Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[CH2:4][OH:5].[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].C1(NC2CCCCC2)CCCCC1>CC(C)=O>[S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)([O:5][CH2:4][C:3]1[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=1[CH3:1])(=[O:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cccc([N+](=O)[O-])c1CO
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)OCc2c(C)cccc2[N+](=O)[O-])cc1
Reaction time: 24 h
Yield: 37.9 %

Procedure:
A 100 mL round bottomed flask equipped with a dropping funnel was charged with 2.50 g of 2-methyl-6-nitrobenzyl alcohol and 3.14 g of tosyl chloride dissolved in 30 mL of dry acetone under argon. To the mixture was added dropwise 3.30 mL of dicyclohexylamine dissolved in 5 mL of dry acetone while cooling so as to keep the temperature below 15° C. The reaction mixture was brought to room temperature and stirred for 1 day. The mixture was filtered to remove dicyclohexylamine hydrochloride, the solvent removed under vacuum, and the residue chromatographed over silica gel using carbon tetrachloride as the eluent. The product was recrystallized from methylene chloride/pentane to give 1.82 g (38% yield) of white crystals.
Reaction SMILES: Br[CH:2]([CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])[C:3]([CH3:11])([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[O-]CC.[Na+]>O1CCCC1>[Cl:14][C:13]([Cl:15])([Cl:16])[CH:12]=[CH:2][C:3]([CH3:10])([CH3:11])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)(C)C(Br)CC(Cl)(Cl)Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(C)C=CC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
Two milliliters of a solution of anhydrous tetrahydrofuran containing 709 mg (2 mmoles) of ethyl 4-bromo-6,6,6-trichloro-3,3-dimethylhexanoate was added dropwise to a suspension of 163 mg (2.4 mmoles) of sodium ethoxide in 20 ml of anhydrous tetrahydrofuran. The mixture was stirred at room temperature for about 16 hours, poured into ice water and extracted with diethyl ether. The extract was dried over magnesium sulfate and then distilled to give 448 mg (82% yield) of ethyl 6,6,6-trichloro-3,3-dimethyl-4-hexenoate, b.p. 83°-85°/0.1 mm.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([SH:12])[CH:9]=[C:8]([CH3:13])[C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[C:14]1([N:20]2[C:24](=[O:25])[CH:23]=[CH:22][C:21]2=[O:26])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:14]1([N:20]2[C:24](=[O:25])[CH2:23][CH:22]([S:12][C:10]3[CH:9]=[C:8]([CH3:13])[C:6]([NH2:7])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:11]=3)[C:21]2=[O:26])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1C=CC(=O)N1c1ccccc1
Reactant: Cc1cc(S)cc(C(C)(C)C)c1N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(SC2CC(=O)N(c3ccccc3)C2=O)cc(C(C)(C)C)c1N
Yield: 38 %

Procedure:
A stirred solution of 1.0 g (5 mmol) of 2-tert-butyl-4-mercapto-6-methylaniline, 0.9 g (5 mmol) of N-phenylmaleimide and 0.1 g (1 mmol) of triethylamine in 10 mL of toluene is heated at 50° C. for 18 hours. The solvent is removed in vacuo and the residue is purified by flash chromatography (silica gel, ethyl acetate eluent) to give 0.7 g (37%) of the title compound as a white solid melting at 126°-128° C.
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:34]2[N:35]=[C:36]([NH:39][CH:40]=[O:41])[S:37][CH:38]=2)[C:7]([NH:9][C@@H:10]2[C:32](=[O:33])[N:12]3[C:13]([C:19]([O:21]CC4C=CC([N+]([O-])=O)=CC=4)=[O:20])=[C:14]([O:17][CH3:18])[CH2:15][S:16][C@H:11]23)=[O:8])[CH2:3][CH2:2]1.[H][H].O1CCCC1.C(O)(=O)C>[Pd].CO>[CH:1]1([O:4][N:5]=[C:6]([C:34]2[N:35]=[C:36]([NH:39][CH:40]=[O:41])[S:37][CH:38]=2)[C:7]([NH:9][C@@H:10]2[C:32](=[O:33])[N:12]3[C:13]([C:19]([OH:21])=[O:20])=[C:14]([O:17][CH3:18])[CH2:15][S:16][C@H:11]23)=[O:8])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)C(=NOC3CC3)c3csc(NC=O)n3)[C@H]2SC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: COC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NOC3CC3)c3csc(NC=O)n3)[C@H]2SC1
Yield: 50.1 %

