Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:6].CS[C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:17][N:16]=1>N1C=CC=CC=1>[CH3:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:17][N:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CSc1ncc(Cc2ccc(O)cc2)c(=O)[nH]1
Reactant: CN(CCCN)c1ccccn1
Solvent: c1ccncc1
Product: CN(CCCNc1ncc(Cc2ccc(O)cc2)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(3-aminopropyl)-N-methylamino]pyridine (1.98 g) and 2-methylthio-5-(4-hydroxybenzyl)pyrimid-4-one (2.48 g) were heated together under reflux in pyridine (5 ml) for 24 hr. After stripping, the residue was triturated with water (pH adjusted to 7.0 with 2N hydrochloric acid). Recrystallisation from ethanol/water and again from methanol gave 2-[3-(N-methyl-N-pyrid-2-ylamino)propyl-amino]-5-(4-hydroxybenzyl) pyrimid-4-one, 2.4 g (66%) mp 109°-11° C. (analytical sample from methanol).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>C1COCC1>[CH3:5][C:2]1([CH3:6])[CH2:3][O:4][C:20]([C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:24])[F:25])=[CH:23][CH:22]=2)=[N:1]1
Reactant: CC(C)(N)CO
Reactant: FC(F)(F)c1ccc(CCl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccc(C(F)(F)F)cc2)=N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To an ice-cold solution of 2-amino-2-methyl-1-propanol (21.4 g, 240 mmol) and triethylamine (16.8 mL, 120 mmol) in THF was added dropwise 4-trifluoromethyl benzyl chloride (25.0 g, 120 mmol). After the addition, the reaction mixture was stirred at 0° C. for 30 mins and then stirred at ambient temperature for 8 hrs. The precipitate was removed by filtration and the filtrate was concentrated by evaporating the solvent under reduced pressure. The resulting residue was treated dropwise with thionyl chloride with vigorous stirring at 0° C. After complete addition, the reaction mixture was further stirred at ambient temperature for 1 hr. Ether was poured into the reaction mixture and the precipitate was collected by filtration. The precipitate was dissolved in water and the aqueous solution was hydrolyzed with 10% (w/v) NaOH. The aqueous phase was extracted three times with ether, and the combined organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The crude residue was purified by column chromatography (Hex/EtOAc=5/1) to yield the title compound (25.4 g, 87%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:38])[C@@H:13]2[CH2:17][C@@H:16]([NH:18][C:19](=[O:30])[C@H:20]([OH:29])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:15][N:14]2C(OC(C)(C)C)=O)[CH:2]=1>FC(F)(F)C(O)=O.C(Cl)(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:38])[C@@H:13]2[CH2:17][C@@H:16]([NH:18][C:19](=[O:30])[C@H:20]([OH:29])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:15][NH:14]2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)[C@H](O)CCc2ccccc2)C[C@H]1C(=O)Nc1cnc2ccccc2c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H]1CN[C@H](C(=O)Nc2cnc3ccccc3c2)C1)[C@H](O)CCc1ccccc1
Reaction time: 1 h
Yield: 71 %

Procedure:
N-tert-butoxycarbonyl-trans-4-((R)-2-hydroxy-4-phenylbutyrylamino)-L-proline 3-quinolylamide (1.55 g) was dissolved in trifluoroacetic acid (10 mL)-chloroform (20 mL). After stirring for 1 hr, the reaction mixture was evaporated in vacuo. The residue was diluted with chloroform, and washed with saturated sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give the title compound (888 mg) as a colorless foam.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[CH:6]=[CH2:7]>C1(C)C=CC=CC=1>[CH2:5]([O:8][C:9]([NH:11][CH2:12][C:13]([Cl:3])=[O:15])=[O:10])[CH:6]=[CH2:7]
Reactant: O=S(Cl)Cl
Reactant: C=CCOC(=O)NCC(=O)O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)NCC(=O)Cl
Reaction time: 2 h

