Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]1[O:5][C:4](=[O:6])[CH2:3]1.[Br:7]Br.[C:9]([O:12][CH2:13][C:14]1[CH2:15][S:16][C@@H:17]2[CH:24]([NH2:25])[C:23](=[O:26])[N:18]2[C:19]=1[C:20]([OH:22])=[O:21])(=[O:11])[NH2:10].C[Si](CC(N)=O)(C)C>C(Cl)Cl.C(OCC)(=O)C.O>[C:9]([O:12][CH2:13][C:14]1[CH2:15][S:16][C@@H:17]2[CH:24]([NH:25][C:4](=[O:6])[CH2:3][C:2](=[O:1])[CH2:5][Br:7])[C:23](=[O:26])[N:18]2[C:19]=1[C:20]([OH:22])=[O:21])(=[O:11])[NH2:10]
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: C=C1CC(=O)O1
Reactant: BrBr
Agent: C[Si](C)(C)CC(N)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CC(=O)CBr)[C@H]2SC1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 58.1 %

Procedure:
To a solution of 4-methylene-2-oxetanone (0.4 g.) in dried methylene chloride (5 ml.) was dropwise added a solution of bromine (0.75 g.) in dried methylene chloride (5 ml.) under cooling at -30° C., and then the mixed solution was stirred for 15 minutes at -10° to -5° C. Thus obtained solution was dropwise added to a solution of 3-carbamoyloxymethyl-7-amino-3-cephem-4-carboxylic acid (1.1 g.) and trimethylsilylacetamide (6.3 g.) in dried methylene chloride (15 ml.) under cooling at -20° C. The reaction temperature was gradually raised to at room temperature, and then the reaction mixture was stirred for 10 minutes at room temperature. After cooling the reaction mixture to at -20° C., water was added thereto, and then the mixture was stirred. The mixture was added a mixture of water (40 ml.) and ethyl acetate (80 ml.) with stirring, and the mixture was further stirred for 5 minutes, and then ethyl acetate layer was separated therefrom. The ethyl acetate layer was filtered, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then treated with activated carbon. After distillation of the solvent from the ethyl acetate layer, the residue was pulverized in diethyl ether, collected by filtration and then dried to give 3-carbamoyloxymethyl-7-(3-oxo-4-bromobutyramido)-3-cephem-4-carboxylic acid (1.02 g.)
Reaction SMILES: O[CH:2]([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24][CH2:23]2)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])[CH2:8][CH2:7]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+].C(OCC)C>ClC(Cl)C>[CH3:19][C:13]1[C:14]([CH3:18])=[CH:15][CH:16]=[CH:17][C:12]=1[N:9]1[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH:3]=[CH:2][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25](=[O:30])[CH2:24][CH2:23]3)[CH2:11][CH2:10]1
Reactant: Cc1cccc(N2CCN(CCCC(O)c3ccc4c(c3)CCC(=O)N4)CC2)c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(Cl)Cl
Product: Cc1cccc(N2CCN(CCC=Cc3ccc4c(c3)CCC(=O)N4)CC2)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.8 Grams of 6-{1-hydroxy-4-[4-(2,3-dimethylphenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyril and 0.5 g of p-toluenesulfonic acid were dissolved in 100 ml of dichloroethane then the mixture was refluxed for 20 minutes. The reaction mixture was concentrated under a reduced pressure to dryness then to the residue thus obtained were added 10N-NaOH and diethyl ether and stirred at a room temperature for 30 minutes. The crystals thus precipitated were collected by filtration and separated by a silica-gel chromatography. Recrystallized from ethanol-acetone-chloroform to obtain 6-{4-[4-(2,3-dimethylphenyl)piperazinyl]-1-butenyl}-3,4-dihydrocarbostyril in colorless needle-like crystals. Yield: 1.9 g.