Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[C:14]#[N:15].S(=O)(=O)(O)[OH:17]>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[C:14]([NH2:15])=[O:17]
Reactant: Cc1nn(-c2ccccc2)c(N)c1C#N
Reactant: O=S(=O)(O)O
Product: Cc1nn(-c2ccccc2)c(N)c1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed sulfuric acid (90 mL). To the resulting mixture was then added 5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile (30 g, 151.52 mmol, 1.00 equiv), in portions at 10° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of water/ice (100 mL). The pH value of the solution was adjusted to about 8-9 with potassium carbonate (conc.). The solids were collected by filtration, to yield 5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carboxamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7](=O)[NH:6][C:5]([CH:9]2[CH2:11][CH2:10]2)=[N:4][C:3]=1[C:12]([OH:14])=[O:13].C(OCC)(=O)C.CN(C)C=O.S(Cl)([Cl:28])=O>O>[Cl:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[N:4][C:5]([CH:9]2[CH2:11][CH2:10]2)=[N:6][C:7]=1[Cl:28]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1nc(C2CC2)[nH]c(=O)c1Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)c1nc(C2CC2)nc(Cl)c1Cl
Temperature: 68 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
A 500 mL multi-neck flask with overhead stirrer, thermocouple and condenser was charged with 5-chloro-2-cyclopropyl-1,6-dihydro-6-oxo-4-pyrimidinecarboxylic acid (35.0 g, 0.163 mol), ethyl acetate (105 mL) and N,N-dimethylformamide (1.19 g, 0.016 mol) at room temperature. Thionyl chloride (48.5 g, 0.408 mol) was added at room temperature over 50 minutes, and the reaction mixture was heated at 68° C. for 7 h. The reaction mixture was cooled to 25° C. and added over 30 minutes into a 500-mL multi-neck flask containing water (100 mL) while maintaining the temperature at 10-20° C. The resulting mixture was stirred for additional 30 minutes, and the organic layer was separated from the aqueous layer. The aqueous layer was extracted with additional ethyl acetate (20 mL), and the combined organic layers were washed with water. The organic layer containing 35.0 g (93% yield) of the title product was directly carried over to the next step.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH2:45]([O:47][C:48](=[O:52])[CH2:49][NH:50][CH3:51])[CH3:46]>C(N(CC)CC)C.C1COCC1>[CH2:45]([O:47][C:48](=[O:52])[CH2:49][N:50]([C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:18][CH:17]=1)[CH3:51])[CH3:46]
Reactant: CCOC(=O)CNC
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CN(C)C(=O)c1ccccc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(4-fluorobenzoyl)benzoic acid (3.00 g), 1-hydroxybenzotriazole (2.07 g), 1,3-dicyclohexylcarbodiimide (3.00 g) and anhydrous THF (50 ml) was stirred at room temperature for 1 hour. To this mixture were added N-methylglycine ethyl ester hydrochloride (2.84 g) and triethylamine (2.58 ml), followed by stirring at room temperature for 16 hours and with heating and refluxing for 4 hours. After the solvent was distilled off, ethyl acetate was added to the residue, and the insoluble crystals were separated by filtration. The filtrate was washed successively with water, aqueous sodium hydrogen carbonate, water, dilute hydrochloric acid and water and then dried, after which the solvent was distilled off, to yield N-[2-(4-fluorobenzoyl)benzoyl]-N-methylglycine ethyl ester as a colorless oily substance (4.2 g).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[C:16](OC)=[N:15][S:14](=[O:20])(=[O:19])[N:13]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.CC1NC=NC=1CSCCN.[NH:46]([C:50]1[S:51][CH:52]=[C:53]([CH2:55][S:56][CH2:57][CH2:58][NH2:59])[N:54]=1)[C:47]([NH2:49])=[NH:48]>CO>[NH:46]([C:50]1[S:51][CH:52]=[C:53]([CH2:55][S:56][CH2:57][CH2:58][NH:59][C:16]2[C:12]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:3]3[N:4]=[CH:5][NH:6][C:2]=3[CH3:1])=[N:13][S:14](=[O:20])(=[O:19])[N:15]=2)[N:54]=1)[C:47]([NH2:49])=[NH:48]
