Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[CH3:30][O:31][C:32](=[O:37])[CH2:33][CH2:34][CH2:35][NH2:36].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[CH3:30][O:31][C:32](=[O:37])[CH2:33][CH2:34][CH2:35][NH:36][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:28])=[CH:20][CH:21]=1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Reactant: COC(=O)CCCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: COC(=O)CCCNC(=O)c1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccccc2C)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with methyl-4-aminobutyrate hydrochloride using BOP reagent in tetrahydrofuran to give the title compound as a colorless foam, MS (ESI+): m/z=475.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[NH2:10].O.O.[C:13](O)(=[O:17])[C:14](O)=[O:15]>Cl>[CH3:8][C:7]1[CH:6]=[C:5]([CH3:9])[CH:4]=[C:3]2[C:2]=1[NH:1][C:13](=[O:17])[C:14](=[O:15])[NH:10]2
Reactant: O=C(O)C(=O)O
Reactant: Cc1cc(C)c(N)c(N)c1
Agent: Cl
Solvent: O
Product: Cc1cc(C)c2[nH]c(=O)c(=O)[nH]c2c1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
A mixture of 1,2-diamino-4,6-dimethylbenzene (424 mg, 3.11 mmole) and oxalic acid dihydrate (432 mg, 3.43 mmole, used as received) in 4N HCl (20 mL) was refluxed at 120°-5° C. for 3 h, then cooled to room temperature. The mixture was centrifuged and the supernatant was removed. The yellow solid was washed with cold water (2×2 mL), collected by filtration, and dried in vacuo for 2 h, affording 516 mg of crude 5,7-dimethyl-1,4-dihydro-2,3-quinoxalinedione (87%) as a yellow powder. The crude product was taken up in 1N NaOH (10 mL) and filtered. The filtrate was acidified to pH=3, affording the pure title compound (490 mg) as a light yellow powder; mp: 345°-347° C. (dec); IR (KBr, cm-1): 3460, 3190, 2986, 1716, 1709, 1630. 1H NMR (DMSO-d6): δ11.858 (s, 1H), 11.173 (s, 1H), 6.766 (s, 1H), 6.745 (s, 1H), 2.280 (s, 3), 2.211 (s, 3). HRMS: calcd for C10H10N2O2 (M+) m/z: 190.0714; found: 190.0744.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:11]([F:14])([F:13])[F:12])=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].[CH:15](I)([CH3:17])[CH3:16]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:11]([F:13])([F:14])[F:12])=[N:8][N:9]([CH:15]([CH3:17])[CH3:16])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CC(C)I
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Product: CCOC(=O)c1cn(C(C)C)nc1C(F)(F)F

Procedure:
Prepared according to Preparation 45 using 3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (Preparation 112) and isopropyl iodide. Taken directly on to the next step.
Reaction SMILES: [I:1][N:2]([C:7]([O:9][CH2:10][C:11]#[CH:12])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[I:13][CH:14](O)[C:15]#[CH:16].Cl.CN(CCCN=C=NCC)C>C(Cl)Cl.O1CCOCC1.CN(C)C1C=CN=CC=1>[I:13][CH:14]([O:5][C:4](=[O:6])[CH2:3][N:2]([C:7]([O:9][CH2:10][C:11]#[CH:12])=[O:8])[I:1])[C:15]#[CH:16]
Reactant: C#CCOC(=O)N(I)CC(=O)O
Reactant: C#CC(O)I
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C#CCOC(=O)N(I)CC(=O)OC(I)C#C
Temperature: 0 °C
Reaction time: 17 h