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.[CH3:10][O:11][C:12]([C:14]1[S:15][C:16]([CH2:19][CH2:20][CH2:21][C:22](=O)[CH2:23]Br)=[CH:17][CH:18]=1)=[O:13]>CN(C=O)C>[CH3:10][O:11][C:12]([C:14]1[S:15][C:16]([CH2:19][CH2:20][CH2:21][C:22]2[NH:9][C:4]3[N:3]=[C:2]([NH2:1])[NH:7][C:6](=[O:8])[C:5]=3[CH:23]=2)=[CH:17][CH:18]=1)=[O:13]
Reactant: Nc1cc(=O)[nH]c(N)n1
Reactant: COC(=O)c1ccc(CCCC(=O)CBr)s1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCCc2cc3c(=O)[nH]c(N)nc3[nH]2)s1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.6 %

Procedure:
To a suspension of 2,6-diaminopyrimidin-4-one (315 mg, 2.5 mmol) in anhydrous DMF (15 mL) was added 7 (about 2.4 mmol). The resulting mixture was stirred under N2 at room temperature for 3 days. After evaporation of solvent under reduced pressure, MeOH (20 mL) was added followed by silica gel (1.5 g). The resulting plug was loaded on to a silica gel column (3.5×12 cm) and eluted with CHCl3 followed by 3% MeOH in CHCl3 and then 5% MeOH in CHCl3. Fractions with an Rf=0.56 (MeOH/CHCl3 1:5) were pooled and evaporated to afford 300 mg of 8 as white powder in 38% yield. 1H NMR (DMSO-d6): δ 1.89-1.97 (m, 2H), 2.49-2.54 (t, J=7.2 Hz, 2H), 2.82-2.85 (t, J=7.2 Hz, 2H), 3.78 (s, 3H), 5.89 (s, 1H), 5.96 (s, 2H), 6.97-6.98 (d, J=3.6 Hz, 1H), 7.64-7.65 (d, J=3.6 Hz, 1H), 10.13 (s, 1H), 10.82 (s, 1H).
Reaction SMILES: ClC1C=CC=CC=1CN1C(CC(O)=O)=CN=C1SCCC.[CH2:22]([C:26]1[N:27]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[Cl:50])[C:28](/[C:31](/C)=C(\C2C=CN=CC=2)/C(O)=O)=[CH:29][N:30]=1)[CH2:23][CH2:24][CH3:25].[CH2:51]([CH:58]([C:64]1[S:65][CH:66]=[CH:67][CH:68]=1)[CH2:59][C:60]([O:62]C)=[O:61])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>>[CH2:22]([C:26]1[N:27]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[Cl:50])[C:28](/[CH:31]=[C:59](\[CH:58]([C:64]2[S:65][CH:66]=[CH:67][CH:68]=2)[CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)/[C:60]([OH:62])=[O:61])=[CH:29][N:30]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCc1ncc(/C(C)=C(/C(=O)O)c2ccncc2)n1Cc1ccccc1Cl
Reactant: COC(=O)CC(Cc1ccccc1)c1cccs1
Agent: CCCSc1ncc(CC(=O)O)n1Cc1ccccc1Cl
Product: CCCCc1ncc(/C=C(/C(=O)O)C(Cc2ccccc2)c2cccs2)n1Cc1ccccc1Cl

Procedure:
The title compound was prepared using the procedure of Example 1 (i, ii, iii, iv [Method B]) replacing methyl 3-(2-thienyl)propanoate with methyl 3-benzyl-3-(2-thienyl)propanoate [prepared following the procedure described in Tetra. 44 (7) 2055 (1988]; mp 200°-202° C.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:13][C:14]([CH3:29])=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25]Cl)=[CH:21][C:20]=3[O:27][CH3:28])[N:16]=2)[CH:7]=1)(=[O:4])=[O:3].[OH:30][C:31]1[C:35]([CH:36]=[O:37])=[CH:34][N:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:32]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:13][C:14]([CH3:29])=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][O:30][C:31]4[C:35]([CH:36]=[O:37])=[CH:34][N:33]([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:32]=4)=[CH:21][C:20]=3[O:27][CH3:28])[N:16]=2)[CH:7]=1)(=[O:4])=[O:3]