Procedure:
5.7 ml of thionyl chloride are added at 0° to 3.18 g of allyloxycarbonylaminoacetic acid. At the same temperature, the mixture is then stirred under a protective gas for 2 hours. It is then diluted with absolute toluene and concentrated in a rotary evaporator. IR (CH2Cl2): 3435, 1800, 1725 cm-1.
Reaction SMILES: [OH-].[Na+].[C:3]([CH:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)[CH:6]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH2:7][C:8]([O:10]C)=[O:9])#[N:4]>CO>[C:3]([CH:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)[CH:6]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH2:7][C:8]([OH:10])=[O:9])#[N:4]
Reactant: COC(=O)CC(c1ccc(F)cc1)C(C#N)c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#CC(c1cccc(F)c1)C(CC(=O)O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under protective gas (Ar), 10 ml of 2 molar aqueous sodium hydroxide solution were added to 1.75 g (5.55 mmol) of methyl 4-cyano-3-(4-fluorophenyl)-4-(3-fluorophenyl)butanoate (Example A1) in 50.0 ml of methanol, and the mixture was stirred at 25° C. for 8 h. The methanol was removed under reduced pressure. The residue was acidified with concentrated hydrochloric acid (pH=3) and extracted three times with in each case 15 ml of dichloromethane. The combined organic phases were dried over sodium sulphate and the solvent was removed under reduced pressure. This gave 1.62 g (96.9% of theory) of the title compound in the form of colourless crystals (erythro:threo=49:51 according to comparison of the multiplets in the 1H-NMR in CDCl3 at 2.60 and 2.85 ppm).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:9]=[C:8]2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:30][C:31]#[N:32].C(=O)([O-])[O-].[Cs+].[Cs+]>>[C:1]1([N:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:9]=[C:8]2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([O:28][CH2:30][C:31]#[N:32])[CH:22]=[CH:21]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc2cc(-c3ccc(-c4ccccc4)n3-c3ccccc3)ccc2c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: N#CCOc1ccc2cc(-c3ccc(-c4ccccc4)n3-c3ccccc3)ccc2c1
Yield: 76.8 %

Procedure:
In a similar manner as described in step 6 of Example 1, the title compound was prepared from 6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthol (0.200 g, 0.553 mmol), bromoacetonitrile (0.0796 g, 0.664 mmol) and cesium carbonate (0.900 g, 2.77 mmol) with the exception that the product was extracted with two portions each of methylene chloride and EtOAc. Purification on a Biotage Horizon™ system with a KP-Sil Flash 40+M column (100 g Silica Gel, 60 Å) using 55% to 95% methylene chloride in hexane as the eluent gave {[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile as a white solid (0.170 g, 77%), mp 229–230° C. Elemental Analysis for C28H20N2O.0.05 CH2Cl2 Calc'd: C, 83.24; H, 5.01; N, 6.92. Found: C, 83.12; H, 4.77; N, 6.89.
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[NH2:18][C:19]([NH2:21])=[S:20].II.[O-]S([O-])(=S)=O.[Na+].[Na+]>CCO>[NH2:21][C:19]1[S:20][C:9]([C:10]#[N:11])=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:18]=1
Reactant: NC(N)=S
Reactant: N#CCC(=O)c1ccccc1
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCO
Solvent: c1ccncc1
Product: N#Cc1sc(N)nc1-c1ccccc1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To a solution of benzoylacetonitrile derivative (1 eq.) in EtOH is added pyridine (1 eq.). The resulting mixture is stirred at 70° C. for 15 min then cooled at r.t. A previously stirred suspension of thiourea (2 eq.) and iodine (1 eq.) in EtOH is then slowly added. After 1 h at r.t. a cold 1 M Na2S2O3 solution is added under stirring. The resulting precipitate is filtered, washed with water, and finally dried under vacuo to afford the amino-4-phenyl-thiazole-5-carbonitrile derivative.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([S:7]([CH3:10])(=[O:9])=[O:8])=[CH:5][CH:6]=1.S(=O)(=O)(O)O.[N+:16]([O-])([O-:18])=[O:17].[Na+]>>[Br:1][C:2]1[S:3][C:4]([S:7]([CH3:10])(=[O:9])=[O:8])=[CH:5][C:6]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])[O-]
Reactant: CS(=O)(=O)c1ccc(Br)s1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CS(=O)(=O)c1cc([N+](=O)[O-])c(Br)s1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 47 %