Procedure:
N-Iodopropargyloxycarbonyl glycine (compound 1, 4.96 g., 17.52 mmole) was dissolved in a mixture of methylene chloride and 1,4-dioxane (450 ml., 20 ml. respectively) and cooled to 0° C. with an ice bath. Iodopropargyl alcohol (3.51 g., 19.29 mmole) was added, followed by 4-dimethylaminopyridine (0.22 g., 1.80 mmole) and N-(dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (4.17 g., 21.75 mmole). The reaction mixture was stirred at 4° C. for 17 hours. Upon warming to room temperature, the reaction mixture was diluted with methylene chloride, washed with water, 10% aqueous potassium hydrogen sulfate, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford N-iodopropargyloxycarbonyl glycine iodopropargyl ester (compound 4) as a white crystalline solid (8.26 g.). m.p. 86°-88° C.; 1H-NMR (200 MHz, CDCl3) δppm =4.05, d, J=5.6 Hz., 2H (NH--CH2 --), 4.89, d, J=10.2 Hz., 4H (C--CH2 --O), 5.32, m, 1H (--NH--).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:41])[CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:31][C:30]=1[Cl:42].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:41])[CH2:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[CH:31][C:30]=1[Cl:42]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(C)(C)CC(=O)c1ccc(CN)c(Cl)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)CC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)c(Cl)c1
Yield: 21 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (300 mg, 0.71 mmol) with 1-(4-aminomethyl-3-chloro-phenyl)-3,3-dimethyl-butan-1-one (338 mg, 1.41 mmol) by using tris(dibenzylideneacetone)dipalladium(0) (130 mg, 9.142 mmol), BINAP (177 mg, 0.284 mmol) and cesium carbonate (324 mg, 0.994 mmol) in anhydrous toluene (31 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (92:8) followed by reverse phase HPLC [Hichrom Kromasil C18, 5 □M 21.2×100 mm, eluting with water/acetonitrile (0.05% TFA in each) (1:4 to 1:19 gradient over 5 min), flow rate 25 mL/min, UV detector (230 nm)] to give 7-chloro-6-[2-chloro-4-(3,3-dimethyl-butyryl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (77 mg, 21%). MS (ES+) m/z: 516 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.Cl.[CH2:32]([NH2:34])[CH3:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:32]([NH:34][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:14][CH2:15]2)=[N:20][CH:21]=1)[CH3:33]
Reactant: CCN
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.6 %

Procedure:
(S)-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinic acid (87 mg, 0.213 mmol) and ethanamine hydrochloride (17.4 mg, 0.213 mmol) were suspended in DMF (1.065 mL) and treated with DIPEA (0.186 mL, 1.065 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (162 mg, 0.426 mmol). The reaction mixture was stirred at room temperature for 3 h and purified using HPLC (10-95% acetonitrile in water, NH4HCO3 buffered) to afford (S)—N-ethyl-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinamide (26.4 mg, 0.061 mmol, 28.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.09 (t, J=7.20 Hz, 3H) 1.82-2.02 (m, 3H) 2.18 (d, J=2.27 Hz, 1H) 2.41 (t, J=4.80 Hz, 5H) 3.20-3.29 (m, 2H) 3.34-3.44 (m, 3H) 3.51-3.63 (m, 5H) 3.95-4.03 (m, 1H) 6.82 (d, J=9.09 Hz, 1H) 6.99 (d, J=1.77 Hz, 1H) 7.61 (d, J=1.77 Hz, 1H) 7.93 (dd, J=9.09, 2.53 Hz, 1H) 8.23 (t, J=5.31 Hz, 1H) 8.57 (d, J=2.27 Hz, 1H) 10.44 (s, 1H); [M+H] calc'd for C23H29N7O2, 422. found, 422.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH2:5][CH2:4][O:3]1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[OH:3][CH2:4][CH2:5][CH:6]([N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[C:2]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:1]
Reactant: C1COCCN1
Reactant: O=C1OCCC1N1CCCC1=O
Product: O=C(C(CCO)N1CCCC1=O)N1CCOCC1
Temperature: 110 °C
Yield: 81.9 %

Procedure:
5.07 g (0,03 mol) of 1-(tetrahydro-2-oxo-3-furyl)-2-pyrrolidinone are mixed with 10.45 g (0.12 mol) of morpholine and the reaction mixture is heated at 110° C. for 5 hours. Upon cooling, the product crystallizes. The product is filtered and recrystallized from diethyl ether. 6.3 g (yield: 82% of theory) of 4-[4-hydroxy-2-(2-oxo-1-pyrrolidinyl)butyryl]-morpholine are obtained. M.P.: 105°-106° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[CH3:13][N:14]1[C:18]([CH3:19])=[C:17]([CH:20]=O)[CH:16]=[N:15]1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:13][N:14]1[C:18]([CH3:19])=[C:17]([CH:20]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)[CH:16]=[N:15]1
Reactant: Cc1c(C=O)cnn1C
Reactant: O=C(O)CNC(=O)c1cccs1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cc1c(C=C2N=C(c3cccs3)OC2=O)cnn1C
Temperature: 90 °C
Yield: 42.7 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 1,5-dimethyl-1H-pyrazol-4-carboxaldehyde (41 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 35 mg of the above-captioned compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:13][C:12]=2[CH:11]=[C:10]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:9]=1.[CH3:35][NH2:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][NH:36][CH3:35])[CH2:13][C:12]=2[CH:11]=[C:10]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:9]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(-c4ccccc4)cc(-c4ccccc4Cl)c3O2)cc1
Product: CNCC1Cc2cc(-c3ccccc3)cc(-c3ccccc3Cl)c2O1

