Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-]#N.[K+].Br[CH2:5][C:6]1[C:7]([Cl:13])=[N:8][C:9]([Cl:12])=[CH:10][CH:11]=1.BrCC1(CBr)C=CC(Cl)=[N:18][CH:17]1Cl>O.C(O)C>[Cl:13][C:7]1[C:6]([CH2:5][C:17]#[N:18])=[CH:11][CH:10]=[C:9]([Cl:12])[N:8]=1
Reactant: Clc1ccc(CBr)c(Cl)n1
Reactant: ClC1=NC(Cl)C(CBr)(CBr)C=C1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(Cl)nc1Cl
Temperature: 40 °C
Reaction time: 16 h

Procedure:
Potassium cyanide (1.0 g) was dissolved in water by heating to 40° C. A mixture of 3-bromomethyl-2,6-dichloro-pyridine, 3,3-dibromomethyl-2,6-dichloro-pyridine, and 2,6-dichloro-3-methyl-pyridine (Example 4.1) (3.2 g) suspended in ethanol (20 ml) was added dropwise at 40° C. over a period of 30 minutes. The reaction mixture was heated to reflux for 3 hours. The reaction mixture was cooled to 40° C. and another equivalent of potassium cyanide was added. The reaction mixture was heated to reflux for a further 3 hours and then stored at ambient temperature for 16 hours. The reaction mixture was filtered to remove the solids and the solids were washed with ethyl acetate. The combined filtrates were concentrated. The residue was diluted with ethyl acetate. The organic solution washed with aqueous sodium hydrogen carbonate (saturated) and brine, dried over magnesium sulfate, and concentrated. This residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane from 3:100 to 1:1) to give slightly impure (2,6-dichloro-pyrid-3-yl)-acetonitrile (1.5 g) which solidified on standing. This material was used without further purification. 1H-NMR (400 MHz, CDCl3): 3.83 (s, 2H), 7.37 (d, 1H), 7.85 (d, 1H) ppm.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:33]2[CH2:45][CH2:44][N:36]3[C:37]4[CH2:38][CH2:39][CH2:40][CH2:41][C:42]=4[CH:43]=[C:35]3[C:34]2=[O:46])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:21][N:20]=2)[C:15](=[O:31])[N:14]([CH3:32])[CH:13]=1)(=O)C.[Li+].[OH-]>CC(O)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:33]2[CH2:45][CH2:44][N:36]3[C:37]4[CH2:38][CH2:39][CH2:40][CH2:41][C:42]=4[CH:43]=[C:35]3[C:34]2=[O:46])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:21][N:20]=2)[C:15](=[O:31])[N:14]([CH3:32])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCNCC4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2ccc(N3CCNCC3)cn2)c1=O
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 27.8 %

Procedure:
A mixture of 127a (190 mg, 0.31 mmol) and LiOH (571 mg, 13.6 mmol) in iPrOH/THF (1:1, 3.5 mL) and H2O (0.5 mL) was stirred at 35° C. for 0.5 h. It was then evaporated in vacuo and the residue was extracted with EtOAc (5 mL×2). The combined EtOAc extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 127 (50 mg, 26.9%). MS: [M+H]+ 581.3. 1H NMR (500 MHz, CDCl3) δ 8.63 (d, J=2.0, 1H), 8.49 (d, J=5.0, 1H), 7.91 (d, J=3.5, 1H), 7.82 (d, J=2.0, 1H), 7.77 (s, 1H), 7.37 (d, J=5.0, 1H), 7.20-7.25 (m, 1H), 6.89 (s, 1H), 6.81 (d, J=9.0, 1H), 5.04-5.02 (m, 1H), 4.64-4.61 (m, 1H), 4.50 (d, J=5.0, 1H), 4.34-4.31 (m, 1H), 4.18-4.08 (m, 2H), 3.89-3.86 (m, 1H), 3.71 (s, 3H), 3.05-3.06 (m, 8H), 2.62-2.56 (m, 4H), 1.92-1.88 (m, 2H), 1.81-1.78 (m, 3H)
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[F:14])[CH2:3][C:4]([OH:6])=[O:5].[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.O>CN(C=O)C>[F:14][C:8]1[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=1[CH:2]([N:1]1[C:18](=[O:19])[C:17]2[C:16](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]1=[O:20])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: NC(CC(=O)O)c1ccc(F)cc1F
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CC(c1ccc(F)cc1F)N1C(=O)c2ccccc2C1=O
Temperature: 135 °C

