Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25](C3N=CN=C(N)C=3OC)[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:38]1[N:43]=[CH:42][N:41]=[C:40]([NH2:44])[C:39]=1[O:45][CH:46]([CH3:48])[CH3:47]>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)[N:9]=[C:8]2[CH:22]2[CH2:23][CH2:24][N:25]([C:38]3[N:43]=[CH:42][N:41]=[C:40]([NH2:44])[C:39]=3[O:45][CH:46]([CH3:48])[CH3:47])[CH2:26][CH2:27]2)[CH2:2][CH2:3][CH2:4]1
Reactant: COc1c(N)ncnc1N1CCC(c2nc(-c3ccnc(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Reactant: CC(C)Oc1c(N)ncnc1Cl
Product: CC(C)Oc1c(N)ncnc1N1CCC(c2nc(-c3ccnc(C(F)(F)F)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-methoxypyrimidin-4-amine using 6-chloro-5-isopropoxypyrimidin-4-amine instead of 6-Chloro-5-methoxy-pyrimidin-4-ylamine. LC-MS: (M+1=531, obsd.=531).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:28])[C@@H:15]([N+:25]([O-])=O)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH3:24])[CH2:12][O:11][C@@H:10]([O:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@@H:9]1[CH3:35])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.[Ni](Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:28])[C@@H:15]([NH2:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH3:24])[CH2:12][O:11][C@@H:10]([O:29][CH2:30][C:31]([CH3:32])([CH3:34])[CH3:33])[C@@H:9]1[CH3:35])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCc1ccccc1C[C@@H]([C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C)[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCc1ccccc1C[C@H](N)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Dissolve the mixture of diastereomers from the previous reaction containing (2R,3S,5R)-2-(2,2-dimethylpropoxy)-5-[(1R,2S)-3-(2-ethylphenyl)-1-hydroxy-2-nitropropyl]-3-methylmorpholine-4-carboxylic acid tert-butyl ester in dry methanol (12 mL) and add nickel (II) chloride (267 mg, 2.06 mmol). To the resulting suspension, add sodium borohydride (284 mg, 7.5 mmol) portion-wise over 1 minute. After 30 minutes, quench with water and reduce the volume on the rotary evaporator. Add more water and saturated aqueous sodium chloride. Extract with ethyl acetate. Combine the extracts, dry (sodium sulfate), filter and concentrate to give a diastereomeric mixture of amines containing the desired compound as a light brown oil (418 mg, 85%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:12](O)[CH2:13][OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[O:11]1[CH2:12][CH2:13][O:14][CH:10]1[C:7]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1cc(C2OCCO2)ccc1F
Temperature: 70 °C

Procedure:
To a solution of 2-fluoro-5-formylbenzonitrile (450 mg, 3 mmol) in toluene (10 mL) was added ethylene glycol (2 mL) and p-toluene sulfonic acid (25 mg). The solution was heated to 70° C. overnight. The solution was cooled to room temperature. Ethyl acetate (100 mL) was added and the solution was washed with sat. sodium bicarbonated (10 mL), water (10 mL) and brine (10 mL), dried over MgSO4 and concentrated to a clear oil (567 mg, 98%). 1H NMR (400 MHz, CDCl3) δ 7.78 (dd 1H, J=6.3, 2.3 Hz), 7.74-7.70 (m, 1H), 7.27-7.24 (m, 1H), 5.80 (s, 1H), 4.14-4.08 (m, 4H).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH2:5]([OH:11])[CH2:6][O:7][CH2:8][CH2:9][OH:10]>C1COCC1.[H-].[Na+]>[CH2:1]([O:11][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10])[CH:2]=[CH2:3]
Reactant: OCCOCCO
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOCCOCCO
Yield: 82 %