Procedure:
The title compound was prepared (0.066 g, 84%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2-chlorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.10 g, 0.20 mmol) and methylamine (0.30 g, 9.8 mmol). 192-194 mp ° C.
Reaction SMILES: [I-].[C:2]1([CH:8]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[O:9][C:10]([C:12]2[N:17]3[C:18](=[O:29])[C@@H:19]([NH:20][C:21](=[O:28])[CH2:22][C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[C@H:16]3[S:15][CH2:14][C:13]=2[CH:30]=[C:31]2C=CC=CC2[PH+](C2C=CC=CC=2)C2C=CC=CC=2)=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].C=O>C(Cl)Cl>[S:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[CH2:22][C:21]([NH:20][C@@H:19]1[C:18](=[O:29])[N:17]2[C:12]([C:10]([O:9][CH:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)=[O:11])=[C:13]([CH:30]=[CH2:31])[CH2:14][S:15][C@H:16]12)=[O:28]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=C3C=CC=CC3[PH+](c3ccccc3)c3ccccc3)CS[C@H]12
Agent: C=O
Agent: O=C([O-])O
Agent: [I-]
Solvent: ClCCl
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
A solution of [4-diphenylmethoxycarbonyl-7β-(2-thienylacetamido)ceph-3-em-3-ylmethyly] triphenylphosphonium iodide (430 mg.), RF 0.0, in methylene chloride (10 ml.) was shaken with 5%-sodium bicarbonate solution (10 ml.) for five minutes. The separated organic layer was treated with 40%-formaldehyde solution (2 ml.) and 5% aqueous sodium bicarbonate solution (5 ml.) and the mixture stirred vigorously at room temperature until the chromophore of the starting material at 388 nm. had disappeared (ca. 30 minutes). The organic layer was separated and washed with 0.5N-hydrochloric acid and water, then dried and evaporated in vacuo. The residue was crystallised from methanol to give diphenylmethyl 7β-(2-thienylacetamido)-3-vinylceph-3-em-4-carboxylate (90 mg. 36%), RF 0.5, as needles, λmax. 296 nm. (ε 13,200), identified by infrared spectroscopy with material described previously.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:6]=1[CH3:16])=O.[NH2:17][C:18]([NH2:20])=[S:19]>CCO>[CH3:16][C:6]1[CH:7]=[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:17]=[C:18]([NH2:20])[S:19][CH:2]=1
Reactant: NC(N)=S
Reactant: Cc1cc(S(C)(=O)=O)cc(C)c1C(=O)CBr
Solvent: CCO
Product: Cc1cc(S(C)(=O)=O)cc(C)c1-c1csc(N)n1
Yield: 46.6 %

Procedure:
A mixture of 2-bromo-1-(2,6-dimethyl-4-(methylsulfonyl)phenyl)ethanone (7.60 g, 24.9 mmol) and thiourea (1.90 g, 25.0 mmol) in 95% EtOH (35.6 mL) was heated at reflux for 90 min. The solution was concentrated and mixed with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (20 mL). The solids were filtered and dried under vacuum to give 4-(2,6-dimethyl-4-(methylsulfonyl)phenyl)thiazol-2-amine (3.28 g) as yellow solids in 47% yield: 1H NMR (500 MHz, CDCl3) δ 7.64 (s, 2 H), 6.34 (s, 1 H), 5.19 (m, 1 H), 3.04 (s, 3 H), 2.26 (s, 6 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1N.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:20].[K+]>O>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[I:20]
Reactant: Cc1cc(N)c(F)cc1C
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Cc1cc(F)c(I)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a stirred suspension of 50.8 mmol 2-fluoro-4,5-dimethyl-phenylamine (commercial, CAS: 117832-17-4) in 70 ml water was added dropwise at 0° C. a solution of 5 ml concentrated sulfuric acid in 15 ml water. A solution of 66.0 mmol sodium nitrite in 15 ml water was then added dropwise and stirring continued at 0° C. for 60 min. A solution of 173 mmol potassium iodide in 50 ml water was then added dropwise over 30 min while maintaining the reaction temperature between 0 and 5° C. The reaction mixture was then warmed to room temperature and stirred for 3 h before being quenched with aqueous sodium thiosulphite solution and diluted with ethyl acetate. The phases were separated and the organic phase was washed with water and then dried over sodium sulfate and concentrated in vacuo to yield the title compound as a brown solid (69% yield). MS (m/e): 251 ([M+H]+, 100%).
Reaction SMILES: [CH3:1][N:2]([C:10](=[O:20])[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].O1CCCC1>[C].[Pd].C(O)C>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:20])=[CH:16][CH:15]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 112 %