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2cccc(OS(C)(=O)=O)c2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2cccc(OS(C)(=O)=O)c2)oc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
To a mixture of 3-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl methanesulfonate (2.00 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.81 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 0.19 g) at room temperature, and the mixture was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl methanesulfonate as colorless crystals (1.43 g, yield 56%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 146-148° C.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:9][CH3:10])[C:6]([OH:8])=O)(=[O:3])[CH3:2].N1C=CC=CC=1.ClC(=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1>[C:1]([NH:4][CH:5]([CH2:9][CH3:10])[C:6](=[O:8])[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:3])[CH3:2]
Reactant: CCC(NC(C)=O)C(=O)O
Reactant: CCOC(=O)C(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(CC)NC(C)=O
Temperature: 25 °C

Procedure:
9.2 g (63.4 mmol) 2-(Acetylamino)butanoic acid are suspended in 120 ml tetra-hydrofurane and heated to reflux together with 15.0 g (190 mmol) pyridine and a bit of N,N-dimethylaminopyridine. While heating at reflux, 17.3 g (127 mmol) ethyl chloro(oxo)acetate are added dropwise. The reaction mixture is heated at reflux until no more evolution of gas can be observed. After cooling down to room temperature, the reaction mixture is added to ice water and the organic phase extracted with ethyl acetate. The dried organic phase is evaporated to dryness in vacuo, dissolved in ethanol and the solution directly used for the next reaction.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]1[NH:17][C:18](=[O:25])[C:19]([CH:22]([CH3:24])[CH3:23])([CH3:21])[N:20]=1)[C:10]([C:26]([OH:28])=[O:27])=[CH:9]2>CO>[CH:22]([C:19]1([CH3:21])[C:18](=[O:25])[NH:17][C:16]([C:11]2[C:10]([C:26]([OH:28])=[O:27])=[CH:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([N:5]=[C:1]=[S:2])[CH:7]=3)[N:12]=2)=[N:20]1)([CH3:24])[CH3:23]
Reactant: S=C(Cl)Cl
Reactant: CC(C)C1(C)N=C(c2nc3ccc(N)cc3cc2C(=O)O)NC1=O
Solvent: CO
Product: CC(C)C1(C)N=C(c2nc3ccc(N=C=S)cc3cc2C(=O)O)NC1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
Thiophosgene (0.12 mL, 1.56 mmol) is added to a solution of the above prepared formula III 6-amino-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-3-quinolinecarboxylic acid (170 mg, 0.521 mmol) and methanol (25 mL). The reaction mixture is stirred for five minutes at room temperature and then concentrated in vacuo. The residue is redissolved into a small amount of methanol, filtered and the filtrate is added to 25 mL of ether. The resulting precipitate is collected, washed with ether and dried under reduced pressure to give 2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl) -6-isothiocyano-3-quinolinecarboxylic acid as a brown powder (190 mg). The product is obtained in the form of a tricyclic anhydride which hydrolyses to the acid in water or during subsequent reaction in aqueous media. The purity of this material is determined by TLC on silica gel with chloroform, methanol and acetic acid (220:30:6) elution.