Procedure:
5.0 g of rac-3-amino-3-(2,4-difluorophenyl)propanoic acid (24.85 mmol) and 3.68 g of phthalic anhydride (24.85 mmol) were dissolved in 20 ml of DMF and the mixture was heated at reflux at 135° C. overnight. The reaction solution was added to about 160 ml of water and extracted twice with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulphate, filtered and concentrated. The crude product was purified by silica gel chromatography (mobile phase: dichloromethane/methanol 80:1, isocratic) and then by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). This gave 3.43 g of the title compound (27% of theory).
Reaction SMILES: C([Si](C)(C)[O:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH2:9][CH2:8]1)(C)(C)C.[Li+].CC([N-]C(C)C)C.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Br)=[C:32]([Cl:38])[CH:31]=1.Cl>CO.O.C1COCC1>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH:15]2[CH2:16][CH2:17][N:13]([C@H:10]3[CH2:9][CH2:8][C@@H:7]([OH:6])[CH2:12][CH2:11]3)[C:14]2=[O:18])=[C:32]([Cl:38])[CH:31]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCCC2=O)CC1
Reactant: Clc1cc(Br)ccc1CBr
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C1C(Cc2ccc(Br)cc2Cl)CCN1[C@H]1CC[C@@H](O)CC1
Temperature: -78 °C

Procedure:
Charge a flask with cis-1-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-pyrrolidin-2-one (Preparation 17) (1.0 g, 3.4 mmol), dissolve with THF (0.2 M) and cool to −78° C. Add LDA (1.1 to 1.5 eq) and stir at −78° C. for 5 minutes. Add 4-bromo-1-bromomethyl-2-chloro-benzene (1.4 g, 5.0 mmol) and warm to room temperature overnight. Dilute with methanol (0.2 M) and add concentrated HCl (10 eq.) and stir at room temperature. Pour into water after reaction complete by HPLC and extract with methylene chloride, dry over sodium sulfate, filter and concentrate in vacuo. Purify the residue over silica gel (20% hexane in ethyl acetate) to afford 911 mg (70%) of the title compound: Mass spectrum (apci) m/z=387.9 (M+H).
Reaction SMILES: C[C@H:2]([OH:6])/[CH:3]=[CH:4]/[CH3:5].C([C:9]([CH2:16][CH3:17])(CC)C([O-])([O-])[O-])C.CP(=O)(F)[O:20][CH:21](C)[C:22](C)(C)C>>[CH2:21]([O:20][C:2](=[O:6])[CH2:3][C@H:4]([CH3:5])[CH:17]=[CH:16][CH3:9])[CH3:22]
Reactant: C/C=C/[C@H](C)O
Reactant: CC(OP(C)(=O)F)C(C)(C)C
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Product: CC=C[C@@H](C)CC(=O)OCC

