Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CCOCC.CCCCCC>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19]
Reactant: Brc1ccccn1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOC(=O)C(=O)c1ccccn1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 20 mL (210 mmol) of 2-bromopyridine in 500 mL of dry ether at −78° C. under Ar was added 85 mL of a 2.5 M solution of n-butyllithium in hexane in a slow stream. After stirring in the cold for 30 min, the solution was transferred over a 5 min period via two cannula into a 0° C. stirred solution of 100 mL (736 mmol) of diethyl oxalate in 1.0 L of dry ether under Ar. After stirring for 2 h in the cold, the reaction mixture was washed with 600 mL of sat. NaHCO3, water, and brine. The solution was dried over MgSO4 and the solvents concentrated at reduced pressure to give a red oil that was purified by SiO2 chromatography (10×15 cm) using 1:4 to 35:65 EtOAc-hexanes. The product-containing fractions were concentrated at reduced pressure to afford I-1-1 as a reddish oil: 1H NMR (CDCl3) δ1.42 (t, 3H), 4.45-4.55 (m, 2H), 7.55-7.6 (m, 1H), 7.9-7.95 (m, 1H), 8.11 (d, 1H), 8.78 (d, 1H).
Reaction SMILES: [CH:1]1(C(Cl)=O)CCCC1.[CH:9]1([C:14]([N:16]=[C:17]=[S:18])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26]N=[C:24]2[O:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[C:36]([F:41])[CH:35]=1.C1(C)C=CC=CC=1>C(O)C>[CH:9]1([C:14]([N:16]=[C:17]=[S:18])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH:9]1([C:14]([NH:16][C:17]([NH:38][C:37]2[CH:39]=[CH:40][C:34]([O:33][C:24]3[C:23]4[C:28](=[CH:29][C:30]([O:31][CH3:32])=[C:21]([O:20][CH3:19])[CH:22]=4)[N:27]=[CH:26][CH:1]=3)=[CH:35][C:36]=2[F:41])=[S:18])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(Cl)C1CCCC1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(N=C=S)C1CCCC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)C4CCCC4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
1-Cyclopentanecarbonyl isothiocyanate was prepared using commercially available 1-cyclopentanecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 1-Cyclopentanecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (35 mg, yield 47%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([S:19][CH3:20])[C:3]=1[C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28].C(Cl)Cl.[CH:33]([NH2:35])=O>>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]1[N:35]=[CH:33][N:1]=[C:2]2[N:6]([C:7]3[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=3[Cl:18])[N:5]=[C:4]([S:19][CH3:20])[C:3]=12
Reactant: CSc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(=O)c1ccccc1Cl
Reactant: NC=O
Solvent: ClCCl
Product: CSc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c2ncnc(-c3ccccc3Cl)c12
Temperature: 150 °C

Procedure:
A suspension of 669 mg (1.39 mmol) of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(2-chlorobenzoyl)-3-methylthiopyrazole in 5 mL of formamide was heated at 150° C. overnight. A pale yellow solid precipitated upon cooling of the reaction mixture. A total of 50 mL of water was added to the stirred suspension to complete the precipitation of the product which was filtered off and washed with water. An inseparable trace of starting material was observed in the product by thin layer chromatography (TLC) and so the above procedure was repeated on the mixture giving a brown solid containing no trace of starting material. Trituration of this solid with methylene chloride gave a pale yellow solution which was concentrated to give the desired product as a white crystalline solid, m.p. 156-158° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[CH:8]([NH:10][C:11]1[N:16]=[C:15]([N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]2)[CH:14]=[CH:13][N:12]=1)[CH3:9].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+].Cl>CS(C)=O.CCOC(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:4][CH:3]1[CH:8]([NH:10][C:11]1[N:16]=[C:15]([N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]2)[CH:14]=[CH:13][N:12]=1)[CH3:9]
Reactant: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CNCCN1C
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CN(Cc2ccccc2)CCN1C