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: COC1=NS(=O)(=O)N=C1NCCSCc1nc[nH]c1C
Agent: Cc1[nH]cnc1CSCCN
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Product: Cc1[nH]cnc1CSCCNC1=NS(=O)(=O)N=C1NCCSCc1csc(NC(=N)N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a well stirred solution at -10° of 3-{2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethylamino}-4-methoxy 1,2,5-thiadiazole 1,1-dioxide [prepared from the dihydrochloride of 2-{(5-methyl-1H-imidazol-4-yl)methylthio}ethylamine (2.73 g; 11.2 mmole) by the procedure of Step A of Example 1] was rapidly added a solution of 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine (from the dihydrochloride, 3.41 g; 11.2 mmoles) [prepared according to the procedure described in South African Pat. No. 78/2129] in 35 ml of methanol. After stirring at -10° for 30 minutes, the solution was allowed to warm to ambient temperature. The reaction mixture was evaporated under reduced pressure and the residue was placed on 45 g of silica gel and chromatographed using 1 liter of methylene chloride-methanol (4:1). The appropriate fractions were combined and evaporated, and the residue (5.82 g) was placed on 80 g of aluminum oxide and chromatographed using a gradient elution of ethyl acetate-methanol. The appropriate fractions were combined, filtered through Celite and evaporated under high vacuum to yield the title compound (2.5 g) as an amorphous solid containing approximately 2/3 mole of ethyl acetate, as ascertained by the NMR spectrum (100 MHz) in d6 dimethyl sulfoxide.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[C:47](OC(=O)C)(=[O:49])[CH3:48].O.[OH-].[Na+]>C(O)(=O)C>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:49])[CH3:48])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Reaction time: 3 h

Procedure:
To a solution 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazole-3-yl}phenylamine (0.200 g, 0.63 mmol), in acetic acid (6.0 mL) was added acetic anhydride (0.178 mL, 1.89 mmol). The reaction mixture was heated to reflux temperature for 12 hours. Water was added (10 mL) and the mixture was neutralized with 2.0 N aqueous sodium hydroxide. The product was extracted with ethyl acetate and concentrated to dryness. The crude oil was dissolved in 4 mL of ethanol and treated with 4 mL of commercial solution of hydrogen peroxide and 0.200 mL of 2.0 N aqueous sodium hydroxide. After 3 hours, the solvent was removed under reduced pressure. The resulting oil was dissolved in 5 mL of dimethoxy dimethyl formamide acetal and the solution was heated to reflux temperature for 3 hours. The solvent was removed under reduced pressure and the residue was dissolved in 10 mL of acetic acid and treated with 1 mL of anhydrous hydrazine. The reaction mixture was heated to reflux temperature for 12 hours. After neutralization with aqueous sodium hydroxide (2.0 N), the crude was extracted with ethyl acetate and purified by preparative HPLC (15–80% acetonitrile in water) (0.040 g, 20% over 5 steps): 1H NMR (DMSO-d6) δ 13.4 (br s, 1H), 10.1 (s, 1H), 8.7 (s, 1H), 8.4 (br s, 1H), 8.2 (s, 1H), 8.1 (d, 1H), 7.7 (t, 3H), 7.5 (t, 1H), 2.1 (s, 3H); ES-MS (m/z) 319 [M+1]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([SH:16])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].O.Cl[CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32]>CC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([S:16][CH2:21][N:22]2[C:23](=[O:32])[C:24]3=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]3[C:26]2=[O:27])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1CCl
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)c1cc(SCN2C(=O)c3ccccc3C2=O)cc(C(C)(C)C)c1O
Reaction time: 1 h
Yield: 73.3 %

Procedure:
A vessel was charged with 12.19 grams of 3,5-di-tert-butyl-4-hydroxybenzene thiol and 3.30 grams of potassium hydroxide dissolved in 50 ml of acetone and 2 ml of water at 0° C. which was mixed with 10.0 grams of N-(chloromethyl)phthalimide. After stirring for one hour, the precipitated product was removed by filtration and then recrystallized from ethyl acetate-hexane to give 14.9 grams of product, m.p. 151°-153° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)[CH3:2].[Li]CCCC.B(OC)(OC)[O:16]C>C1COCC1.CN(C)CCN(C)CCN(C)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([F:9])=[C:7]([OH:16])[CH:8]=1)[CH3:2]
Reactant: COB(OC)OC
Reactant: CCc1ccc(F)cc1
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc(F)c(O)c1
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of 1-ethyl-4-fluorobenzene (7.2 g, 58 mmol) in THF (30 mL) and N,N,N′,N″,N″-pentamethyldiethylenetriamine (3.0 mL) was added n-BuLi (1.6M in hexane, 42 mL) at −78° C. After 1 h stirring, trimethyl borate (13 mL) was added. The mixture was stirred from −78° C. to rt overnight. It was quenched by acetic acid (5.0 mL) and hydrogen peroxide solution (30% in water) at 0° C. The mixture was stirred for 2 h before extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4 and concentrate to give 118A (7.6 g, 94% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.19 (t, J=7.69 Hz, 3H) 2.56 (q, J=7.62 Hz, 2H) 6.60-6.71 (m, 1H) 6.83 (dd, J=8.79, 2.20 Hz, 1H) 6.95 (dd, J=10.55, 8.35 Hz, 1H).
Reaction SMILES: C([O:9][C@@H:10]1[C@@H:14]([CH2:15][O:16]C(=O)C2C=CC=CC=2)[O:13][C@@H:12]([N:25]2[CH:32]=[C:31]([C:33](F)(F)F)[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:11]1[O:37][CH3:38])(=O)C1C=CC=CC=1.[OH-].[NH4+:40]>>[CH3:38][O:37][C@@H:11]1[C@H:10]([OH:9])[C@@H:14]([CH2:15][OH:16])[O:13][C@H:12]1[N:25]1[CH:32]=[C:31]([C:33]#[N:40])[C:29](=[O:30])[NH:28][C:26]1=[O:27]
Reactant: CO[C@@H]1[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cc(C(F)(F)F)c(=O)[nH]c1=O
Reactant: [NH4+]
Agent: [OH-]
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(C#N)c(=O)[nH]c1=O
Temperature: 55 °C

Procedure:
3',5'-Di-O-benzoyl-2'-O-methyl-5-trifluoromethyluridine (1.0 g, 2.1 mmoles) was dissolved in concentrated ammonium hydroxide (60 ml) and heated in a sealed tube at 55° C. for 16 hours. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel (30 g) using a gradient of 0-5% methanol in CH2Cl2 to give 0.3 g (50% crude yield) of oil. A small portion of 2'-O-Methyl-5-cyanouridine crystallized from methanol as a slightly impure white solid, mp 208°-211° C. IR (potassium bromide pellet) 2240 cm-1 (sharp, CN); 1H NMR (DMSO-d6): δ3.45(s, 3H, OCH3), 3.5-3.6 (m, 1H, H-5'), 3.7-3.9 (m, 3H, H-3',4',5'), 4.13 (m, 1H, H-2'), 5.17 (d, J=6 Hz, 1H, 3'--OH), 5.48 (br t, 1H, 5'--OH), 5.75 (br s, 1H, H1'), 8.99 (d, J=1.5 Hz, 1H, H-6), 12.08 (br s, 1H, N--H). Anal. Calcd for C11H13N3O6 (283.24): C, 46.64; H, 4.63; N, 14.83. Found: C, 45.98; H, 4.63; N, 14.35.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](F)[C:16]=1[N+:22]([O-:24])=[O:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH2:25]([NH:32][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:16]=1[N+:22]([O-:24])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1c(F)cccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(NCc2ccccc2)cccc1OCc1ccccc1
Temperature: 110 °C
Yield: 88 %

Procedure:
Potassium carbonate (5.71 g., 41.4 mmol) was added to a solution of 1-benzyloxy-3-fluoro-2-nitro-benzene (6.818 g, 27.6 mmol) and benzylamine (3.32 mL, 30.34 mmol) in tetrahydrofuran, and the resulting suspension was heated to 110° C. for 2 hours. After cooling to room temperature, the mixture was poured onto 1 L of ice water and extracted twice with 150 mL ethyl acetate and twice with 75 mL dichloromethane. The combined organic fractions were dried over sodium sulfate and concentrated in vacuo in the presence of 25 g. silica gel. The preloaded silica gel was submitted to flash chromatography (8% to 35% ethyl acetate in hexanes) to give 8.118 g (24.28 mmol, 88%) of benzyl-(3-benzyloxy-2-nitro-phenyl)-amine as an orange solid. MS: 335 (M+H)+.