Procedure:
To a solution of (S)-3-methyl-hex-4-enoic acid ethyl ester* (1.0 g, 6.4 mmol) in 30 mL toluene at −78° C. was added DIBAH (1.0 M in THF, 6.4 mL) dropwise over 5 min. The mixture was stirred at −78° C. 45 min at which time 5 drops of methanol were added, resulting in vigorous H2 evolution. Methanol was added until no more gas evolution was observed (ca. 5 mL). At this time the cold bath was removed and ca. 5 mL of sat. aq. Na+K+ tartrate was added. When the mixture reached room temperature, additional sat. aq. Na+K+ tartrate and Et2O were added and stirring was continued until the phases were mostly clear (ca. 1 h). The phases were separated, and the organic phase washed with brine, dried (MgSO4), and concentrated to ca. 10 mL total volume owing to volatility concerns. The crude mixture was combined with an additional batch of aldehyde prepared from 10 mmol of the ester by the method described above and the whole used without purification. To a suspension of sodium hydride (60% dispersion in mineral oil) in 25 mL THF was added t-butyl-P, P-dimethylphosphonoacetate (3.0 mL, 15 mmol) dropwise over 1 h such that the evolution of H2 was under control. After the addition was complete, the crude aldehyde in toluene (ca. 20 mL total volume) was added quickly dropwise and the mixture stirred at ambient temperature overnight. The mixture was partitioned between Et2O and sat. aq. NH4Cl, the phases separated, the organic phase washed with brine, dried (MgSO4), and concentrated. Flash chromatography of the residue (0→3→5% EtOAc/hexanes) afforded 1.0 g (29%, two steps) of the unsaturated ester as a pale yellow oil: 1H NMR(CDCl3) δ 6.75 (m, 1H), 5.66 (m, 1H), 5.30 (m, 2H), 2.03-2.29 (m, 3H), 1.58 (d, J=6.1 Hz, 3H), 1.41 (s, 9H), 0.91 (d, J=6.6 Hz, 3H). *(S)-3-methyl-hex-4-enoic acid ethyl ester was prepared from (S)-trans-3-Penten-2-ol [Liang, J.; Hoard, D. W.; Van Khau, V.; Martinelli, M. J.; Moher, E. D.; Moore, R. E.; Tius, M. A. J. Org. Chem., 1999, 64, 1459] via Johnson-Claisen rearrangement with triethylorthoacetate according to the literature protocol [Hill, R. K.; Soman, R.; Sawada, S., J. Org. Chem., 1972, 37, 3737].
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:33][C:34](Cl)=[O:35].[F:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1>O1CCCC1.O>[F:37][C:38]1[CH:44]=[CH:43][C:41]([NH:42][CH2:33][C:34]([N:13]2[CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:11]3[CH2:12]2)=[O:35])=[CH:40][CH:39]=1
Reactant: O=C(Cl)CCl
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Reactant: Nc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=C(CNc1ccc(F)cc1)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.9 %

Procedure:
Hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (0.20 g, 0.68 mmol) was dissolved in tetrahydrofuran (3 mL). With ice cooling, diisopropylethylamine (1 mL) and chloroacetyl chloride (70 μL, 0.82 mmol) were added thereto, and the mixture was stirred at room temperature for 3 hours. Next, 4-fluoroaniline (0.13 mL, 1.4 mmol) was added thereto, and the mixture was stirred at 50° C. for 16 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1) and crystallized from hexane to obtain the title compound (45 mg, yield 15%).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:13][N:14]([CH3:18])[C:15](=[S:17])[S-:16].C[NH2+]C>C(=S)=S>[CH3:13][N:14]([CH3:18])[C:15](=[S:16])[S:17][CH:6]([CH2:7][N+:8]([O-:10])=[O:9])[C:5]1[CH:11]=[CH:12][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])C=Cc1ccc(Br)cc1
Reactant: CN(C)C(=S)[S-]
Agent: C[NH2+]C
Solvent: S=C=S
Product: CN(C)C(=S)SC(C[N+](=O)[O-])c1ccc(Br)cc1

Procedure:
As in Example 17, reaction of p-bromo-β-nitrostyrene with dimethylammonium dimethyldithiocarbamate in the presence of carbon disulfide gave p-bromo-α-(nitromethyl)benzyl dimethyldithiocarbamate melting at 70° C.-81° C. when recrystallized without heating from acetone-ethanol solution.
Reaction SMILES: Br[CH:2]([S:4]([O-:7])(=[O:6])=[O:5])[CH3:3].[Na+].[CH2:9]([CH2:11][NH2:12])[OH:10].[CH2:13]([OH:15])[CH3:14]>O>[OH:10][CH2:9][CH2:11][N:12]([CH2:14][CH2:13][OH:15])[CH2:3][CH2:2][S:4]([OH:7])(=[O:6])=[O:5]
Reactant: CC(Br)S(=O)(=O)[O-]
Reactant: NCCO
Reactant: CCO
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)CCN(CCO)CCO