Procedure:
p-Nitrobenzyl 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-methoxy-3-cephem-4-carboxylate (syn isomer) (0.9 g) was hydrogenated under 1 atmospheric pressure of hydrogen in the presence of 10% palladium on carbon (0.9 g) in a mixture of methanol (20 ml), tetrahydrofuran (400 ml), and acetic acid (0.01 ml) at ambient temperature for 2 hours. The catalyst was filtered off and washed successively diluted aqueous solution of sodium bicarbonate and tetrahydrofuran. The filtrate and the washings were combined and washed with ethyl acetate. The aqueous solution was adjusted to pH 3 with 1N hydrochloric acid and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate, concentrated in vacuo, and triturated in diisopropyl ether to give 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer) (0.35 g) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[OH-].[Na+].[CH2:20]([NH2:23])[CH2:21][CH3:22]>ClCCl>[CH2:20]([NH:23][C:11](=[O:13])[CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH2:21][CH3:22]
Reactant: COc1ccc(CCC(=O)O)cc1
Reactant: CCCN
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCNC(=O)CCc1ccc(OC)cc1
Reaction time: 1 h

Procedure:
3-(4-methoxyphenyl)-propionic acid (8.8 g, 49 mmol) was refluxed in dichloromethane (200 mL) with thionylchloride (6,6 mL, 90 mmol) for 1 h. The volatiles were evaporated and the resulting oil was dissolved in dichloromethane (100 mL). This was added to a vigorously stirred mixture of 5% aqueous NaOH (200 mL), dichloromethane (100 mL) and n-propylamine (3.0 mL, 71 mmol). After stirring for 1 h the layers were separated and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and was dried over MgSO4. Evaporation of the solvent gave the amide in quantitative yield (10.7 g, 49 mmol, 100%). IR (neat) cm−1 3300, 2961; 1734, 1642; MS (EI) m/z 221 (M+). Analyses were in agreement with literature data.
Reaction SMILES: [H-].[Na+].[C:3]([O:12][CH2:13][CH:14]=[CH2:15])(=[O:11])[CH2:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].Cl[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1.Cl>O1CCOCC1.C1COCC1.O>[CH3:25][O:24][C:22]([C:21]1[CH:26]=[CH:27][C:18]([CH2:17][CH:4]([C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[C:3]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[CH:19][CH:20]=1)=[O:23]
Reactant: COC(=O)c1ccc(CCl)cc1
Reactant: C=CCOC(=O)CC(=O)OCC=C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: C1COCCO1
Product: C=CCOC(=O)C(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
14.42 g (0.36 mol) of sodium hydride are added in portions to a solution of 56.7 g (0.3 mol) of diallyl malonate in 375 ml of dioxane and 75 ml of THF at 0° C. After warming to room temperature, the mixture is stirred at 40° C. for 1 hour. Subsequently, 111.88 g (0.6 mol) of methyl 4-chloromethylbenzoate, dissolved in 375 ml of dioxane, are slowly added dropwise at 40° C., and the reaction solution is stirred at 110° C. overnight. After cooling to room temperature, the reaction mixture is added to 1200 ml of water. Care must be taken during this that the pH is <7 (where appropriate, a few ml of 1 M hydrochloric acid are metered in to about pH 2). The mixture is then extracted three times with ethyl acetate, and the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness in vacuo. The resulting crude product is purified by flash chromatography (mobile phase: petroleum ether/ethyl acetate 10:1; 3 kg of silica gel). 85.4 g (0.26 mol, 85% yield) of a colorless solid are obtained.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:24])=[N:19][CH:20]=[CH:21][C:22]=3[F:23])[CH:12]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1>>[F:24][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[C:22]([F:23])[CH:21]=[CH:20][N:19]=1
Reactant: Fc1cccc(Br)c1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1
Product: O=C(c1cccc(F)c1)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12j and 1-bromo-3-fluorobenzene
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][NH:8][C:9]1[C:14]([C:15](OCC)=[O:16])=[CH:13][N:12]=[C:11]([S:20][CH3:21])[N:10]=1>C1COCC1>[CH3:7][NH:8][C:9]1[C:14]([CH2:15][OH:16])=[CH:13][N:12]=[C:11]([S:20][CH3:21])[N:10]=1
Reactant: CCOC(=O)c1cnc(SC)nc1NC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1nc(SC)ncc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a suspension of lithium aluminum hydride (LiAlH4) (1.140 g, 30 mmol) in THF (100 mL) was added ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate (4.536 g, 20 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The solution was carefully quenched with H2O (2 mL), sodium hydroxide (NaOH) (aq., 15%, 2 mL) and additional H2O (7 mL), and then stirred for 1 hour. The mixture was extracted with EtOAc (2×100 mL), and the combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated to give (4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methanol (3.2 g, 85%) as a yellowish solid. MS (ES+) C7H11N3OS requires: 185. Found: 186 [M+H]+.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[C:15]([CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:37]=[CH:38][CH:39]=1)[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([C:32](O)=[O:33])=[CH:29][CH:30]=2)[C:25]([CH3:35])=[C:24]1[CH3:36])#[N:16]>>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]([NH:14][C:32]([C:28]2[CH:27]=[C:26]3[C:31](=[CH:30][CH:29]=2)[N:23]([CH2:22][C:21]2[CH:37]=[CH:38][CH:39]=[C:19]([O:18][CH2:17][C:15]#[N:16])[CH:20]=2)[C:24]([CH3:36])=[C:25]3[CH3:35])=[O:33])[CH3:13])=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: Cc1c(C)n(Cc2cccc(OCC#N)c2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1ccc(C(C)(C)C)cc1
Agent: Cl
Product: Cc1c(C)n(Cc2cccc(OCC#N)c2)c2ccc(C(=O)N[C@@H](C)c3ccc(C(C)(C)C)cc3)cc12