Procedure:
To a solution of 2-[1-(1-methylpiperazine-2-yl)-ethylamino]-4-[benzimidazol-1-yl]-pyrimidine (EXAMPLE 20; 3 mg) in 4 mL of DMSO was added benzyl bromide (2 μL) and K2CO3 (2.2 mg). The mixture was stirred for 2d at room temperature, then diluted with 5 mL of EtOAc and poured into 10 mL of 1N HCl. The phases were separated and the aqueous phase was basified (pH>11) with 5N NaOH and extracted with 4×5 mL of EtOAc. The combined organics were dried over Na2SO4 and concentrated. The residue was purified by preparative thin-layer chromatography, eluting with 95:5 CH2Cl2—MeOH to provide 1.9 mg of the title compound. Mass spectrum (ESI) 428.4 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[Br:13][CH2:14][CH2:15]Br>>[Br:13][CH2:14][CH2:15][O:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=1
Reactant: CCCCOc1cccc(O)c1
Reactant: BrCCBr
Product: CCCCOc1cccc(OCCBr)c1
Yield: 84.6 %

Procedure:
Prepared analogously to the method described in Example D above from 3-(n-butoxy)phenol (16.6 g; 0.1 mol; from Example B above) and 1,2-dibromoethane (100 ml; 1.16 mol). Following work up, the residue was chromatographed on silica gel with diisopropyl ether as eluent. The resultant oil was distilled to to yield 23.1 g (85%) of the title compound as an oil which subsequently crystallised (98% purity). bp 105-108° C. (0.01 mm Hg) mp 32-34° C. MW=273 (GC-MS)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:14][N:13]=[C:12]([C:15]([OH:17])=O)[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:42]1([CH2:48][NH2:49])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:42]1([CH2:48][NH:49][C:15]([C:12]2[CH:11]=[C:10]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][N:2]=[CH:3]4)[O:14][N:13]=2)=[O:17])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: NCC1CCCCC1
Reactant: O=C(O)c1cc(-c2ccc3[nH]ncc3c2)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC1CCCCC1)c1cc(-c2ccc3[nH]ncc3c2)on1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
5-(1H-Indazol-5-yl)isoxazole-3-carboxylic acid (35 mg, 0.15 mmol, Example 71A), was dissolved in N,N-dimethylformamide (0.8 mL) followed by the addition of HATU (60 mg, 0.15 mmol) dissolved in N,N-dimethylformamide (0.8 mL). Then a solution of 1-cyclohexylmethanamine (17 mg, 0.17 mmol), dissolved in N,N-dimethylformamide (0.8 mL) was added, followed by diisopropylethylamine (56 μL, 0.31 mmol) dissolved in N,N-dimethylformamide (0.8 mL). The resulting mixture was shaken for 3 hours at 40° C. The reaction was filtered, checked by LC/MS and concentrated to dryness. The residues were dissolved in 1:1 dimethyl sulfoxide/methanol and purified by reverse phase HPLC (Phenomenex® Luna® C8(2) 5 μm 100A AXIA™ column (30 mm×75 mm), 50 mL/min, 10-100% acetonitrile/0.1% trifluoroacetic acid in water) to provide the title product. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.91-0.97 (m, 2H), 1.12-1.27 (m, 4H), 1.61-1.75 (m, 5H), 3.08-3.16 (m, 2H), 7.22-7.24 (m, 1H), 7.71-7.75 (m, 1H), 7.87-7.92 (m, 1H), 8.23-8.27 (m, 1H), 8.38-8.41 (m, 1H). MS (ESI+) m/z 325 (M+H)+; (ESI−) m/z 323 (M−H)−.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15]([NH:17][C@@H:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:19][SH:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].[N+:25](/[CH:28]=[CH:29]/[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([O-:27])=[O:26]>C(#N)C>[C:10]([O:14][C:15]([NH:17][C@@H:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:19][S:20][CH:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:28][N+:25]([O-:27])=[O:26])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: COC(=O)[C@@H](CS)NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](CSC(C[N+](=O)[O-])c1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
Diisopropylethylamine (3.38 mL, 19.4 mmol) was added to a solution of methyl N-(tert-butoxycarbonyl)-D-cysteinate (3.04 g, 12.9 mmol) and □-trans-nitrostyrene (1.93 g, 12.92 mmol) in acetonitrile (80 mL). After 15 min, the reaction was concentrated. Purification by silica gel chromatography (100% hexanes→30% ethyl acetate/hexanes) gave the title compound (4.52 g).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:51])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][CH:23]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH2:24]2)[CH:17]=[C:16]([C:36]([O:38]CC)=[O:37])[C:15]3=[O:41])=[C:8]([C:42]2[S:43][CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[N:46]=2)[CH:7]=1)[CH3:2].[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([NH:3][C:4](=[O:51])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][CH:23]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH2:24]2)[CH:17]=[C:16]([C:36]([OH:38])=[O:37])[C:15]3=[O:41])=[C:8]([C:42]2[S:43][CH:44]=[C:45]([C:47]([F:50])([F:48])[F:49])[N:46]=2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3CC2CCN(CCN3CCOCC3)C2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3CC2CCN(CCN3CCOCC3)C2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
Ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-((1-(2-morpholinoethyl)pyrrolidin-3-yl)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Example 240, 340 mg) was dissolved in methanol (3 mL) and tetrahydrofuran (3 mL). To this solution was added 24 wt % sodium hydroxide (1 mL) and the reaction mixture was stirred at room temperature for 3 h. The solution was concentrated under reduced pressure to remove the organics. Water (7 mL) was added and the aqueous layer was carefully acidified to pH˜3 with 1N hydrochloric acid. A solid precipitated, and the mixture was centrifuged to help collect the solid which was then washed with cold water once and dried to give a light yellow solid (270 mg, 81.2%).
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:41][NH2:42].C1COCC1>>[C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:40])([CH3:38])[CH3:39])[C:10]1[C:11]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([NH:41][NH2:42])[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: NN
Reactant: Cc1cc2nc(OS(=O)(=O)C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc2nc(NN)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 80 °C