Procedure:
A solution of 90 g of sodium bromoethanesulphonate (Organic Synthesis, Coll. Vol. II, p; 558) and 110 g of ethanolamine in 1500 ml of water was heated over a steam bath for about 2 hours and the reaction mixture left to stand for one night. The excess diethanolamine and water were then distilled off under vacuum, and the residue taken up in 100 ml of water and 800 ml of concentrated hydrochloric acid. The solution was cooled and filtered from the sodium chloride by a filter pump. It was then concentrated under vacuum until an oil was obtained which was taken up in boiling ethanol. On cooling, a crystalline product was obtained having a melting point of 163°-165° C., which was recrystallised from ethanol and water. 16 G of product were obtained, the analytical and spectroscopic data of which confirmed the identity of the product as the compound (III).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH:10]=[CH:9]1.[CH3:28][NH2:29]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:14]=3[N:13]=[C:12]([NH:29][CH3:28])[C:11]=2[CH:10]=[CH:9]1
Reactant: CN
Reactant: Cc1ccccc1-n1ccc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Product: CNc1nc2c(OCC(F)(F)F)cccc2c2c1ccn2-c1ccccc1C
Temperature: 180 °C

Procedure:
1-(2-methylphenyl)-4-chloro-6-β,β,β-trifluoroethoxypyrrolo[3,2-c]quinoline(600 mg, 1.5 mmol) was dissolved in aqueous solution of methylamine(40%, 10 ml) in the pressure tube, and the resultant was refluxed at 180° C. for 3 hours. After removing the excess solvent by distillation under reduced pressure, the residue was diluted in dichloromethane(20 ml), and washed with water(15 ml) for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 446 mg of desired compound as solid in 77% of yield.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.Cl.[NH2:17][CH2:18][C:19](O)=[O:20].[NH2:22][C:23]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:24]=1[C:25](=[N:33][CH2:34][CH2:35][OH:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32]>CN(C)C=O.O.O1CCCC1>[NH2:17][CH2:18][C:19]([NH:22][C:23]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:24]=1[C:25](=[N:33][CH2:34][CH2:35][OH:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])=[O:20]
Reactant: Nc1ccc(Cl)cc1C(=NCCO)c1ccccc1F
Reactant: NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: NCC(=O)Nc1ccc(Cl)cc1C(=NCCO)c1ccccc1F
Yield: 44.5 %

Procedure:
To a solution of 4.5g of N,N'-dicyclohexylcarbodiimide in 100ml of dimethylformamide is added a solution of 2.2g of glycine hydrochloride in 2.2ml of water in a period of about 30 seconds under stirring and ice-cooling. Immediately a solution of 3.2g of 2-{[2-amino-5-chloro-α-(2-fluorophenyl)benzylidene]amino}ethanol in 10ml of tetrahydrofuran is added dropwise to the above solution and the mixture is stirred for further 3 hours. After completion of the reaction, the reaction mixture is treated by the same manner as described in the Example 1, yielding 1.7g of the desired product melting at 128°-132° C.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][NH:24][CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)=[CH:9][C:6]=1[C:7]#[N:8])[CH3:3].C(N(CC)C(C)C)(C)C.Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>C(#N)C>[C:7]([C:6]1[CH:9]=[C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][N:24]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:11]=[CH:12][C:5]=1[O:4][CH:2]([CH3:1])[CH3:3])#[N:8]
Reactant: CCOC(=O)CBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3OCCNC4)no2)cc1C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CN1CCOc2c(cccc2-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)C1
Temperature: 80 °C
Yield: 96.5 %

