were added. The mixture was stirred at room temperature overnight. Water was added under stirring and the precipitate was filtered, washed with water and dried in vacuo to yield 9 g of the title compound (90%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[CH3:10]N(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+].IC>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:10])=[C:4]([Cl:9])[CH:3]=1
Reactant: CN(C)C=O
Reactant: Oc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Product: COc1ccc(Br)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-2-chlorophenol (7.0 g, 33.0 mmol, 1 eq), N,N-dimethylformamide (50 mL) and cesium carbonate (8.5 g, 42.0 mmol, 1.2 eq) was stirred at room temperature then iodomethane (2.5 mL, 1.2 eq) was added. The mixture was heated to 50° C. overnight, cooled to room temperature and treated with water (500 mL). The reaction was extracted with dichloromethane, dried (sodium sulfate) and concentrated in vacuo. The crude was purified by flash chromatography eluting with cyclohexane. 7.5 g of clean product in a quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:11])[C:5]([C:9]#[N:10])=[C:6](Cl)[N:7]=1.C([Sn](CCCC)(CCCC)[C:17]1[O:18][CH2:19][CH2:20][CH:21]=1)CCC>O1CCOCC1.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>[NH2:1][C:2]1[NH:3][C:4](=[O:11])[C:5]([C:9]#[N:10])=[C:6]([C:17]2[O:18][CH2:19][CH2:20][CH:21]=2)[N:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCO1
Reactant: N#Cc1c(Cl)nc(N)[nH]c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: N#Cc1c(C2=CCCO2)nc(N)[nH]c1=O
Temperature: 100 °C
Yield: 27.2 %

Procedure:
To a stirred solution of 200 mg (1.17 mmol) 2-amino-4-chloro-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile in 10 ml dioxane under argon at room temperature were added 463 mg (1.29 mmol) tributyl-(4,5-dihydro-furan-2-yl)-stannane and 82 mg (0.12 mmol) bis(triphenylphosphine)palladium(II) chloride. The reaction mixture was heated at 100° C. for 16 h, then cooled to room temperature and concentrated in vacuo. Flash chromatography (ethyl acetate/hexane 1/1 then ethyl acetate then 5/95 methanol/ethyl acetate) afforded 65 mg (27%) 2-amino-4-(4,5-dihydro-furan-2-yl)-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile as a light yellow crystalline solid. ES-MS m/e (%): 205 (M+H+, 100).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1)([CH2:18][CH:19]=[CH2:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>O1CCCC1>[Cl:28][C:23]1[CH:22]=[C:21]([C:12]([NH:11][CH:1]=[O:2])([CH2:18][CH:19]=[CH2:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:26]=[CH:25][C:24]=1[Cl:27]
Reactant: C=CCC(N)(C(=O)OCC)c1ccc(Cl)c(Cl)c1
Reactant: O=CO
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: C=CCC(NC=O)(C(=O)OCC)c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Under cooling on ice, formic acid (140 mL) was added to acetic anhydride (255 mL), followed by stirring at 50° C. for 30 minutes. The reaction mixture was cooled with ice. Subsequently, ethyl 2-amino-2-(3,4-dichlorophenyl)-4-pentenoate (298 g) in tetrahydrofuran (1.5 L) was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was neutaralized with saturated aqueous sodium bicarbonate. The resultant mixture was subjected to extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate anhydrate. The solvent was removed under reduced pressure, to thereby give the title compound (334 g). The title compound was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]1([CH2:22][CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH:21]=[CH:20][N:19]=[CH:18]1>>[N:17]1([CH2:22][CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:8]=4)[NH:12][C:11]3=[O:16])[NH:30][C:29]=2[CH3:36])=[O:27])[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCCn1ccnc1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(-c4ccccc4)cc32)c(C)c1C(=O)NCCCn1ccnc1
Yield: 58.9 %

Procedure:
5-Phenyl-1,3-dihydroindol-2-one (8 mg, 0.04 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-imidazol-1-ylpropyl)amide (10 mg) to give 10 mg (59%) of the title compound as an orange solid.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:5])[CH3:4].[H-].[Na+].Br[CH2:9][C:10]1[N:15]=[C:14]([C:16]#[N:17])[C:13]([CH3:18])=[CH:12][CH:11]=1.O>C1COCC1>[C:16]([C:14]1[N:15]=[C:10]([CH2:9][N:2]([CH3:1])[C:3](=[O:5])[CH3:4])[CH:11]=[CH:12][C:13]=1[CH3:18])#[N:17]
Reactant: Cc1ccc(CBr)nc1C#N
Reactant: CNC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N(C)Cc1ccc(C)c(C#N)n1
Reaction time: 0.25 h
Yield: 69 %

Procedure:
A solution of N-methylacetamide (416 mg, 5.69 mmol) in THF (15 mL) at room temperature was treated with NaH (228 mg, 5.69 mmol), stirred for 15 min, treated with 6-bromomethyl-3-methylpyridine-2-carbonitrile (1.0 g, 4.74 mmol), stirred for 16 h, poured into water (50 mL), extracted with EtOAc (3×15 mL) and the combined organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (665 mg, 69%) as a yellow oil; NMR δH (400 MHz, CDCl3) 2.15 (3H, s), 2.53 (3H, s), 3.09 (3H, s), 4.65 (2H, s), 7.43 (1H, d, J 8.0 Hz) and 7.61 (1H, d, J 8.0 Hz); M/Z 204 (M+H)+