Procedure:
A mixture of ethyl 3-[methyl(4-nitrobenzoyl)amino]propanoate (26.6 g) synthesized above, 5% palladium-carbon (8.9 g), tetrahydrofuran (150 mL) and ethanol (150 mL) was stirred at room temperature overnight under a hydrogen atmosphere. 5% palladium-carbon was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title compound (26.6 g, 90%) as an oil.
Reaction SMILES: [CH3:1][CH:2](C)[C:3](NC1C=CC(C2CCNCC2)=CC=1)=[O:4].[NH2:19][C:20]1[CH:21]=[C:22]([CH:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.C(Cl)(=O)CC>>[NH:29]1[CH2:28][CH2:27][CH:26]([C:22]2[CH:21]=[C:20]([NH:19][C:3](=[O:4])[CH2:2][CH3:1])[CH:25]=[CH:24][CH:23]=2)[CH2:31][CH2:30]1
Reactant: CC(C)C(=O)Nc1ccc(C2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Agent: CCC(=O)Cl
Product: CCC(=O)Nc1cccc(C2CCNCC2)c1

Procedure:
Prepared by the procedure for 2-methyl-N-[4-(4-piperidinyl)phenyl]propanamide using tert-butyl 4-(3-aminophenyl)-1-piperidinecarboxylate and propanoyl chloride: Anal. Calcd for C14H20N2O: C, 72.2; H, 8.63; N, 12.1. found: C, 72.4; H, 8.68; N, 12.1; ESMS m/e: 233.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]2[C:12]([C:13]3[CH:25]=[CH:24][O:23][C:14]=3[CH2:15][O:16]2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>O1CCOCC1.C(O)(=O)C.[Pd]>[C:29]([O:28][C:26]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]2[C:12]([C@H:13]3[CH2:25][CH2:24][O:23][C@H:14]3[CH2:15][O:16]2)=[CH:11][CH:10]=1)=[O:27])([CH3:31])([CH3:32])[CH3:30]
Reactant: [H][H]
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2c1OCc1occc1-2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2c1OC[C@@H]1OCC[C@H]21
Yield: 99.1 %

Procedure:
A solution of methyl 7-[bis-(tert-butoxycarbonyl)amino]-4H-furo[2,3-c]-chromene-6-carboxylate (Intermediate 3, 0.15 g) in a mixture of dioxane (15 mL) and acetic acid (1.5 mL) was treated under an atmosphere of nitrogen with palladium on carbon (10%, 0.02 g). The mixture was stirred and the nitrogen was replaced by hydrogen then the mixture was stirred under an atmosphere of hydrogen for 3 hours. The mixture was filtered through Celite, the pad was washed thoroughly with dioxane and the filtrate was evaporated to dryness to give methyl cis-(3aRS,9bRS)-7-[bis-(tert-butoxycarbonyl)amino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylate (0.15 g) as a gum.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[C:8](=[O:14])[NH:9][C:10](=S)[NH:11][CH:12]=2)=[CH:4][CH:3]=1.CC1C=CC(CC2C(=O)NC(SC)=NC=2)=CC=1.N1C=CC=NC1=O.[CH3:41][C:42]1[NH:46][CH:45]=[N:44][C:43]=1[CH2:47][S:48][CH2:49][CH2:50][NH2:51].[ClH:52]>>[ClH:52].[ClH:52].[CH3:41][C:42]1[NH:46][CH:45]=[N:44][C:43]=1[CH2:47][S:48][CH2:49][CH2:50][NH:51][C:10]1[NH:9][C:8](=[O:14])[C:7]([CH2:6][C:5]2[CH:15]=[CH:16][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:12][N:11]=1
Reactant: Cc1ccc(Cc2c[nH]c(=S)[nH]c2=O)cc1
Reactant: Cc1[nH]cnc1CSCCN
Agent: CSc1ncc(Cc2ccc(C)cc2)c(=O)[nH]1
Agent: Cl
Agent: O=c1nccc[nH]1
Product: Cc1ccc(Cc2cnc(NCCSCc3nc[nH]c3C)[nH]c2=O)cc1