Procedure:
Diethylene glycol monoallyl ether was prepared by reacting allyl bromide with excess diethylene glycol in THF-NaH (tetrahydrofuran-sodium hydride). The product was obtained in 82% yield after distillation. b.p.=96-99° C./7 mmHg.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:32])[CH:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=2)[CH2:20][CH2:21][CH3:22])=[CH:13][CH:12]=1)(=[O:4])=[O:3].Cl.[Cl-].[OH:35][NH3+:36].C(N(CC)CC)C>CO.O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:32])[CH:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[NH:31])[NH:36][OH:35])[CH:25]=2)[CH2:20][CH2:21][CH3:22])=[CH:15][CH:16]=1)(=[O:3])=[O:4]
Reactant: [NH3+]O
Reactant: CCCC(Oc1cccc(C#N)c1)C(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: CCCC(Oc1cccc(C(=N)NO)c1)C(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A solution of 1.40 g (3.12 mmol) of 2-(3-cyanophenoxy)pentanoic acid (2′-methanesulfonylbiphenyl-4-yl)amide in 50 ml of methanol is treated with 695 mg (10.0 mmol) of hydroxylammonium chloride hydrochloride and 1.01 g (10.0 mmol) of triethylamine and stirred at 60° C. for 18 hours. It is allowed to cool, the solvent is stripped off, the residue is taken up in water and the resulting precipitate is filtered off. A colourless solid is obtained; FAB 482
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CS([C:11]1[N:12]=[C:13]([CH2:37][CH2:38][CH3:39])[C:14]2[N:19]=[C:18]([C:20]3[CH:34]=[C:33]([CH3:35])[C:23]([O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:22]([CH3:36])[CH:21]=3)[O:17][C:15]=2[N:16]=1)(=O)=O.[F:40][C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=1[OH:48]>CN1C(=O)CCC1.C(OCC)(=O)C>[F:40][C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=1[O:48][C:11]1[N:12]=[C:13]([CH2:37][CH2:38][CH3:39])[C:14]2[N:19]=[C:18]([C:20]3[CH:34]=[C:33]([CH3:35])[C:23]([O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:22]([CH3:36])[CH:21]=3)[O:17][C:15]=2[N:16]=1
Reactant: CCCc1nc(S(C)(=O)=O)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Reactant: Oc1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCCc1nc(Oc2cc(F)ccc2F)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Temperature: 110 °C
Yield: 38.1 %

Procedure:
68 mg of potassium carbonate were added to a solution of 107 mg of tert-butyl [4-(5-methanesulfonyl-7-propyloxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethylphenoxy]acetate in 1.1 ml of NMP, and 32 mg of 2,5-difluorophenol were then added. The reaction mixture was heated in a microwave synthesizer to 110° C. for 5 min and then cooled and poured onto ice. The precipitated compound was taken up in ethyl acetate, washed with water until neutral, dried over sodium sulfate, filtered and concentrated. The crude product was chromatographed on silica gel (heptane/ethyl acetate), giving 45 mg (38%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].[CH2:22](O)[CH3:23]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH2:22][CH3:23])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1F
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1ccc(C)c(F)c1
Temperature: 25 °C

Procedure:
To a solution (50 mL) of 3-fluoro-4-methylbenzoic acid (5.0 g, 32 mmol) in ethanol was added conc. sulfuric acid (0.25 mL), and the mixture was heated under reflux overnight. The reaction mixture was allowed to cool to room temperature, and neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained crude product was purified by column chromatography (hexane-hexane/ethyl acetate=80/20) to give the title compound as a colorless oil.
Reaction SMILES: C[O-].[Na+].Cl.[C:5]([NH2:8])(=[NH:7])[CH3:6].[Cl:9][CH:10]([C:15](=O)[CH3:16])[C:11](OC)=[O:12].Cl>CO.CCOCC>[Cl:9][C:10]1[C:11]([OH:12])=[N:7][C:5]([CH3:6])=[N:8][C:15]=1[CH3:16]
Reactant: COC(=O)C(Cl)C(C)=O
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: Cc1nc(C)c(Cl)c(O)n1
Temperature: 80 °C