Procedure:
2-bromo-5-methylsulfonyl-thiophene (0.3 g, 1.24 mmol) was added to the concentrated sulfuric acid at 0° C. cooling in an ice bath. The resulted mixture was stirred at 0° C. for 5 minutes. Then sodium nitrate was introduced and the mixture was stirred at 0° C. for 1 hour. After this time, the reaction mixture was poured onto to the ice-water (10 mL) and was extracted with ethyl acetate. The organic phase was dried (Na2SO4) and concentrated under vacuum. The residue was purified by silica gel chromatography using a mixture of 95:5 hexane and ethyl acetate as eluent to afford the title product as a solid (0.17 g, 47% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.37 (1H, s), 2.50 (3H, m).
Reaction SMILES: N1C=CC=CC=1.Cl.[CH3:8][O:9][C:10](=[O:13])[CH2:11][NH2:12].[CH:14]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20])=[O:15]>O1CCCC1>[CH3:8][O:9][C:10]([CH2:11][NH:12][C:14]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[CH:19]=[O:20])=[O:15])=[O:13]
Reactant: COC(=O)CN
Reactant: O=Cc1cccc(C(=O)Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)CNC(=O)c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 20.1 %

Procedure:
To a mixture of 200 ml of tetrahydrofuran, 26.00 g of pyridine and 20.70 g of glycine methyl ester hydrochloride was added a solution of 16.00 g of 3-formylbenzoic acid chloride in 20 ml of tetrahydrofuran at 10° C. After stirred at room temperature for 60 hours, insolubles were filtered and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 4.23 g of oily 3-[[(methyoxycarbonylmethyl)amino]carbonyl]benzaldehyde [Compound No. (b)].
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH2:35][OH:36])[CH:19]=[C:20]([F:34])[C:21]=1[O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=1>CN(C=O)C>[F:15][C:16]1[CH:17]=[C:18]([CH:19]=[C:20]([F:34])[C:21]=1[O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]([F:33])([F:31])[F:32])[CH:24]=1)[CH2:35][O:36][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: OCc1cc(F)c(Oc2ccc(F)c(C(F)(F)F)c2)c(F)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1cc(F)c(Oc3ccc(F)c(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (30 mg, 0.162 mmol), sodium hydride (12.93 mg, 0.323 mmol) and (3,5-difluoro-4-(4-fluoro-3-(trifluoromethyl)pheno-xy)phenyl)m-ethanol (52.1 mg, 0.162 mmol) in DMF (1.5 ml).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[F:5][C:6]([F:13])([F:12])[C:7](=[CH2:11])[C:8](O)=[O:9]>C(OC(=O)C)(=O)C>[F:5][C:6]([F:13])([F:12])[CH:7]1[CH2:11][NH:4][C:2](=[O:3])[NH:1][C:8]1=[O:9]
Reactant: NC(N)=O
Reactant: C=C(C(=O)O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Product: O=C1NCC(C(F)(F)F)C(=O)N1
Yield: 66.4 %

Procedure:
In 160 ml of acetic anhydride, 13.5 g of urea was suspended and 30 g of trifluoromethacrylic acid was added to the suspension. The resulting mixture was allowed to react at 100° C. for 1 hour and the reaction mixture was concentrated under reduced pressure. The obtained oil was crystallized from 150 ml of water and then recrystallized from 150 ml of water to obtain 25.9 g of 5-trifluoromethyl-5,6-dihydrouracil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@H:16]1[C@@H:20]([CH2:21][F:22])[CH2:19][N:18]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:17]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][C@H:16]3[C@@H:20]([CH2:21][F:22])[CH2:19][N:18]([C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:24])[CH2:17]3)=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1CF
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cnn2cc(Br)cc2c1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1CF
Yield: 80.1 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 2, 740 mg, 2.70 mmol), (3S,4S)-benzyl 3-amino-4-(fluoromethyl)pyrrolidine-1-carboxylate (Intermediate 10, 714 mg, 2.83 mmol) and DIPEA (0.989 mL, 5.66 mmol) in DMF (8 mL) was heated to 80° C. for 16 hrs. The reaction mixture was concentrated and purified on silica gel column with Hexanes/EtOAc (1/1) to give the title compound (1.06 g, 80% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.94 (br. s., 1H), 7.42-7.27 (m, 5H), 7.15 (s, 1H), 5.16-4.94 (m, 3H), 4.70-4.54 (m, 2H), 3.90-3.41 (m, 4H), 3.02-2.84 (m, 1H), MS (ES+) m/z: 490.1, 492.1 (M+H); LC retention time: 3.261 min (analytical HPLC Method H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([NH:14][CH2:15][C:16](O)=[O:17])[CH3:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:16](=[O:17])[CH2:15][N:14]([CH2:12][CH3:13])[C:10]1=[S:11]
Reactant: CCNCC(=O)O
Reactant: Cc1ccc(N=C=S)c(C)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2ccc(C)cc2C)C1=S
Yield: 43.6 %