Reaction SMILES: O.O.[Sn](Cl)Cl.[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[N+:17]([O-])=O)[CH:10]=[N:9][CH:8]=1.[OH-].[Na+]>Cl>[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[NH2:17])[CH:10]=[N:9][CH:8]=1
Reactant: O=[N+]([O-])c1cccc2cncc(Cl)c12
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Nc1cccc2cncc(Cl)c12
Temperature: 25 °C
Yield: 67.5 %

Procedure:
Tin(II) chloride dihydrate (1.70 g) was dissolved in concentrated hydrochloric acid (1 ml), added with a mixture of Intermediate 89 (315 mg) and 2 N aqueous hydrochloric acid (2 ml) with ice cooling and refluxed with heating for 2 hours. The reaction mixture was cooled to room temperature, added with 5 N aqueous sodium hydroxide (7 ml) and extracted twice with chloroform (20 ml for each time). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (182 mg).
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:23][CH:22]=1)([S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH2:6][CH2:7][CH3:8])C>CO.[OH-].[Na+]>[N:30]1([CH2:29][CH2:28][O:27][C:24]2[CH:23]=[CH:22][C:21]([CH2:20][C:5]([S:9]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)(=[O:10])=[O:11])([CH2:6][CH2:7][CH3:8])[C:4]([OH:37])=[O:3])=[CH:26][CH:25]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCCC(Cc1ccc(OCCN2CCCCCC2)cc1)(C(=O)OCC)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(Cc1ccc(OCCN2CCCCCC2)cc1)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Yield: 34 %

Procedure:
2-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2 (4-methoxy-benzenesulfonyl)-pentanoic acid was prepared starting from 2-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-pentanoic acid ethyl ester (2 g, 3.76 mmol) dissolved in methanol (300 ml) and 10 N NaOH (15 ml). The resulting mixture was worked up as outlined in example 1. Yield 830 mg (44%); brown solid; mp 55° C.; MS: 504.4 (M+H)+.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[N:15]=[C:14]([Cl:16])[CH:13]=[C:12]([CH3:17])[N:11]=1.[CH3:18][C:19]([CH3:23])=[CH:20][CH2:21]Br.O>C1COCC1.C(OCC)(=O)C>[Cl:9][C:10]1[N:15]=[C:14]([Cl:16])[CH:13]=[C:12]([CH2:17][CH2:21][CH:20]=[C:19]([CH3:23])[CH3:18])[N:11]=1
Reactant: CC(C)=CCBr
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)=CCCc1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.3 %

Procedure:
The above synthesis may be carried out as follows: To a solution of LDA (1.28 g, 12 mmol) in THF (30 mL) at −78° C. was added 2,4-dichloro-6-methylpyrimidine (1.96 g, 12 mmol) in THF (15 mL). After stirring for 15 minutes, 3,3-dimethylallyl bromide (1.79 g, 12 mmol) in THF (5 mL) was added dropwise. After the reaction warmed to ambient temperature, water and ethyl acetate was added. The organic layer was separated, the solvent was removed in vacuo, and the residue was chromatographed (ethyl acetate/hexane, 1/19) to give 2.06 g (74%) of 2,4-dichloro-6-(4-methyl-3-pentenyl)pyrimidine (1H NMR (CDCl3) δ 7.15 (s, 1), 5.10 (t, 1), 2.80 (t, 2), 2.45 (m, 2), 1.70 (s, 3), 1.55 (s, 3)). To a solution of NaIO4 (17 g, 81 mmol) and KMnO4 (251 mg, 1.59 mmol) in water was added K2CO3 (1.29 g, 9.38 mmol) and 2,4dichloro-6-(4-methyl-3-pentenyl)pyrimidine (2.06 g, 8.9 mmol) in t-butanol. After stirring for 16 hours, the reaction was acidified to pH 3 and extracted with ethyl acetate. The organic layer was extracted with aqueous NaHCO3. The aqueous layer was acidified to pH 3 and extracted with ethyl acetate. The organic layer was dried and the solvent removed in vacuo