Procedure:
Sodium methoxide (328 mg, 6.08 mmol, 30% solution in MeOH) was added to a stirring suspension of acetamidine hydrochloride (191 mg, 2.03 mmol) and methyl 2-chloro-3-oxobutanoate (500 mg, 3.04 mmol) in MeOH (10.1 mL). The reaction mixture was heated to 80° C. for 3 hours and then cooled to room temperature. With stirring, the reaction was treated with 2N HCl in Et2O (50 mL), and then concentrated in vacuo. The resulting solid was suspended in 1:1 acetone/CH2Cl2, stirred vigorously for 10 mins, and the solids collected by filtration to afford the title compound as a light yellow solid. The isolated product was sufficiently pure to use in the subsequent step without further purification. LRMS m/z (M+H) 159.2 found, 159.0 required.
Reaction SMILES: [CH2:1]([C:4]([CH2:15][CH2:16][C:17]([OH:19])=O)([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3].C(Cl)(=O)C([Cl:23])=O>C1C=CC=CC=1>[C:5]([C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH2:1][CH:2]=[CH2:3])[CH2:15][CH2:16][C:17]([Cl:23])=[O:19])([O:7][CH2:8][CH3:9])=[O:6]
Reactant: C=CCC(CCC(=O)O)(C(=O)OCC)C(=O)OCC
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: C=CCC(CCC(=O)Cl)(C(=O)OCC)C(=O)OCC
Temperature: 70 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
A benzene solution (14.5 ml) containing diethyl allyl(2-carboxyethyl)malonate (1.95 g, 7.2 mmol) and oxalyl chloride (2.3 g, 18.1 mmol) was stirred at 70° C. for 1 hour. After cooling to room temperature, the reaction liquid was freed of solvent by vacuum distillation. Thus there was obtained 1.92 g of 4,4-dicarboethoxy-6-heptenic acid chloride (yields: 91%). Characteristic Values of 4,4-dicarboethoxy-6-peptenic acid chloride
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[N:20]1[N:24]=[CH:23][CH:22]=[N:21]1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=2[N:20]2[N:24]=[CH:23][CH:22]=[N:21]2)=[O:11])=[N:27][CH:28]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-n2nccn2)[C@@H]1CN
Reactant: Clc1ccc(Br)nc1
Product: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-n2nccn2)[C@@H]1CNc1ccc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(4,5-difluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. ESI-MS (m/z): 447 [M+1]+.
Reaction SMILES: [Na+].[I-].C([O-])([O-])=O.[K+].[K+].[CH2:9]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH2:10][CH2:11][CH3:12].Cl[CH2:20][CH2:21][CH2:22][N:23]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][CH2:25][C:24]1=[O:33]>C(#N)C.CO>[CH2:9]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:20][CH2:21][CH2:22][N:23]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH2:25][C:24]2=[O:33])[CH2:15][CH2:14]1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCC1CCNCC1
Reactant: O=C1COc2ccccc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: CCCCC1CCN(CCCN2C(=O)COc3ccccc32)CC1
Reaction time: 13 h

Procedure:
NaI (1.33 g, 8.87 mmol), K2CO3 (1.23 g, 8.90 mmol, and 4-butylpiperidine (0.66 g, 4.71 mmol) in acetonitrile (10 mL) were stirred at rt. 4-(3-chloropropyl)-4H-benzo[1,4]oxazin-3-one (1.0 g, 4.43 mmol) in acetonitrile (15 mL) was added via a syringe. The reaction was stirred at 60 C. for 13 hours and then at 80 C. for another 5 hours under nitrogen atmosphere and concentrated in vacuo. Water (150 mL) was added and the reaction mixture was extracted with ethyl acetate (3×150 mL). The combined organic phases were dried (Na2SO4) and concentrated in vacuo to give 1.58 g of crude. The crude product was subjected to CC[eluent:EtOAC:MeOH(100:1-5%)] to give the pure title compound. Yield 0.82 g 56.0% HPLC-MS [M+H]+331 (UV/MS(%)=11/99. 1H NMR (CDCl3): δ 0.88 (t, 3H), 1.21 (m, 6H), 1.26 (m, 3H), 1.66 (d, 2H), 1.86 (m, 4H, 2.37 (t, 2H), 2.86, (d, 2H), 3.97 (t, 2H), 4.58 (s, 2H), 6.99 (m, 3H), 7.11 (d, 1H), 13C NMR (CDCl3): δ 14.22, 23.04, 24.90, 29.17, 32.68, 35.95, 36.46, 39.74, 54.31, 56.02, 67.77, 115.26, 117.15, 122.83, 123.83, 128.78, 145.50, 164.34.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([CH3:12])[CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]([F:28])[C:23]([C:26]#[CH:27])=[N:24][CH:25]=2)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]([F:28])[C:23]([C:26]#[C:27][C:2]3[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([CH3:12])[CH:3]=3)=[N:24][CH:25]=2)=[CH:16][CH:15]=1
Reactant: Cc1cc(I)ccc1OCCO
Reactant: C#Cc1ncc(-c2ccc(Cl)cc2)cc1F
Product: Cc1cc(C#Cc2ncc(-c3ccc(Cl)cc3)cc2F)ccc1OCCO