Procedure:
The title compound was prepared by the procedure described in Example 9 using 16.3 g of 2,4-dimethylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 250 mL of chloroform. Crystallization from ethanol afforded the title compound (10.8 g) as a light peach solid, m.p. 161°-162° C. Anal. Calcd. for. C13H16N2OS: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.63; H, 6.45; N, 11.17. Mass spectrum (EI, M.+) m/z 248.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=2)[C:20]([F:23])([F:22])[F:21])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5].FC(F)(F)S(O[CH2:39][C:40]([F:43])([F:42])[F:41])(=O)=O>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=2)[C:20]([F:23])([F:21])[F:22])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:39][C:40]([F:43])([F:42])[F:41])[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NC1CCN(CC(F)(F)F)CC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reaction time: 0.17 h
Yield: 47.9 %

Procedure:
To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol) in THF (5.0 mL) was added TEA (0.06 mL, 0.64 mmol) and stirred for 10 min. Then 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.03, 0.16 mmol) was added and stirred for 16 h at ambient temperature. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3 solution and brine solution. The combined EtOAc layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a brown solid (0.05 g, 44%).
Reaction SMILES: N[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[CH:3]=1.Cl.C(O)(=[O:20])C>>[OH:20][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[CH:3]=1
Reactant: CC(=O)O
Reactant: Cn1c(=O)cc(N)n(-c2ccccc2)c1=O
Agent: Cl
Product: Cn1c(=O)cc(O)n(-c2ccccc2)c1=O
Temperature: 100 °C
Yield: 68 %

Procedure:
6-Amino-3-methyl-1-phenyluracil as obtained in Reference Example 1 (8.7 g, 40 mM) was dissolved in 80 ml of acetic acid and hydrochloric acid (16 ml) was added, followed by heating at 100° C. for 1 hour. The solvent acetic acid was then distilled off under reduced pressure and water war added to the residue. The pH of the resulting solution was adjusted to 1 by adding hydrochloric acid and a product was extracted with dichloromethane. After the solvent dichloromethane was distilled off under reduced pressure from the dichloromethane layer, crystallization with ethanol was performed to give 6-hydroxy-3-methyl-1-phenyluracil (yield: 5.9 g, or 68% based on 6-amino-3-methyl-1-phenyluracil).
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:55][O:56][CH3:57])[C:27]([NH:29][C@@H:30]2[C:37](=[O:38])[N:36]3[C@@H:31]2[CH2:32][S:33][C:34](/[CH:46]=[CH:47]/[CH2:48][N:49]2[CH:53]=[CH:52][N:51]=[C:50]2[CH3:54])=[C:35]3[C:39]([O:41]C(C)(C)C)=[O:40])=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)=O>[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:55][O:56][CH3:57])[C:27]([NH:29][C@@H:30]2[C:37](=[O:38])[N:36]3[C@@H:31]2[CH2:32][S:33][C:34](/[CH:46]=[CH:47]/[CH2:48][N:49]2[CH:53]=[CH:52][N:51]=[C:50]2[CH3:54])=[C:35]3[C:39]([OH:41])=[O:40])=[O:28])[N:25]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)(C)C)=C(/C=C/Cn3ccnc3C)SC[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C/Cn3ccnc3C)SC[C@H]12)c1csc(N)n1

Procedure:
80.5 mg of the product of Step A and 1 ml of 66% formic acid were heated for 3 hours at 60°-65° C. and then was evaporated to dryness under reduced pressure. The residue was taken up twice consecutively with 5 ml of water, then evaporated to dryness. The residue was taken up in 7 ml of ether, stirred for half-an-hour, then separated to obtain 41.5 mg of syn isomer of (6S,7S) 7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-3-[3-(2-methyl-1H-imidazol-1 yl)1-(E)-propenyl]-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([OH:17])(=O)[C:6]1[CH:15]=[CH:14][C:11]([O:12][CH3:13])=[C:8]([O:9][CH3:10])[CH:7]=1>C1C=CC=CC=1.N1C=CC=CC=1>[C:5]([Cl:3])(=[O:17])[C:6]1[CH:15]=[CH:14][C:11]([O:12][CH3:13])=[C:8]([O:9][CH3:10])[CH:7]=1
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Cl)cc1OC
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 99.9 %