Procedure:
The mixture of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate (compound of Example 26) (10 mg) and hydrazine in THF (1.0 N, 1 mL, 1 mmol) was heated at 80° C. for 12 hours. Concentration under reduced pressure gave (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-hydrazinyl-7-methylquinolin-6-yl)ethyl pivalate, which was used for next step without purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H35ClN3O3: 484.2. Found: 484.3.
Reaction SMILES: [N+:1](=C)=[N-].[CH:4](=[C:11]1[NH:15][C:14](=[O:16])[C:13]([N+:17]([O-:19])=[O:18])=[C:12]1O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N>CCOCC.CO>[NH2:1][C:12]1[C:11](=[CH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:15][C:14](=[O:16])[C:13]=1[N+:17]([O-:19])=[O:18]
Reactant: C=[N+]=[N-]
Reactant: O=C1NC(=Cc2ccccc2)C(O)=C1[N+](=O)[O-]
Agent: N
Solvent: CO
Solvent: CCOCC
Product: NC1=C([N+](=O)[O-])C(=O)NC1=Cc1ccccc1
Yield: 75 %

Procedure:
An excess of diazomethane in ether is added to a suspension of 0.46 g (2 mmol) benzylidene-4-hydroxy-3-nitro-3-pyrrolin-2-one (prepared by the method of H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, vol. 331, pp. 389-394) and Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in 20 ml methanol. When the evolution of nitrogen has subsided, the solvent is stripped off, the residue is dissolved in methanol and the solution is heated under reflux with an excess of ammonia solution for five minutes, whereupon yellow crystals precipitate out, which are filtered off with suction and washed with methanol. 4-Amino-5-benzylidene-3-nitro-1,5-dihydropyrrol-2-one obtained with a melting point of >260° C. in a yield of 75%.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][O:5][CH:6]([C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[N:13][CH:14]=1)[C:7]#[N:8].C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC>C(Cl)Cl>[Br:17][CH2:2][CH2:3][CH2:4][O:5][CH:6]([C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[N:13][CH:14]=1)[C:7]#[N:8]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ncc(C(C#N)OCCCO)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ncc(C(C#N)OCCCBr)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(3-hydroxypropoxy)-2-(2-methylpyrimidin-5-yl)acetonitrile (54 mg, 0.26 mmol) and CBr4 (259 mg, 0.782 mmol) in DCM (3 ml) was cooled at 0° C. Triphenylphosphine (205 mg, 0.782 mmol) in DCM (1 ml) was added dropwise over a period of 5 minutes. The reaction was stirred for 2 hours and then allowed to warm to room temperature. To the mixture was added Et2O (5 mL) and the cloudy solution was filtred through a plug of celite. The resulting solution was concentrated in vacuo and purified by flash chromatography to yield 2-(3-Bromopropoxy)-2-(2-methylpyrimidin-5-yl)acetonitrile.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[C:8]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)=[O:9].CS(O[CH2:22][CH2:23][C:24]1[CH:28]=[CH:27][S:26][CH:25]=1)(=O)=O.O>CN(C)C=O>[CH3:16][N:13]1[CH2:14][CH2:15][CH:10]([C:8]([C:4]2[N:3]([CH2:22][CH2:23][C:24]3[CH:28]=[CH:27][S:26][CH:25]=3)[CH:7]=[CH:6][N:5]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: CS(=O)(=O)OCCc1ccsc1
Reactant: CN1CCC(C(=O)c2ncc[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(C(=O)c2nccn2CCc2ccsc2)CC1
Yield: 61.8 %