to give 980 mg of 3-(2,4-dichloropyrimidin-6-yl)propionic acid (the compound of formula (XIX)), 1H NMR (CDCl3) δ 7.30 (s, 1), 3.05 (t, 2), 2.90 (t, 2). The acid was coupled to piperonylamine under standard conditions with isobutyl chloroformate and N-methylmorpholine to give the compound of formula (XX). Imidazole was added under standard conditions (1-trimethylsilylimidazole and CsF in DMF at 60° C.) to give N-[(1,3-benzodioxol-5-yl)ethyl]-6-chloro-2-(1H-imidazol-1-yl)pyrimidine-4-propionamide (the compound of formula (Ihh)); MS: 386 (M+H)+.
Reaction SMILES: CS(C)=O.[NH2:5][C@@H:6]1[C:24](=[O:25])[N:8]2[C:9]([C:21]([OH:23])=[O:22])=[C:10]([CH2:13][O:14][C:15](=[O:20])[CH2:16][C:17](=[O:19])[CH3:18])[CH2:11][S:12][C@H:7]12.[C:26](=O)([O:32]C(C)(C)C)[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].O>C(OCC)(=O)C>[C:28]([O:27][C:26]([NH:5][C@@H:6]1[C:24](=[O:25])[N:8]2[C:9]([C:21]([OH:23])=[O:22])=[C:10]([CH2:13][O:14][C:15](=[O:20])[CH2:16][C:17](=[O:19])[CH3:18])[CH2:11][S:12][C@H:7]12)=[O:32])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]2SC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
To 500 ml of dimethyl sulfoxide is added 200 g of 7β-amino-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid. To this 200 g of di-tert-butyl carbonate is added at room temperature and the mixture is stirred for 16 hours. To the reaction mixture are added 200 g of ice, 2 liters of water and 1 liter of ethyl acetate, and the mixture is stirred. After phase separation, the upper layer is discarded. To the aqueous layer is added 1 liter of ethyl acetate, and 129 g of phosphoric acid is added dropwise thereto while stirring (pH 4). After thorough mixing, the upper layer is separated and the lower layer is extracted with 1 liter of ethyl acetate. The organic layers are combined, washed with two 2-liter portions of ice-water and then with 1 liter of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated. To the residue is added 100 ml of methylene chloride, and the resulting mixture is concentrated and dried to give 194 g (74% yield) of the above-identified compound as a glassy solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][C:10]#[CH:11])=[CH:4][CH:3]=1.C[Li].I[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].CN(C)P(=O)(N(C)C)N(C)C>C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][C:10]#[C:11][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:6][CH:7]=1
Reactant: C#CCC(O[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Reactant: CCCCCI
Agent: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCC#CCC(O[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
To 2.2 g (63 mmol) of the silylacetylene of Example 2 dissolved in 50 ml of dry THF and cooled to -78° C. under argon was added dropwise 5.6 ml (7.0 mmol) of a 1.25M solution of methyl lithium in diethyl ether. Upon addition, the reaction was warmed to -10° C. and stirred at -10° C. for 30 min. Iodopentane (1.2 ml, 9.0 mmol) was then added followed by 5.0 ml of hexamethylphosphoric triamide (HMPA) whereupon the reaction mixture was warmed to R.T. and stirred overnight. The reaction was quenched with about 5.0 ml of H2O, then poured into hexane and washed 4× with H2O, and 1× with brine. The organic layer was dried (MgSO4) and the solvent removed to yield a dark red oil which was purified by medium pressure liquid chromotography (MPLC) eluting with hexane to yield 2.14 g of the titled product as a pale yellow oil.