Procedure:
The product was obtained analogously to Example 7.1e starting from 2-(4-iodo-2-methylphenoxy)ethanol and 5-(4-chlorophenyl)-2-ethynyl-3-fluoropyridine. Yield: 1.40 g (68% of theoretical); C22H17ClFNO2 (M=381.827); calc.: molpeak (M+H)+: 382/384 (Cl); found: molpeak (M+H)+: 382/384 (Cl); HPLC-MS: 6.29 minutes (method B).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[N:10][C:9]([Br:27])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].[N-:32]=[N+:33]=[N-].[Na+].CCOCC>C(O)(C(F)(F)F)=O.O>[N:1]([C:2]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([S:18]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)(=[O:19])=[O:20])=[CH:16][CH:17]=2)=[N:10][C:9]([Br:27])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[N+:32]=[N-:33]
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(S(=O)(=O)N3CCOCC3)cc2)c1N
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)c1cc(Br)nc(-c2ccc(S(=O)(=O)N3CCOCC3)cc2)c1N=[N+]=[N-]
Reaction time: 0.33 h
Yield: 87.6 %

Procedure:
Methyl 3-amino-6-bromo-2-(4-(morpholinosulfonyl)phenyl)-isonicotinate (0.988 g, 2.17 mmol) was dissolved in TFA (11 mL) and the yellow solution was cooled in an ice bath. Powdered sodium nitrite (0.299 g, 4.33 mmol) was added with stirring to give a dark red mixture with gas evolution. After 20 min, powdered sodium azide (1.41 g, 21.7 mmol) was added over 5 min followed by Et2O (11 mL). A thick precipitate formed and, after 30 min, water was added and the mixture was extracted with EtOAc. The organic phase was washed with water (3×), brine (1×), saturated aqueous Na2CO3 solution (so that the aqueous phase was basic), and brine. After drying the solvent with sodium sulfate, the solvent was removed and silica gel chromatography (step gradient elution with DCM containing 0 to 10% EtOAc) afforded methyl 3-azido-6-bromo-2-(4-(morpholinosulfonyl)phenyl)isonicotinate (918 mg, 1.90 mmol, 88% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 7.93-7.96 (2H, m), 7.87 (1H, s), 7.85 (2H, d, J=8.24 Hz), 4.03 (3H, s), 3.73-3.77 (4H, m), 3.03-3.07 (4H, m).
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:36][C:37]1[CH:42]=[C:41]([CH2:43][OH:44])[CH:40]=[CH:39][N:38]=1.[F:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]([N:54]2[CH2:59][CH2:58][N:57]3[N:60]=[C:61](O)[CH:62]=[C:56]3[CH2:55]2)=[O:53])=[CH:48][CH:47]=1>C1COCC1>[F:45][C:46]1[CH:47]=[CH:48][C:49]([C:52]([N:54]2[CH2:59][CH2:58][N:57]3[N:60]=[C:61]([O:44][CH2:43][C:41]4[CH:40]=[CH:39][N:38]=[C:37]([CH3:36])[CH:42]=4)[CH:62]=[C:56]3[CH2:55]2)=[O:53])=[CH:50][CH:51]=1
Reactant: Cc1cc(CO)ccn1
Reactant: O=C(c1ccc(F)cc1)N1CCn2nc(O)cc2C1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(COc2cc3n(n2)CCN(C(=O)c2ccc(F)cc2)C3)ccn1
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 35.5 %

Procedure:
Di-tert-butyl azodicarboxylate (0.138 g, 0.6 mmol) was added to a stirred solution of triphenylphosphine (0.157 g, 0.6 mmol), (2-methylpyridin-4-yl)methanol (0.074 g, 0.6 mmol) and 5-[(4-fluorophenyl)carbonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ol (0.157 g, 0.6 mmol) in THF (3 mL) in a sealed tube and under nitrogen. The mixture was stirred at 130° C. for 20 minutes under microwave irradiation and the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7 M solution of ammonia in methanol in DCM 0/100 to 5/95, twice). The desired fractions were collected, the solvents evaporated in vacuo and the residue triturated with DIPE to yield 5-[(4-fluorophenyl)carbonyl]-2-[(2-methylpyridin-4-yl)methoxy]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (0.078 g, 35% yield) as a white solid. C20H19FN4O2. 1H NMR (400 MHz, CDCl3) δ ppm 2.56 (s, 3 H), 4.08 (br. s., 4 H), 4.74 (br. s., 2 H), 5.17 (s, 2 H), 5.52 (br. s., 1 H), 7.10-7.18 (m, 3 H), 7.21 (br. s, 1 H), 7.45-7.52 (m, 2 H), 8.47 (d, J=5.1 Hz, 1 H).
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[F:14][C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1>C(O)CC(C)C>[F:14][C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][CH2:25][N:24]([C:3]3[NH:12][C:11](=[O:13])[C:10]4[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=4[N:4]=3)[CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1
Reactant: Fc1cccc(N2CCNCC2)c1
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Solvent: CC(C)CCO
Product: O=c1[nH]c(N2CCN(c3cccc(F)c3)CC2)nc2c1CCCC2