Procedure:
In a 2-neck 100 ml-round bottom flask, 10.0 g (54.9 m mol) of veratric acid was dissolved in 50 ml of benzene, and after adding 2 to 3 drops of pyridine to the solution, 13 g (109 m mol) of thionyl chloride was dropped into the solution while stirring the solution at room temperature within 3 min. Then the content was heated to 70° to 80° C. on a water bath, and maintained at the temperature for 2 hours under a reflux condenser and agitation. Then, the solvent and excess thionyl chloride were evaporated off under a reduced pressure to obtain 11.0 g of veratroyl chloride as colourless powder in a yield of 100%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]([C:14]1[N:15]=[N:16][N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=4)[CH:21]=3)[N:18]=1)=[CH:6]2.[C:38](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:38])[C:8](=[O:13])[C:7]([C:14]1[N:15]=[N:16][N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=4)[CH:21]=3)[N:18]=1)=[CH:6]2
Reactant: COc1ccc2[nH]c(=O)c(-c3nnn(Cc4cccc(OCc5ccc6ccccc6n5)c4)n3)cc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)cc(-c1nnn(Cc3cccc(OCc4ccc5ccccc5n4)c3)n1)c(=O)n2C
Temperature: 80 °C
Reaction time: 4 h
Yield: 81.2 %

Procedure:
To a mixture of 6-methoxy-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one (1.61 g, 3.30 mmol) and potassium carbonate (684 mg, 4.95 mmol), was added DMF (30 ml). Methyl iodinate (562 mg, 3.96 mmol) was added dropwise to the resultant mixture, and thereafter stirred for four hours at a bath temperature of 80° C. The solvent of the reaction mixture was removed under reduced pressure. Water was added to the mixture, and the organic phase was extracted therefrom with a mixture of chloroform-methanol (10:1). The organic phase was dried over sodium sulfate anhydrate, subjected to silica gel column chromatography (with chloroform-methanol (50:1)), and concentrated under reduced pressure. The resultant residue was recrystallized from a chloroform-n-hexan-ether mixture, to thereby obtain the title compound (1.35 g, 2.68 mmol, 81.1%) as pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4](Cl)[N:3]=1.O1CCOCC1.[CH2:16]([NH2:34])[CH2:17][CH2:18][CH2:19][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][CH3:33].[OH-].[Na+]>O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:34][CH2:16][CH2:17][CH2:18][CH2:19][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][CH3:33])[N:3]=1
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: Nc1nc(N)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCCCNc1nc(N)nc(N)n1
Reaction time: 1 h
Yield: 90.9 %

Procedure:
A mixed solution of 14.5 g (0.1 mol) of 2,4-diamino-6-chloro-1,3,5-triazine prepared in Reference Example 1, 60 mL of water, 60 mL of 1,4-dioxane, and 26.9 g (0.1 mol) of octadecylamine was warmed with stirring and allowed to react at a reflux temperature for 3 hours. Further, an aqueous solution of 4.0 g (0.1 mol) of sodium hydroxide in 20 mL of water was dropwise added thereto over 1 hour and the mixture was allowed to react for additional 2 hours. After cooling the reaction mixture, the solvent was distilled off under reduced pressure, and 100 mL of water and 100 mL of toluene were added to extract the product in the organic layer. After washing the organic layer with water sufficiently, the solvent was distilled off from the organic layer to obtain 34.4 g (yield 91%) of the titled compound. Melting point: 91° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[N:16]=[C:15]([C:17]2[S:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](=[O:23])[N:22]=2)[CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34]([N:36]([CH2:40][CH3:41])[C:37](Cl)=[O:38])[CH3:35]>C(#N)C>[CH2:34]([N:36]([CH2:40][CH3:41])[C:37]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([C:17]2[S:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](=[O:23])[N:22]=2)[N:16]=1)=[O:38])[CH3:35]
Reactant: NCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: CCN(CC)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCN(CC)C(=O)NCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 31.4 %

Procedure:
A mixture of 2-[6-(2-aminoethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (0.40 g, 1.0 mmol), potassium carbonate (0.41 g, 3.0 mmol) and acetonitrile (20 ml) was stirred at room temperature for 20 minutes. Successively N,N-diethylcarbamoyl chloride (0.54 g, 4.0 mmol) was added to the mixture, and the mixture was stirred at room temperature for 4 hrs. The precipitates were filtered, and the filtrate was concentrated. The residue was subjected to a silica gel column chromatography. The fractions eluted with chloroform-ethanol (30:1, v/v) were collected, concentrated and recrystallized from ethanol-hexane to give the titled compound (0.12 g, 31%) as white crystals.