Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:36][CH2:37][CH3:38])=[C:28]([CH:35]=1)[O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:36][CH2:37][CH3:38])=[C:28]([CH:35]=2)[O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:4][CH:5]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCCc1ccc(O)cc1OCC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1OCC(=O)OC
Temperature: 90 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.79 g), methyl 2-(5-hydroxy-2-propylphenoxy)acetate (1.17 g), anhydrous potassium carbonate (0.72 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (1.60 g, 61%) of methyl 2-[5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-2-propylphenoxy]acetate from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 100-101° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[S:45][N:44]=[N:43][C:42]=1[CH3:46])=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:39]([C:41]2[S:45][N:44]=[N:43][C:42]=2[CH3:46])=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Reactant: CON(C)C(=O)c1snnc1C
Product: Cc1nnsc1C(=O)c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1F

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3) and N-methoxy-N,4-dimethyl-1,2,3-thiadiazole-5-carboxamide
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]#[CH:15])[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26](I)=[C:25]([F:30])[CH:24]=1>[Cu](I)I.C(NCC)C>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([C:15]#[C:14][C@H:11]2[CH2:12][CH2:13][C@H:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:9][CH2:10]2)=[C:25]([F:30])[CH:24]=1
Reactant: C#C[C@H]1CC[C@H](CCCCCCC)CC1
Reactant: Fc1cc(-c2ccccc2F)ccc1I
Agent: I[Cu]I
Solvent: CCNCC
Product: CCCCCCC[C@H]1CC[C@H](C#Cc2ccc(-c3ccccc3F)cc2F)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1-(trans-4-heptylcyclohexyl)acetylene (28.40 mmol), 2′,3-difluoro-4-iodobiphenyl (28.40 mmol), tetrakis(triphenylphosphine)palladium(0)dichloromethane (0.85 mmol), copper iodide (1.43 mmol), and diethylamine (200 ml) is stirred for 4 hrs at room temperature. The reaction mixture obtained is extracted with toluene (200 ml) twice. The extract is washed with water (150 ml) three times and dried over anhydrous magnesium sulfate. The toluene solution is concentrated under reduced pressure, purified by silica-gel chromatography, and further recrystallized to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:31]1([N:37]=[C:38]=[S:39])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH:21][C:38]([NH:37][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[S:39])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8]
Reactant: S=C=NC1CCCCC1
Reactant: COc1ccc(Cl)cc1C(=O)NCCC1CCN(S(N)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(Cl)cc1C(=O)NCCC1CCN(S(=O)(=O)NC(=S)NC2CCCCC2)CC1
Yield: 44.5 %

Procedure:
376 mg (1 mmol) of 4-(2-(5-chloro-2-methoxybenzamido)ethyl)piperidine-1-sulfonamide and 652 mg (2.0 mmol) of cesium carbonate were heated in 5 ml of N-methyl-2-pyrrolidone with 0.3 ml (2 mmol) of cyclohexyl isothiocyanate at 80° C. for 10 minutes. The reaction mixture was poured onto ice/2 M hydrochloric acid, and the precipitated solid was filtered off with suction, washed with water until neutral, dissolved in methanol, filtered after addition of activated carbon and crystallized using diethyl ether. 230 mg (45%) of the title compound were obtained as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17]O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br>C(OCC)(=O)C.CO.ClCCl.CN(C)C=O>[N:19]([CH2:17][C@@H:13]1[C@@H:14]([OH:16])[CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(OCc1ccccc1)N1C[C@H](CO)[C@@H](O)C1
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Temperature: 60 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
Process (B): (3R,4R)-[1-Benzyloxycarbonyl-4-hydroxypyrrolidin-3-yl]methanol (3.00 g), sodium azide (2.32 g), triphenylphosphine (3.43 g) and N,N-dimethylformamide (60 mL) were mixed with each other. While the mixture was cooled on an ice bath, a dichloromethane solution (14 mL) of carbon tetrabromide (4.34 g) was added dropwise. The reaction mixture was stirred for 25 hours at room temperature and additional 2 hours at 60° C., followed by addition of methanol (5 mL) and concentration under reduced pressure. The resulting residue was dissolved in ethyl acetate (200 mL) and was washed with a saturated aqueous solution of sodium chloride (2×50 mL), followed by drying over anhydrous sodium sulfate and concentration under reduce pressure. The resulting residue was purified on silica gel column (eluant=ethyl acetate:hexane=2:1) to give 2.94 g of (3R,4R)-3-azidomethyl-1-benzyloxycarbonyl-4-hydroxypyrrolidine as a pale brown syrup-like product. This compound was identical to the compound obtained by Process (A).
Reaction SMILES: C(OC(=O)[N:7]([CH3:25])[C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](SC)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)(C)(C)C.[NH2:27][CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH3:25][NH:7][C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:27][CH:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1
Reactant: CSc1nccc(-c2cnc3c(N(C)C(=O)OC(C)(C)C)nccn23)n1
Reactant: NC1CCOCC1
Product: CNc1nccn2c(-c3ccnc(NC4CCOCC4)n3)cnc12