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(4-(tert-butyl)phenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the 1-(3-(cyanomethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 494 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][CH2:10][CH2:11][CH2:12][NH2:13].[C:14]([C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1)#[N:15]>C(Cl)Cl>[Cl:9][CH2:10][CH2:11][CH2:12][NH:13][C:23]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]#[N:15])=[CH:17][CH:18]=1)=[O:24]
Reactant: NCCCCl
Reactant: N#Cc1ccc(N=C=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(NC(=O)NCCCCl)cc1
Yield: 53.7 %

Procedure:
Triethylamine (13.8 g; 137 mmole) was slowly added to a mixture of 3-chloropropylamine hydrochloride (17.8 g; 137 mmole), 4-cyanophenyl isocyanate (19.7 g; 137 mmole), and methylene chloride (200 ml). The resulting solution was stirred until the mild exothermic reaction had subsided and the solvent was removed in vacuo. The product was dissolved in ether, washed with water, dried, and part of the ether removed. The colorless crystals which precipitated out were filtered and dried to give 1-(3-chloropropyl)-3-(4-cyanophenyl)urea (17.5 g; 54% yield). A small portion of the product was recrystallized from water/acetone to give pure product, m.p. 95°-97° C.
Reaction SMILES: O[C@:2]12[CH2:19][CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:20])[C@@H:11]1[CH2:10][CH2:9][C@H:8]1[C@:3]2([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH2:7]1.S(=O)(=O)(O)O>C(Cl)Cl>[CH3:17][C@:16]12[CH2:18][CH:19]=[C:2]3[C@@H:11]([CH2:10][CH2:9][C@H:8]4[C@:3]3([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH2:7]4)[C@@H:12]1[CH2:13][CH2:14][C:15]2=[O:20]
Reactant: C[C@]12CCC(=O)C[C@H]1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@]12O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: C[C@]12CCC(=O)C[C@H]1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of compound 1.1 (26.0 g, 85.4 mmol) in DCM (520 mL) was added concentrated sulfuric acid (7.53 g, 76.8 mmol) over 15 minutes under an inert atmosphere at 10° C. The temperature was raised to 25° C. and the resulting solution was stirred for 2 h. At this point no more starting material remained as evidenced by TLC. The reaction was quenched by the addition of 10% aqueous NaHCO3 solution (200 mL). The layers were separated and the aqueous layer was extracted twice with DCM (2×100 mL). The organic layers were combined and washed sequentially with water (100 mL) and saturated brine solution (100 mL). The organic phase was then dried over Na2SO4 (75 g) and filtered. The filtrate was evaporated under vacuum to provide compound 1.2 (23.0 g, 94%) as an off-white solid. This product was used “as is” in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:9]3)[CH:7]=1.[CH3:34][O:35][C:36]1[N:37]=[CH:38][C:39]([C:42](O)=[O:43])=[N:40][CH:41]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C=O)C>[C:25]([NH:24][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:14][N:15]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH2:16][C@:8]2([C:6]2[CH:7]=[C:2]([NH:1][C:42]([C:39]3[CH:38]=[N:37][C:36]([O:35][CH3:34])=[CH:41][N:40]=3)=[O:43])[CH:3]=[CH:4][C:5]=2[F:33])[N:9]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1cnc(C(=O)O)cn1
Reactant: Nc1ccc(F)c([C@]23CN(c4ncc(F)cn4)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cnc(C(=O)Nc2ccc(F)c([C@]34CN(c5ncc(F)cn5)C[C@H]3CSC(NC(=O)c3ccccc3)=N4)c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