Procedure:
A dispersion of sodium hydride in mineral oil (50%) (0.088 mol) was added portionwise in N,N-dimethylformamide (150 ml) under nitrogen with stirring. (1H-imidazol-2-yl)-(1-methyl-4-piperidinyl)methanone (0.08 mol) was added portionwise and the mixture was stirred for 1 hour. 3-Thiopheneethanol methanesulfonate (ester) (0.086 mol) dissolved in a little N,N-dimethylformamide was added dropwise and the mixture was stirred on an oil bath at 60° C. overnight. The mixture was cooled, decomposed with water and extracted with dichloromethane. The organic layer was dried, filtered off and evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /(CH3OH/NH3)95/5). The pure fractions were collected and evaporated, yielding 15 g (61.8%) of (1-methyl-4-piperidinyl)[1-[2-(3-thienyl)ethyl]-1H-imidazol-2-yl]methanone (interm. 8).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([CH:14]=[CH2:15])[CH:11]=[C:10]2[C:16]#[N:17])=[CH:5][CH:4]=1.N1C=CC=CC=1.CS([Cl:28])(=O)=O>ClCCl.CN(C)C1C=CN=CC=1>[Cl:28][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([CH:14]=[CH2:15])[CH:11]=[C:10]2[C:16]#[N:17])=[CH:5][CH:4]=1
Reactant: C=Cc1cc(C#N)n(-c2ccc(CO)cc2)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=Cc1cc(C#N)n(-c2ccc(CCl)cc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
To a solution of 1-(4-hydroxymethylphenyl)-4-vinylpyrrole-2-carbonitrile (910 mg) in dichloromethane (15 ml) was added pyridine (385 mg), 4-dimethylaminopyridine (20 mg), methanesulfonyl chloride (560 mg) successively at 5° C. The mixture was stirred at ambient temperature for 4 hours and then pyridine (385 mg) and methanesulfonyl chloride (560 mg) was added therein. The mixture was stirred at the same temperature overnight, washed with aqueous hydrochloric acid, dried, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluted by dichloromethane to yield 1-(4-chloromethylphenyl)-4-vinylpyrrole-2-carbonitrile (831 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[C:26]4[CH:25]=[CH:24][C:23]([CH3:27])=[C:22]([NH2:28])[C:21]=4[CH:20]=[CH:19][N:18]=3)=[CH:12][C:11]=2[C:29]([F:32])([F:31])[F:30])[CH2:5][CH2:4]1)[CH3:2].[CH:33]1([NH:36][C:37]2[C:38]3[S:45][CH:44]=[C:43]([C:46](O)=[O:47])[C:39]=3[N:40]=[CH:41][N:42]=2)[CH2:35][CH2:34]1>>[CH:33]1([NH:36][C:37]2[C:38]3[S:45][CH:44]=[C:43]([C:46]([NH:28][C:22]4[C:23]([CH3:27])=[CH:24][CH:25]=[C:26]5[C:21]=4[CH:20]=[CH:19][N:18]=[C:17]5[NH:16][C:13]4[CH:14]=[CH:15][C:10]([CH2:9][N:6]5[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]5)=[C:11]([C:29]([F:31])([F:30])[F:32])[CH:12]=4)=[O:47])[C:39]=3[N:40]=[CH:41][N:42]=2)[CH2:35][CH2:34]1
Reactant: CCN1CCN(Cc2ccc(Nc3nccc4c(N)c(C)ccc34)cc2C(F)(F)F)CC1
Reactant: O=C(O)c1csc2c(NC3CC3)ncnc12
Product: CCN1CCN(Cc2ccc(Nc3nccc4c(NC(=O)c5csc6c(NC7CC7)ncnc56)c(C)ccc34)cc2C(F)(F)F)CC1
Yield: 50.4 %