Procedure:
5-(4-Methylbenzyl)-2-thiouracil (4.65 g) was converted into 5-(4-methylbenzyl)-2-methylthio-4-pyrimidone (m.p. 208.5°-211° ex methanol/ethanol) by the method described in Example 1(i). Reaction of this pyrimidone (1.6 g) with 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.2 g) by the method described in Example 1(ii) and acidification with dilute ethanolic hydrogen chloride followed by evaporation to dryness and recrystallisation from ethanol gave 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-methylbenzyl)-4-pyrimidone dihydrochloride, m.p. 197°-198.5°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][C:25](=[O:27])[O:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:6]=2[N:5]=1)[CH3:2].Cl[CH:36]1[CH2:40][O:39][C:38](=[O:41])[O:37]1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][C:25](=[O:27])[O:24][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[C:28]([C:32]([O:34][CH:36]3[CH2:40][O:39][C:38](=[O:41])[O:37]3)=[O:33])=[CH:29][CH:30]=[CH:31][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reactant: O=C1OCC(Cl)O1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1nc2cccc(C(=O)OC3COC(=O)O3)c2n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Yield: 16.8 %

Procedure:
A solution of 2-ethoxy-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (1.0 g), 4-chloro-1,3-dioxolan-2-one (0.41 g) and triethylamine in DMF was stirred at 90° C. for 12 hrs. The reaction mixture was concentrated, and the residue was dissolved in chloroform and iN hydrochloric acid. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound (0.20 g, 22%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH:12]=O)[C@@H:7]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2].[Cl-].[CH3:20][O:21]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].O1CCCC1.Cl>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][CH:20]=[O:21])[C@@H:7]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)[C@H]1[C@@H](CC=O)CCN1C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1[C@@H](CCC=O)CCN1C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 0.663 g of cis 1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-acetaldehyde in 10 ml anhydrous tetrahydrofuran under nitrogen, cooled to -78°, is added dropwise a solution of 2.21 g of methoxymethyl-triphenylphosphonium chloride in 20 ml of anhydrous tetrahydrofuran to which is added 2.6 ml of potassium tert-butoxide/tetrahydrofuran (1.6M). Solution is stirred at room temperature for 4 hours; 15 ml of 2N hydrochloric acid is added and the mixture stirred for 45 minutes. The solution is concentrated and then extracted with methylene chloride. The extract is dried over sodium sulfate, filtered and concentrated; purification by flash chromatography using ethyl acetate/hexane (1:5 to 3:7) yields cis 1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-propionaldehyde.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7](Cl)=[CH:6][C:5]=1[NH:12]C(=O)C)([O-:3])=[O:2].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.[OH-].[K+].[K+].[Br-]>CS(C)=O>[N+:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:6][C:5]=1[NH2:12])([O-:3])=[O:2]
Reactant: C1CCNC1
Reactant: CC(=O)Nc1cc(Cl)c(F)cc1[N+](=O)[O-]
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1cc(N2CCCC2)c(F)cc1[N+](=O)[O-]
Yield: 85.3 %

Procedure:
2-Nitro-4-fluoro-5-(pyrrolidin-1-yl)aniline (12.3 g, 85%) was prepared by an analogous procedure to that described in preparation 1 (step 3) using N-(2-nitro-4-fluoro-5-chlorophenyl)acetamide (15.0 g, 0.064 mol) (obtained in preparation 1, step 2), pyrrolidine (22.9 g, 0.32 mol), potassium hydroxide (5.4 g, 0.096 mol) and dimethyl sulfoxide (60 mL). mp 115-116° C.; IR (KBr) 3478, 1536 cm-1 ; 1H NMR (CDCl3) δd 1.98 (m, 4H, (CH2)2), 3.50 (m, 4H, N(CH2)2), 5.64 (d, J=7.8 Hz, 1H), 6.09 (brs, 2H, NH2), 7.72 (d, J=14.6 Hz, 1H); Mass (m/z) 225 (M+.).