N-[(4aR,7aS)-7a-(5-Amino-2-fluoro-phenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (0.361 g, 0.77 mmol, isomer 1) is dissolved in a mixture of dichloromethane (4 mL) and DMF (0.5 mL). 5-Methoxypyrazine-2-carboxylic acid (240 mg, 1.55 mmol), 1-hydroxybenzotriazole (210 mg, 1.55 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (300 mg, 1.55 mmol) are added to the mixture and the mixture is stirred overnight at room temperature. The reaction solution is added directly onto a 12 g silica gel loading column and purified using a 40 g silica gel column and eluting with a 0-100% ethyl acetate/hexanes gradient. The product is dissolved in ethyl acetate (200 mL), washed with 1 N NaOH (2×50 mL), and with brine (1×50 mL). The silica gel purification is repeated as described above to give the title compound (350 mg, 74%). ES/MS (m/e): 603 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:22]=[CH:21][C:10]([CH2:11][N:12]3[CH2:16][C@H:15]([C:17](O)=[O:18])[NH:14][C:13]3=[O:20])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[OH:25][N:26]1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.C[Si](C)(C)CCON.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.O>[OH:25][NH:26][C:17]([C@H:15]1[CH2:16][N:12]([CH2:11][C:10]2[CH:21]=[CH:22][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:24][CH:23]=3)=[CH:8][CH:9]=2)[C:13](=[O:20])[NH:14]1)=[O:18]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)[C@H]1CN(Cc2ccc(Oc3ccc(F)cc3)cc2)C(=O)N1
Agent: CCN=C=NCCCN(C)C
Agent: C[Si](C)(C)CCON
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NO)[C@H]1CN(Cc2ccc(Oc3ccc(F)cc3)cc2)C(=O)N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (4R)-l -[4-(4-fluorophenoxy)benzyl]-2-oxo-imidazolidine-4-carboxylic acid (120 mg, 0.36 mmol) in methylene chloride (5 mL) were added sequentially 1-hydroxybenztria zole (73 mg, 0.54 mmol), diisopropylethylamine (0.13 mL, 0.75 mmol), O-(2-trimethylsilylethyl)hydroxylamine hydrochloride (92 mg, 0.54 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (104 mg, 0.54 mmol). The reaction mixture was stirred at room temperature for 16 hours and was then diluted with methylene chloride and water. The organic phase was washed successively with aqueous 1M HCI solution, water, aqueous saturated NaHCO3 solution and brine. After drying over MgSO4, the solution was concentrated to an oil. The title compound, an oil (85 mg, 53%), was isolated by chromatography on silica gel eluting with ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[CH2:8][CH:9]([C:11]1[C:16]2[CH2:17][C:18]([CH3:21])([CH3:20])[O:19][C:15]=2[C:14]([O:22][CH3:23])=[CH:13][CH:12]=1)O.C[Si]([C:29]#[N:30])(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:29]([CH:9]([C:11]1[C:16]2[CH2:17][C:18]([CH3:21])([CH3:20])[O:19][C:15]=2[C:14]([O:22][CH3:23])=[CH:13][CH:12]=1)[CH2:8][C:7]1[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=1[Cl:24])#[N:30]
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc(C(O)Cc2c(Cl)cncc2Cl)c2c1OC(C)(C)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C(C#N)Cc2c(Cl)cncc2Cl)c2c1OC(C)(C)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 23.8 %

Procedure:
A solution (70 ml) obtained in Step A of Example 45 of Compound 45a (2.5 g) in methylene chloride was cooled to 0° C. and then trimethylsilylcyanide (5.4 ml) and boron trifluoride ether complex (2.5 ml) were successively added thereto, followed by stirring at 0° C. for 2 hours. The reaction solution was poured into a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with chloroform. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=30/1) to give Compound 63 (0.61 g, 23.8%) as pale-yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+]([O-])(O)=O.[N+:19]([C:22]1[CH:23]=[C:24]([NH:28][C:29]([NH2:31])=[NH:30])[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20].[OH-].[Na+]>COCCO>[CH3:7][C:5]1[S:4][C:3]([C:8]2[CH:9]=[CH:10][N:31]=[C:29]([NH:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=3)[N:30]=2)=[C:2]([CH3:1])[N:6]=1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Reactant: N=C(N)Nc1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: O=[N+]([O-])O
Product: Cc1nc(C)c(-c2ccnc(Nc3cccc([N+](=O)[O-])c3)n2)s1
Yield: 46.1 %