Procedure:
Methyl-{3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-amine was prepared by a process analogous to that described in Example 12 starting from methyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamic acid tert-butyl ester (from Example 8 supra), and 4-amino-tetrahydropyran.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][C:6]1[S:10][C:9]([NH2:11])=[N:8][N:7]=1>C(OCC)(=O)C>[CH3:5][C:6]1[S:10][C:9]([N:11]=[C:1]=[O:2])=[N:8][N:7]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1nnc(N)s1
Solvent: CCOC(C)=O
Product: Cc1nnc(N=C=O)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-methyl-2-amino-1,3,4-thiadiazole (40 grams) in ethyl acetate (300 ml) is added to the reaction vessel and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-methyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [N+]([C@H:3]1[C:6](=[O:7])[NH:5][C@@H:4]1[CH2:8][C:9]([O:15][CH3:16])=[CH:10][C:11]([O:13][CH3:14])=[O:12])#[C-].C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[CH3:16][O:15][C:9]([CH2:8][C@@H:4]1[CH2:3][C:6](=[O:7])[NH:5]1)=[CH:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: [C-]#[N+][C@H]1C(=O)N[C@@H]1CC(=CC(=O)OC)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: COC(=O)C=C(C[C@@H]1CC(=O)N1)OC
Temperature: 25 °C
Yield: 78.8 %

Procedure:
A mixture of methyl 4-[(2R,3R)-3-isocyano-4-oxoazetidin-2-yl]-3-methoxybut-2-enoate[(E,Z)-isomeric mixture](50 mg), tri-n-butyltin hydride (90 μl), and 2,2'-azobis-(2-methylpropionitrile) (5 mg) in benzene (5 ml) was heated to reflux for one hour under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and chromatographed on silica gel (2.5 g) eluting first with dichloromethane and then 4% methanol in dichloromethane to give methyl 3-methoxy-4-[(2R)-4-oxoazetidin-2-yl]but-2-enoate[(E,Z)-isomeric mixture](35 mg) as a crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[N:17]1.Cl.C(N=C=NCCCN(C)C)C>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([O:12][N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[N:17]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)On1nnc2ccccc21
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a solution of 2-tert-butoxycarbonylamino-2-methylpropionic acid (2.03 g) and 1-hydroxybenzotriazole (1.35 g) in N,N-dimethylfolmamide (20 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.91 g) and the mixture was stirred overnight. The reaction mixture was partitioned between a mixture of ethyl acetate and n-hexane and water. The separated organic layer was washed in turn with water, a saturated sodium hydrogencarbonate in water and brine and dried over magnesium sulfate. The organic layer was evaporated under reduced pressure to give benzotriazol-1-yl 2-tert-butoxycarbonylamino-2-methylpropionate (2.94 g, 91.9%) as a solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[CH:21]=[C:20]([CH2:22][C:23]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=4)=[O:24])[NH:19][N:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1.[CH2:33]([NH:35][CH2:36][CH2:37][OH:38])[CH3:34].CN(C)C(=O)C>O>[CH2:33]([N:35]([CH2:36][CH2:37][OH:38])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[CH:21]=[C:20]([CH2:22][C:23]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=4)=[O:24])[NH:19][N:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1)[CH3:34]
Reactant: O=C(Cc1cc(Nc2ncnc3cc(OCCCCl)ccc23)n[nH]1)Nc1cccc(F)c1
Reactant: CCNCCO
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCN(CCO)CCCOc1ccc2c(Nc3cc(CC(=O)Nc4cccc(F)c4)[nH]n3)ncnc2c1
Temperature: 90 °C
Yield: 85 %