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol) and 1-(3-fluorophenyl)piperazine (82.6 μl; 0.51 mmol) are reacted in isoamyl alcohol (1 ml) in accordance with the procedure for Example 1 and worked up; yield: 54 mg (32%), crystals;
Reaction SMILES: C(OC[N:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][C:17](=[O:25])[NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:11]=[N:10]1)(=O)C(C)(C)C.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[CH2:34][CH2:35][C:36](O)=[O:37]>>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[CH2:34][CH2:35][C:36]([N:22]1[CH2:21][CH2:20][CH:19]([NH:18][C:17](=[O:25])[CH2:16][CH2:15][CH2:14][C:12]2[N:11]=[N:10][NH:9][CH:13]=2)[CH2:24][CH2:23]1)=[O:37]
Reactant: O=C(O)CCc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)C(=O)OCn1cc(CCCC(=O)NC2CCNCC2)nn1
Product: O=C(CCCc1c[nH]nn1)NC1CCN(C(=O)CCc2ccc(Cl)cc2Cl)CC1

Procedure:
The title compound was prepared from (4-(4-oxo-4-(piperidin-4-ylamino)butyl)-1H-1,2,3-triazol-1-yl)methyl pivalate (Example 37, step 5) (200 mg, 0.516 mmol) and commercially available 3-(2,4-dichlorophenyl)propanoic acid (Fisher) (113 mg, 0.516 mmol) analogously to Example 38, steps 1 and 2;
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]1=[O:9].[Cl:10][C:11]1[C:12]([C:17]([F:20])([F:19])[F:18])=[N:13][NH:14][C:15]=1[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:10][C:11]1[C:12]([C:17]([F:19])([F:18])[F:20])=[N:13][N:14]([CH:2]2[CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]2=[O:9])[C:15]=1[CH3:16]
Reactant: O=C1OCCCCC1Br
Reactant: Cc1[nH]nc(C(F)(F)F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Cl)c(C(F)(F)F)nn1C1CCCCOC1=O
Temperature: 65 °C
Yield: 19.5 %

Procedure:
To a solution of 3-bromooxepan-2-one (1 g, 5.18 mmol) in DMF (10 mL) was added 4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazole (0.956 g, 5.18 mmol), followed by potassium carbonate (1.07 g, 7.74 mmol). The reaction mixture was then heated at 65° C. for 8 h. After cooling to room temperature, the reaction mixture was partitioned between water (20 mL) and ethyl acetate (30 mL). The organic layers were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography (SiO2, 25% EtOAc/hexanes) gave the title product as a white solid (0.3 g, 1.01 mmol, 20%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O-:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].I[CH:28]([O:30][C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH3:29].O.C(OCC)(=O)C>CS(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O:20][CH:28]([O:30][C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH3:29])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)OC(=O)OC(C)I
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)OC(=O)OC(C)C)=CCS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.6 %

Procedure:
To a solution of sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) (4.0 g) in dimethylsulfoxide (40 ml) was added isopropyl 1-iodoethoxyformate (5.1 g). The mixture was stirred for 30 minutes at ambient temperature and poured into a mixture of cold water and ethyl acetate. The organic layer was separated out and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulfate and evaporated to dryness. The residue was subjected to column chromatography on silica gel (50 g) using a mixture of benzene and ethyl acetate (3:2) as an eluent. The eluates containing an object compound were collected and evaporated to dryness to give 1-isopropoxycarbonyloxyethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) (1.5 g), mp 120° to 125° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (25.55 g, 123 mmol) in CH2Cl2 (250 ml), cooled to 0° C., is slowly added Et3N (18.95 ml, 135.4 mmol) followed by methane sulfonyl chloride (9.569 ml, 123.14 mmol) and DMAP (152 mg, 1.23 mmol). The mixture is stirred at room temperature overnight. The suspension is diluted with CH2Cl2 and the phases are separated. The aqueous phase is re-extracted 3× with CH2Cl2. The combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. Upon concentration, the desired compound precipitates and is collected by filtration to afford, after drying in HV, the title compound as a colorless solid.