Reaction SMILES: C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.[NH2:23][CH:24]([CH2:29][CH2:30][CH2:31][CH3:32])[C:25]([O:27][CH3:28])=[O:26]>ClCCl>[CH:14](=[N:23][CH:24]([CH2:29][CH2:30][CH2:31][CH3:32])[C:25]([O:27][CH3:28])=[O:26])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: CCCCC(N)C(=O)OC
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(N=Cc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Triethylamine (8.67 g) (supplied from Wako Pure chemical Industries), 7.74 g of magnesium sulfate anhydrate and 4.55 g of benzaldehyde were added to a suspension of 7.79 g of methyl 2-aminohexanoate hydrochloride in 70 mL of dichloromethane, and stirred at room temperature overnight. The reaction suspension was filtrated, and the filtrate was concentrated. Then 280 mL of ether was added to the residue. The resulting suspension was filtrated and the filtrate was concentrated. Again 280 mL of ether was added to the residue, and the filtration and the concentration were repeated in the same manner, to yield 10.0 g of the title compound.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][N:7]1[C:11]([NH2:12])=[C:10]([NH2:13])[CH:9]=[N:8]1.[CH2:14]([O:21][C:22]([NH:24][C@@H:25]([CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26](O)=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[NH2:12][C:11]1[N:7]([CH3:6])[N:8]=[CH:9][C:10]=1[NH:13][C:26]([C@@H:25]([NH:24][C:22](=[O:23])[O:21][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:34])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:27]
Reactant: Cn1ncc(N)c1N
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of 1-methyl-1H-pyrazole-4,5-diamine sulfate (2.10 g), (2S)-2-[(benzyloxycarbonyl)amino]-5-[(tert-butoxycarbonyl)amino]pentanoic acid (3.66 g) and triethylamine (3.04 g) in chloroform (50 ml) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.91 g), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude product of 1-benzyl 4-tert-butyl {(1S)-1-[(5-amino-1-methyl-1H-pyrazol-4-yl)carbamoyl]tetramethylene}biscarbamate as an oil. The crude product was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.ClC(Cl)(O[C:29](=[O:35])[O:30][C:31](Cl)(Cl)Cl)Cl.[CH3:37][O:38][C:39]1[CH:40]=C(O)[CH:42]=[CH:43][CH:44]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:30][C:31]2[CH:42]=[CH:43][CH:44]=[C:39]([O:38][CH3:37])[CH:40]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cccc(O)c1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(OC(=O)Nc2cc(C)c(Oc3ccnc4cc(OC)c(OC)cc34)cc2C)c1
Yield: 41 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-methoxyphenol (29 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (30 mg, yield 39%).
Reaction SMILES: [O:1]=[C:2]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]([OH:18])=O)[C:3](=[O:9])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.[NH:19]([C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([CH3:31])[N:22]=1)[NH2:20].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:31][C:23]1[N:22]=[C:21]([NH:19][NH:20][C:16]([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][N:10]2[C:2](=[O:1])[C:3](=[O:9])[C:4]2[S:5][CH:6]=[CH:7][CH:8]=2)=[O:18])[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=1
Reactant: Cc1cc(C(F)(F)F)cc(NN)n1
Reactant: O=C(C(=O)N1CCCCC1C(=O)O)c1cccs1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)cc(NNC(=O)C2CCCCN2C(=O)C(=O)c2cccs2)n1

Procedure:
From Intermediate 3 (267 mg, 1 mmol), 2-hydrazino-6-methyl-4-trifluoromethylpyridine (191 mg, 1 mmol), PyBrop (466 mg, 1 mmol), DMAP (122 mg) and DIEA (2 mL) in THF (30 mL), using the same procedure for Compound 1, the title compound was obtained as a white solid; 110 mg (25%). MS (m/z) 441 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([CH:12]([CH3:14])[CH3:13])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([N:15]2[CH2:19][C@H:18]([C:20]([O:22]C)=O)[O:17][C:16]2=[O:24])[CH:3]=1.[NH3:25]>CO>[F:1][C:2]1[C:7]2[N:8]([CH:12]([CH3:14])[CH3:13])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([N:15]2[CH2:19][C@H:18]([C:20]([NH2:25])=[O:22])[O:17][C:16]2=[O:24])[CH:3]=1
Reactant: COC(=O)[C@H]1CN(c2cc(F)c3c(c2)oc(=O)n3C(C)C)C(=O)O1
Reactant: N
Solvent: CO
Product: CC(C)n1c(=O)oc2cc(N3C[C@H](C(N)=O)OC3=O)cc(F)c21

Procedure:
Prepared from methyl (5R)-3-(4-fluoro-3-isopropyl-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylate (Step 4, 0.250 g, 7.39 mmol) and ammonia in methanol (5 ml) according to the method of EXAMPLE 86, Step 10 (0.14 g, 59%); MS for C14H14FN3O5 m/z 324 (M+H)+; 1H NMR (DMSO-d6, 300 Mhz) δ 7.88 (br s, 1H), 7.63 (br s, 1H), 7.53 (d, 1H), 7.44 (dd, 1H), 5.04 (dd, 1H), 4.55 (m, 1H), 4.26 (t, 1H), 4.02 (dd, 1H), 1.41 (dd, 6H).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[NH:4][CH2:5][CH2:6][CH2:7][N:8]=1.[OH-].[Na+].[O-:11]S([O-])(=O)=O.[Na+].[Na+].C[C:19]1[C:20]([C:28]([F:31])([F:30])[F:29])=[C:21]([N:25]=[C:26]=[O:27])[CH:22]=[CH:23][CH:24]=1>C1COCC1>[OH2:11].[ClH:1].[NH:8]1[CH2:7][CH2:6][CH2:5][N:4]=[C:3]1[NH:2][C:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[CH:19][C:20]=1[C:28]([F:29])([F:30])[F:31])=[O:27]
Reactant: NC1=NCCCN1
Reactant: Cc1cccc(N=C=O)c1C(F)(F)F
Reactant: O=S(=O)([O-])[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O
Product: O=C(NC1=NCCCN1)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 9.90 g (0.073 mol) of 2-amino-1,4,5,6-tetrahydropyrimidine hydrochloride, 6.0 g (0.075 mol) of 50% NaOH and 75 ml of THF was stirred for 0.75 hours at room temperature and then 10 g. Na2SO4 was added. After stirring for 0.5 hours, a solution of 9.36 g. (0.050 mol) of methyl-2-trifluoromethylphenyl isocyanate in 50 ml of THF was added over a period of 0.5 hours. After stirring for 1 hour, the reaction mixture was filtered, the filtrate evaporated in vacuo and the residue dissolved in 50 ml of 10% HCl and 100 ml of H2O with warming. After filtration through a pad of diatomaceous earth, chilling in ice gave the crystalline hydrychloride which was recrystallized from hot H2O affording 10.09 g (63%). This material was dried to constant weight in vacuo (20° C., 5 mm Hg) to give pure N-(1,4,5,6 -tetrahydropyrimidin-2-yl)-N'-(2-trifluoromethylphenyl)urea monohydrochloride hydrate; m.p. (120) 182.5°-184.5° C. IR(CHCl3) 3240 (br), 1717, 1642, 1594 cm-1 ; UV max. (MeOH) 281 infl (ε6,900), 256 nm (ε29,000) and 215 nm (ε14,900).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[N:10]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>O.Cl>[ClH:1].[Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH:4][NH2:10]
Reactant: O=N[O-]
Reactant: Cc1ccc(N)c(Cl)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(NN)c(Cl)c1
Temperature: -5 °C

Procedure:
A suspension of 2-chloro-4-methyl aniline (10.1 mL, 11.63 g, 82.1 mmol) in 64 mL water and 60 mL 12 N HCl was cooled to −5° C. (internal temperature) and stirred with a mechanical stirrer. A solution of sodium nitrite (8.26 g, 119.7 mmol) in 56 mL water was added over 30 minutes. The solution became more clear but some solid remained. The mixture was stirred at −5° C. for 20 minutes and then cooled to −10° C. A solution of tin(II) chloride dihydrate (53.60 g, 237.6 mmol) in 36 mL 12 N HCl was added dropwise over 30 minutes while maintaining an internal temperature of −5 to −10° C. The resulting pinkish-brown mixture was stirred at −5 to −10° C. for 2 hours and then filtered cold through a pre-chilled fritted glass funnel. The collected solids were washed with cold 1% ethanol in ether (100 mL) followed by cold ether (500 μL) and air dried for 30 minutes. After drying in vacuo, the desired product was obtained as a very pale yellow crystalline solid (7.76 g, 49%). 1H NMR δ (300 MHz, CDCl3) δ 10.09 (bs, 2H), 7.89 (s, 1H), 7.25 (dd, 1H, Jm=1.2 Hz), 7.13 (dd, 1H, Jo=8.4 Hz, Jm=1.2 Hz), 7.02 (d, 1H, Jo=8.4 Hz), 2.24 (s, 3H); MS (CI) m/z 157/159.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:12]1([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23]3[N:28]=[C:27]([NH2:29])[CH:26]=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)[CH2:14][CH2:13]1>N1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:29][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH:12]3[CH2:13][CH2:14]3)[CH2:21][CH2:20]2)[N:28]=1)=[O:5]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: Nc1cccc(OC2CCN(CC3CC3)CC2)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cccc(OC2CCN(CC3CC3)CC2)n1)c1ccc(F)cc1Cl
Reaction time: 15 h
Yield: 79.4 %

Procedure:
Add 2-chloro-4-fluorobenzoyl chloride (149 mg, 0.58 mmol) to a solution of 6-(1-cyclopropylmethyl-piperidin-4-yloxy)-pyridin-2-ylamine (preparation 70, 130 mg, 0.53 mmol) in pyridine (7 mL) and beat at 55° C. for 15 hr. Remove pyridine in vacuo, dissolve the residue in CH2Cl2, wash with saturated NaHCO3 solution, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel, eluting with 5% 2M NH3-Methanol in CH2Cl2) provides 170 mg (79%) of the title compound: mass spectrum (ion spray): 404.1 (M+1); 1H NMR (CDCl3, ppm): 8.08 (s, 1H), 7.63 (m, 2H), 7.52 (t, 1H), 7.11 (m, 1H), 6.99 (m, 1H), 6.41 (d, 1H), 4.82 (m, 1H), 2.72 (m, 2H), 2.26 (m, 2H), 2.17 (d, 2H), 1.89 (m, 2H), 1.69 (m, 2H), 0.77 (m, 1H), 0.40 (m, 2H), 0.00 (m, 2H). Hydrochloride salt: Analytical calc. for C21H23ClFN3O2.HCl.0.5H2O: C, 56.13; H, 5.61; N, 9.35. Found: C, 56.12; H, 5.30; N, 9.35.
Reaction SMILES: [C:1]([C:3]1[CH:38]=[CH:37][C:6]([CH2:7][C@@:8]2([CH3:36])[N:12]3[C:13]([S:16]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[C:24]([NH2:26])=[O:25])(=[O:18])=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=3)[C:9]2=[O:35])=[CH:5][CH:4]=1)#[N:2].[C:39](OC(=O)C)(=[O:41])[CH3:40]>>[C:39]([NH:26][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[S:16]([C:13]1[N:12]2[C@@:8]([CH2:7][C:6]3[CH:37]=[CH:38][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)([CH3:36])[C:9](=[O:35])[N:10]([C:27]3[CH:28]=[C:29]([Cl:34])[CH:30]=[C:31]([Cl:33])[CH:32]=3)[C:11]2=[N:15][CH:14]=1)(=[O:18])=[O:17])=[O:25])(=[O:41])[CH3:40]
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(S(=O)(=O)N3CCC[C@H]3C(N)=O)n21
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1
Temperature: 100 °C

Procedure:
(S)-1-[(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl]-pyrrolidine-2-carboxylic acid amide (98 mg, 0.17 mmol) was dissolved in acetic anhydride (3 mL, 0.05 M). The reaction was heated to 100° C. for 18 h. The mixture was concentrated, toluene added, and the mixture concentrated again. The residue was chromatographed over silica with a solvent system of 10% MeOH in methylene chloride to provide 19 mg of the title compound as a white solid (M+1, 615).