Procedure:
2-(3-{[7-(3-Chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide and 2-(ethylamino)ethanol (ideally 12 molar equivalents) were added to N,N-dimethylacetamide under an inert atmosphere (such as provided by nitrogen) and the mixture heated to 90° C. with stirring. After a period of 12-16 hours (ideally 12 hours) the reaction is cooled back to about 85° C. and water added in a controlled manner to maintain the temperature between 80-85° C. The batch is adjusted to 80° C. and seeded with crystals of the preferred form of the product (ideally an amount of about 1% of the expected yield). The mixture was cooled to 20° C. in a carefully controlled manner over a period of about 20 hours so as to crystallise the product in the required form and of a size sufficient to afford a good filtration rate. The product is then filtered and washed with a mixture of water/N,N-dimethylacetamide and acetonitrile and suitably deliquored to afford a hydrated form of the product. Following this, the cake is slurried in situ for a period (ideally 2 hours) with warm acetonitrile (ideally at a temperature of 40° C.) then filtered, washed with more acetonitrile and then dried (in vacuo or under a stream of nitrogen) to afford the almost anhydrous 2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide as an off-white solid in a yield of 85-90%.
Reaction SMILES: [F:1][CH:2]([F:39])[O:3][C:4]1[CH:5]=[N:6][C:7]2[N:8]([N:10]=[CH:11][C:12]=2[C:13]2[CH:14]=[C:15]([C:20]([NH:22][C@H:23]3[C:28]([F:30])([F:29])[CH2:27][CH2:26][CH2:25][C@H:24]3[NH:31]C(=O)OC(C)(C)C)=[O:21])[S:16][C:17]=2[CH2:18][CH3:19])[CH:9]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[NH2:31][C@H:24]1[C@@H:23]([NH:22][C:20]([C:15]2[S:16][C:17]([CH2:18][CH3:19])=[C:13]([C:12]3[CH:11]=[N:10][N:8]4[CH:9]=[C:4]([O:3][CH:2]([F:1])[F:39])[CH:5]=[N:6][C:7]=34)[CH:14]=2)=[O:21])[C:28]([F:29])([F:30])[CH2:27][CH2:26][CH2:25]1
Reactant: CCc1sc(C(=O)N[C@@H]2[C@H](NC(=O)OC(C)(C)C)CCCC2(F)F)cc1-c1cnn2cc(OC(F)F)cnc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1sc(C(=O)N[C@@H]2[C@H](N)CCCC2(F)F)cc1-c1cnn2cc(OC(F)F)cnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl {(1R,2R)-2-[({4-[6-(difluoromethoxy)pyrazolo[1,5-a]pyrimidin-3-yl]-5-ethylthiophen-2-yl}carbonyl)amino]-3,3-difluorocyclohexyl}carbamate (0.037 g, 0.064 mmol) was dissolved in dichloromethane (0.639 mL) and trifluoroacetic acid (0.250 mL, 3.24 mmol) was added. The reaction was stirred at room temperature for 2 h. 5N NaOH (aq) was added and extracted 3× with dichloromethane. The organic layers were combined, dried with sodium sulfate, filtered, and concentrated. The material was purified by column chromatography (0-5% MeOH/DCM) to give the title compound. LRMS (APCI) calc'd for (C20H21F4N5O2S) [M+H]+, 472.1; found 472.1. 1H NMR (CD3OD, 500 MHz) δ 9.04 (d, J=2.4, 1H), 8.59 (d, J=2.4, 1H), 8.35 (s, 1H), 8.13 (s, 1H), 6.97 (t, J=72.5, 1H), 3.24 (s, 1H), 3.02 (q, J=7.5, 2H), 2.15 (s, 1H), 1.48-1.99 (m, 4H), 1.32 (t, 3H), 1.00-1.18 (m, 2H).
Reaction SMILES: [C-:1]1([O:6][CH2:7][C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.[Fe+2:16].P(Cl)(Cl)[Cl:18]>N1C=CC=CC=1.C1C=CC=CC=1>[C-:1]1([O:6][CH2:7][C:8]([Cl:18])=[O:10])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.[Fe+2:16]
Reactant: ClP(Cl)Cl
Reactant: O=C(O)CO[c-]1cccc1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(Cl)CO[c-]1cccc1
Reaction time: 3 h
Yield: 83.8 %