Procedure:
A mixture of 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone (1.0 mmol, 0.21 g) and N-(3-nitro-phenyl)-guanidine nitrate (1.0 mmol, 0.24 g) in 2-methoxyethanol (5 mL) was treated with NaOH (40 mg). The reaction mixture was refluxed under N2 for 20 h. The solvent was evaporated and the residue was purified by flash chromatography (EtOAc/PE, 5:1) and recrystallisation from EtOAc/MeOH to afford the title compound as a yellow solid (151 mg, 46%). M.p. 176-178° C. LC-MS: m/z=328 (M+1). C15H13N5O2S requires: C, 55.03; H, 4.00; N, 21.39; found: C, 54.67; H, 3.88; N, 21.77. 1H-NMR (300 MHz, CDCl3) δ 2.72 (s, 3H, CH3), 2.74 (s, 3H, CH3), 7.06 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.74-7.92 (m, 3H, Ph-H), 8.46 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 8.91 (t, 1H, J=4.3, 2.1 Hz, Ph-H).
Reaction SMILES: C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:21][O:22][C:23]1[N:28]2[N:29]=[C:30]([CH:32]=[N:33]O)[CH:31]=[C:27]2[C:26]([C:35]2[CH:36]([CH3:42])[CH2:37][C:38](=[O:41])[NH:39][N:40]=2)=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:21][O:22][C:23]1[N:28]2[N:29]=[C:30]([C:32]#[N:33])[CH:31]=[C:27]2[C:26]([C:35]2[CH:36]([CH3:42])[CH2:37][C:38](=[O:41])[NH:39][N:40]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(C2=NNC(=O)CC2C)c2cc(C=NO)nn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccc(C2=NNC(=O)CC2C)c2cc(C#N)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
Triethylamine (0.291 mL) and trifluoroaceticanhydride (0.116 mL) were added to a suspension of the compound of Example 344 (63.0 mg) in methylene chloride (6 mL). The mixture was stirred at room temperature for 1 hour. Subsequently, a saturated aqueous sodium bicarbonate solution was added and the mixture was stirred for 30 min. The organic layer was separated and the aqueous layer was extracted with methylene chloride. The combined organic layer was dried over anhydrous magnesium sulfate. Evaporation of the solvent and subsequent purification of the residue by silica gel column chromatography (NH type, methylene chloride:methanol=9:1) afforded the title compound as a pale yellow powder (31.3 mg).
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14]S(C)(=O)=O)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH:25][C:26]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14][N:30]1[CH2:31][CH2:32][CH:27]([C:26]([OH:25])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:28][CH2:29]1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Reactant: CN(CC(CCS(C)(=O)=O)c1ccccc1)C(=O)c1ccccc1
Product: CN(CC(CCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1)c1ccccc1)C(=O)c1ccccc1

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-phenyl-4-methanesulfonylbutyl)benzamide and 4-(hydroxydiphenylmethyl)piperidine to give the title compound.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].BrC.[CH2:20](O)[CH3:21]>>[CH2:20]([S:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1)[CH3:21]
Reactant: Sc1ccc2ccccc2c1
Reactant: CCO
Agent: CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCSc1ccc2ccccc2c1
Reaction time: 8 h

Procedure:
To a solution, stirred under an inert atmosphere at ambient temperature, of 40 g of 2-mercapto naphthalene in 1 liter of anhydrous ethanol, there are slowly added 24.4 g of potash. The addition being completed, stirring is maintained for 2 hours, then there is slowly added a solution of 21 cm3 of bromomethane dissolved in 100 cm3 of anhydrous ethanol. After 3 hours of stirring, the reaction mixture is left overnight, then filtered and the filtrate is concentrated under a vacuum. The resulting crude product is stirred in 800 cm3 of water, then extracted 4 times with 150 cm3 of dichloromethane. The dichloromethane phases are combined, washed with a saturated solution of ammonium chloride, then dried on magnesium sulfate. The solvent is rectified under vacuum and 38 g of 2-ethylthio naphthalene are obtained and used as such for the following reactions.