Procedure:
The procedures of <Step 3> of Example 1 were repeated in sequence, except for using N1-(4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl)-6-methyl-isoquinolin-1,5-diamine (0.015 g, 0.03 mmol) and 4-cyclopropylamino-thieno[3,2-d]pyrimidine-7-carboxylic acid (see WO 2011009687, 0.04 mmol) to obtain the title compound (10 mg, 46%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[C:9]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>>[NH2:8][C:5]1[N:6]=[N:7][C:2]([N:19]2[CH2:18][CH2:17][N:16]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:21][CH2:20]2)=[CH:3][CH:4]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nn2)CC1
Temperature: 140 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 6-chloropyridazin-3-amine (2.58 g, 20 mmol) and N-Boc-piperazine (22.3 g, 120 mmol). The reaction mixture was heated at 140° C. and stirred for 2 h. It was then cooled to room temperature and the resulting solid was washed with ethyl acetate (100 mL), and the resulting residue was purified by flash column chromatography eluting with 30:1 methylene chloride/methanol to afford 330a as a yellow solid (3.5 g, 60%). MS: [M+H]+ 280.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:57][O:58][CH3:59])[C:21]([NH:23][CH:24]2[C:55](=[O:56])[N:26]3[CH:27]([C:31]([O:33][CH:34]([CH2:45][O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:32])[CH:28]=[CH:29][S:30][C@H:25]23)=[O:22])[N:19]=1)=[O:13]>C(Cl)Cl>[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:57][O:58][CH3:59])[C:21]([NH:23][CH:24]2[C:55](=[O:56])[N:26]3[C:27]([C:31]([O:33][CH:34]([CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:45][O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[O:32])=[CH:28][CH2:29][S:30](=[O:9])[C@H:25]23)=[O:22])[N:19]=1)=[O:13]
Reactant: CCCCCCCCOCC(COCCCCCCCC)OC(=O)C1C=CS[C@@H]2C(NC(=O)C(=NOC)c3csc(NC=O)n3)C(=O)N12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCCCCCOCC(COCCCCCCCC)OC(=O)C1=CCS(=O)[C@@H]2C(NC(=O)C(=NOC)c3csc(NC=O)n3)C(=O)N12
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 79.5 %

Procedure:
A solution of 3-chloroperbenzoic acid (0.9 g) in methylene chloride (10 ml) was dropwise added to a stirred solution of 2-n-octyloxy-1-n-octyloxymethylethyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-cephem-4-carboxylate (syn isomer, 3.0 g) in methylene chloride (30 ml) at -7° to -3° C. over 30 minutes, and then stirred at 0° C. for 35 minutes. The resultant mixture was washed with a diluted aqueous solution of sodium bicarbonate and saturated aqueous solution of sodium chloride in turn, and dried over anhydrous magnesium sulfate. After removing the solvent from the solution in vacuo, the residue was subjected to column chromatography on silica gel (120 g) with a mixture of chloroform and methanol (20:1). The eluate was evaporated in vacuo to give powder [2.44 g] of 2-n-octyloxy-1-n-octyloxymethylethyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate-1-oxide (syn isomer).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([OH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[C:11](=O)(OCC)[O:12][CH2:13]C.[OH-].[K+]>C(O)C>[OH:8][CH:3]([C:4]1([CH2:5][CH2:6][CH3:7])[CH2:13][O:12][CH2:11]1)[C:2]([F:10])([F:9])[F:1]
Reactant: CCCCC(O)C(F)(F)F
Reactant: CCOC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCC1(C(O)C(F)(F)F)COC1
Reaction time: 0.5 h

Procedure:
A mixture of 3,3-di-hydroxymethyl)-1,1,1-trifluorohexan-2-ol (2.8 g.), diethyl carbonate (1.6 ml.), potassium hydroxide (0.1 g) and dry ethanol (4.0 mls) was refluxed gently (oil bath 110°), under a current of nitrogen, for 30 minutes. The ethanol was then removed by distillation. Distillation gave (3-(1-hydroxy-2,2,2-trifluoroethyl)-3-n-propyloxetane (1.7 g.), a colourless oil (b.p. 112°, 20-25 m.m.).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1B(O)O>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1
Reactant: Nc1c(F)cc(Br)cc1Cl
Reactant: COc1ccc(Cl)c(B(O)O)c1
Product: COc1ccc(Cl)c(-c2cc(F)c(N)c(Cl)c2)c1
Yield: 31 %

Procedure:
The title compound (39 mg) was prepared from 4-bromo-2-chloro-6-fluoroaniline (100 mg, 0.44 mmol) and 2-chloro-5-methoxyphenylboronic acid (106 mg, 0.62 mmol) as a pale-yellow solid.