Procedure:
To ferrocenyloxyacetic acid (1.56 g, 0.006 m) and pyridine (4 drops) in benzene (100 cm3) was added dropwise phosphorous (III) chloride (5.4 cm3). The mixture was stirred for 3 hours at 60° to 70° C. After this time the benzene solution was decanted and the benzene removed under vacuum. The residue was taken up in benzene and the benzene again removed under vacuum. This procedure was repeated. Recrystallization from light petroleum (40° to 60°) gave 1.40 g (83.8%) of ferrocenyloxyacetyl chloride. The chloride (1.40g, 0.005 m) was taken up in dichloromethane (5cm3) and added dropwise to a mixture of 6-aminopenicillanic acid (1.08 g, 0.005 m) and triethylamine (1.01 g, 0.01 m) in dichloromethane (25 cm3) at 0° C. The mixture was stirred for 15 minutes at 0° C. and for 1 hour at 15° C. The solution was then filtered and the solvent removed under vacuum. The residue was taken up in a mixture of water (100 cm3) and ethyl acetate (25 cm3) and the aqueous layer adjusted to pH 2.5 with 2M HCl. The layers were separated and the ethyl acetate layer washed with water, dried, filtered and a 40% solution of SEH in 4-methylpentan-2-one (2 cm3) added. Worked up as previously the yield was 1.53 (67%) of the sodium salt of 6-(2-ferrocenyloxyacetamido) penicillanic acid. I.r. spectrum showed strong β-lactam absorption at 1770 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][CH:15]([C:17]([OH:19])=O)[N:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]2=[O:26])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH3:27][C:28]1[C:29]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[N:30][CH:31]=[CH:32][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][CH:15]([C:17]([N:37]3[CH2:38][CH2:39][N:34]([C:29]4[C:28]([CH3:27])=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:35][CH2:36]3)=[O:19])[N:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]2=[O:26])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccnc1N1CCNCC1
Reactant: COc1cccc(S(=O)(=O)N2CC(C(=O)O)N(c3ccccc3)C2=O)c1
Product: COc1cccc(S(=O)(=O)N2CC(C(=O)N3CCN(c4ncccc4C)CC3)N(c3ccccc3)C2=O)c1

Procedure:
In analogy to example 1, (RS)-1-(3-methoxy-benzenesulfonyl)-2-oxo-3-phenyl-imidazolidine-4-carboxylic acid (step 4 of example 1) was reacted with 1-(3-methyl-pyridin-2-yl)piperazine to give the title compound as a colorless solid. MS: 536.2 ([M+H]+)
Reaction SMILES: C(O)(=O)C.[CH3:5][N:6]([C:17]1[N:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=1)[N:7]=[C:8]1[CH2:13][CH:12]2[C:14]([CH3:16])([CH3:15])[CH:9]1[CH2:10][CH2:11]2.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH3:5][N:6]([C:17]1[N:18]=[N:19][C:20]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:21][CH:22]=1)[N:7]=[C:8]1[CH2:13][CH:12]2[C:14]([CH3:16])([CH3:15])[CH:9]1[CH2:10][CH2:11]2
Reactant: CN(N=C1CC2CCC1C2(C)C)c1ccc(Cl)nn1
Reactant: C1COCCN1
Solvent: CC(=O)O
Product: CN(N=C1CC2CCC1C2(C)C)c1ccc(N2CCOCC2)nn1
Temperature: 145 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
A mixture of 33.9 g (0.1 moles) of 1,7,7-trimethyl-2-bicyclo(2,2,1)heptylidene-(6-chloro-3-pyridazinyl)-hydrazine acetate and 43.5 g /0.5 moles/ of morpholine is reacted while stirring at 145° C. for 8 hours. Then the excess of morpholine is removed under vacuum, the residue is triturated with 100 ml of water, filtered and dried to give 30.5 g (92.6%) of the title compound; m.p. 188°-190° C. (after recrystallization from ethanol).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:3]=1.Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([N:26]2[CH2:27][CH2:28][CH:23]([C:20]3[CH:19]=[CH:18][C:17]([F:16])=[CH:22][CH:21]=3)[CH2:24][CH2:25]2)[N:3]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:5]=1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(Cl)nc(NCCO)nc1N1CCC(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4,6-dichloro-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (example 41a) was treated with 4-(4-fluoro-phenyl)-piperidine hydrochloride in dioxane in the presence of N-ethyl-diisopropyl-amine at room temperature to yield 4-chloro-6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as a white lyophilisate; MS: [M+H]+=376.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[F:11].[SH:12][C:13]1[N:18]=[C:17]([OH:19])[CH:16]=[C:15]([OH:20])[N:14]=1.[OH-].[K+]>>[F:11][C:4]1[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][S:12][C:13]1[N:18]=[C:17]([OH:19])[CH:16]=[C:15]([OH:20])[N:14]=1
Reactant: Oc1cc(O)nc(S)n1
Reactant: COc1cccc(CBr)c1F
Agent: [K+]
Agent: [OH-]
Product: COc1cccc(CSc2nc(O)cc(O)n2)c1F