Reaction SMILES: N[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH:14]([OH:16])[CH:13]([CH2:17][OH:18])[C:12]2=[CH2:19])=[C:4](I)[N:3]=1.Cl.[OH-:22].[Na+]>>[OH:16][CH:14]1[CH2:15][CH:11]([N:8]2[CH:7]=[N:6][C:5]3[C:4](=[O:22])[NH:3][CH:2]=[N:10][C:9]2=3)[C:12](=[CH2:19])[CH:13]1[CH2:17][OH:18]
Reactant: C=C1C(CO)C(O)CC1n1cnc2c(I)nc(N)nc21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: C=C1C(CO)C(O)CC1n1cnc2c(=O)[nH]cnc21
Temperature: 70 °C
Yield: 60 %

Procedure:
A mixture of 39 (0.5 g, 1.29 mmol) in sodium hydroxide (2 N, 10 mL) was heated at 70° C. under an atmosphere of argon for 1 hour to complete the reaction. The reaction mixture was cooled to 0° C. and neutralized slowly by addition of 3 N HCl. Decolorizing carbon (0.5 g) was added. This mixture was heated at ˜90° C. for 1 hour. The hot mixture was filtered through a bed of diatomaceous earth (Celite®). The resulting clear filtrate was cooled and seeded with 21 to effect crystallization. The product was collected by filtration and dried under vacuum to afford the title compound as a white crystalline solid (0.21 g, 60% yield).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10](O)[CH3:11].[Cl:13]C(Cl)C.S(Cl)(Cl)=O>>[Cl:13][CH:10]([C:2]1[NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1)[CH3:11]
Reactant: CC(O)c1nc2ccccc2[nH]1
Reactant: CC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CC(Cl)c1nc2ccccc2[nH]1
Temperature: 25 °C

Procedure:
1-(1H-Benzimidazol-2-yl)-ethanol (146) (1.00 g, 6.16 mmol) was suspended in dichloro ethane (50 mL, 800 mmol). Thionyl chloride (4.00 mL, 54.8 mmol) was added dropwise and the reaction was stirred at room temperature and then heated to 60° C. for 6 hours. After cooling to room temperature the reaction was evaporated to dryness under reduced pressure. The obtained solid was washed with ethyl acetate. The powder was suspended in ethyl acetate and washed with saturated sodium bicarbonate solution and brine. The organic portion was dried over anhydrous sodium sulfate and concentrated. The obtained off-white solid was used without further purification (147, 0.864 g, 76%). MS (ESI) [M+H+]+=181.2.
Reaction SMILES: [C:1]([N:8]=[N+]=[N-])(=[O:7])[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)C>[C:24]1([P:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:8][C:1]([O:2][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:7])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of t-butyl carbonazidate in diethyl ether, 49.6 g (0.189 mol) of triphenylphosphine was added in small portions under cooling with ice, and the reaction solution was stirred at room temperature for 1 hour, and the precipitated solid was collected by filtration, washed with 200 mL of hexane and dried under reduced pressure to give 67 g of the desired product as white crystals.