Procedure:
The subtitle compound was prepared as a white solid by the method of Example 39 step i) using 1-(bromomethyl)-2-fluoro-3-methoxybenzene (4.5 g), 2-mercaptopyrimidine-4,6-diol (2.96 g) and potassium hydroxide (1.15 g). Yield: 5.0 g.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:20]([C:25]1[CH:30]=[CH:29][C:28]2[O:31][CH2:32][O:33][C:27]=2[CH:26]=1)[C:21]([O:23][CH3:24])=[O:22]>CN(C=O)C>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:20]([C:25]2[CH:30]=[CH:29][C:28]3[O:31][CH2:32][O:33][C:27]=3[CH:26]=2)[C:21]([O:23][CH3:24])=[O:22])=[C:3]([CH2:10][CH2:11][CH3:12])[CH:4]=1
Reactant: COC(=O)C(Br)c1ccc2c(c1)OCO2
Reactant: CCCc1cc(CO)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(CO)ccc1OC(C(=O)OC)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81308200 %

Procedure:
To a solution of 3.84 g (23.13 nmole) of 4-hydroxy-3-n-propylbenzyl alcohol dissolved in 70 mL of anhydrous DMF was added 9.04 g (27.7 mmol) of cesium carbonate and the reaction mixture was magnetically stirred at room temperature for 15 minutes. Methyl α-bromo-3,4-methylenedioxyphenylacetate (7.58 g; 27.7 mmol) was added and the reaction mixture was then stirred for an additional 14 hours at room temperature under a nitrogen atmosphere. The reaction was then partitioned between 5% aqueous citric acid (700 mL) and EtOAc (100 mL) and extracted. The organic layer was separated, washed with saturated aqueous NaCl, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 40% EtOAc-hexane. The purified fractions were combined, evaporated, and dried in vacuo to afford 6.74 g (81%) of the title compound as a yellow oil.
Reaction SMILES: C(O[C:4](=[O:29])[CH2:5][N:6]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:7][CH2:8][CH:9]=[N:10][C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])C.[Li+].CC([N-]C(C)C)C>C1COCC1.[Cl-].[NH4+]>[CH2:22]([O:21][C:19]([N:6]1[CH2:7][CH2:8][C@@H:9]2[C@H:5]1[C:4](=[O:29])[N:10]2[C@@H:11]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:12])=[O:20])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)CN(CCC=N[C@H](C)c1ccccc1)C(=O)OCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C(=O)[C@@H]2[C@H]1CCN2C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 6 h
Yield: 52.1 %

Procedure:
2-{Benzyloxycarbonyl-[3-(1(R)-phenyl-ethylimino)-propyl]-amino}-acetic acid ethyl ester (0.909 g; 2.29 mmol) is dissolved in dry THF (20 ml). The reaction mixture is cooled to −78° C. and LDA (1.6 ml of a 2M solution in THF) is added slowly. The reaction mixture is stirred for 6 hours at −78° C. Then, the reaction mixture is poured in chilled saturated aqueous ammonium chloride solution and extracted with ethyl acetate; the phases are separated. The aqueous phase is extracted twice with ethyl acetate (2 times 100 ml). The combined organic phases are washed with water (50 ml) and with brine twice (2 times 50 ml). The organic phase is dried over magnesium sulfate. The solids are filtered off and the solvent is removed under reduced pressure. The crude product is purified by column chromatography over silicagel (eluent: hexane/ethyl acetate 50:1 to 10:1). 0.418 g of a colorless yellow oil (yield 52%) are obtained.