Procedure:
To a solution of 2-[(1-methylethyl)oxy]-5-[3-(2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)-1,2,4-oxadiazol-5-yl]benzonitrile (Example 32) (110 mg, 0.224 mmol) in acetonitrile (10 mL) was added N,N-diisopropylethylamine (0.08 mL, 0.449 mmol) and ethyl bromoacetate (0.05 mL, 0.449 mmol). The reaction mixture was heated to 80° C. for 2 hours. The mixture was allowed to cool to room temperature. The solvent was evaporated to give the title compound as a brown solid (100 mg).
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:35])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)([CH3:33])[C:28](OCC)=[O:29])=[CH:22][CH:21]=1)([CH3:17])[CH2:9][CH2:8]2)(=O)C.[NH2:36][C:37](N)=[S:38].S1(CCCC1)(=O)=[O:41].Cl>O.COCCO>[OH:4][C:5]1[C:6]([CH3:35])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]3([CH3:33])[S:38][C:37](=[O:41])[NH:36][C:28]3=[O:29])=[CH:24][CH:25]=1)([CH3:17])[CH2:9][CH2:8]2
Reactant: NC(N)=S
Reactant: O=S1(=O)CCCC1
Reactant: CCOC(=O)C(C)(Cl)Cc1ccc(OCC2(C)CCc3c(C)c(OC(C)=O)c(C)c(C)c3O2)cc1
Agent: Cl
Solvent: COCCO
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3(C)SC(=O)NC3=O)cc1)O2

Procedure:
The procedure described in Example 3 was repeated, but using 1.17 g of ethyl 3-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl]-2-chloro -2-methylpropionate (prepared as described in Preparation 46), 0.63 g of thiourea, 3 g of sulfolane, 10 ml of ethylene glycol monomethyl ether, 3 ml of water and 2 ml of 35% w/v aqueous hydrochloric acid, to give the title compound, softening at 69°-72° C.
Reaction SMILES: [O:1]1[CH2:5][CH:4]([CH2:6]O)[O:3][CH2:2]1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[C:23]([NH:42][C:43]1[S:44][CH:45]=[C:46](/[C:48](=[N:80]/[O:81][C:82]([C:95]2[CH:100]=[CH:99][CH:98]=[CH:97][CH:96]=2)([C:89]2[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=2)[C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)/[C:49]([NH:51][CH:52]2[C:78](=[O:79])[N:54]3[C:55]([C:62]([O:64][CH:65]([C:72]4[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=4)[C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)=[S:63])=[C:56](C(=O)C)[CH2:57][S:58][C@H:53]23)=[O:50])[N:47]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N1CCOCC1.[F:107][C:108]([F:120])([F:119])[S:109]([O:112][CH2:113][CH:114]1[CH2:118][O:117][CH2:116][O:115]1)(=[O:111])=[O:110]>C(N(CC)CC)C.N1C=CC=CC=1>[F:120][C:108]([F:107])([F:119])[S:109]([O:112][CH2:113][CH:114]1[CH2:118][O:117][CH2:116][O:115]1)(=[O:111])=[O:110].[C:23]([NH:42][C:43]1[S:44][CH:45]=[C:46](/[C:48](=[N:80]/[O:81][C:82]([C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)([C:95]2[CH:96]=[CH:97][CH:98]=[CH:99][CH:100]=2)[C:89]2[CH:90]=[CH:91][CH:92]=[CH:93][CH:94]=2)/[C:49]([NH:51][CH:52]2[C:78](=[O:79])[N:54]3[C:55]([C:62]([O:64][CH:65]([C:66]4[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=4)[C:72]4[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=4)=[S:63])=[C:56]([CH2:6][CH:4]4[CH2:5][O:1][CH2:2][O:3]4)[CH2:57][S:58][C@H:53]23)=[O:50])[N:47]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(=O)C1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Reactant: OCC1COCO1
Agent: O=S(=O)(OCC1COCO1)C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCN1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C(NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(CC3COCO3)CS[C@H]12)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 100 %

Procedure:
1,3-Dioxolan-4-ylmethyl trifluoromethanesulfonate was prepared in the same manner as in Example 27(a) from 1,3-dioxolan-4-yl-methanol (200 mg), pyridine (0.17 ml) and trifluoromethanesulfonic acid anhydride (596 mg). On the other hand, diphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-acetylthio-3-cephem-4-carboxylate (700 mg) was reacted with morpholine and triethylamine in the same manner as in Example 27(b), followed by reacting the resulting reaction product with the 1,3-dioxolan-4-ylmethyl trifluoromethanesulfonate in the same manner as in Example 27(b). The reaction solution so obtained was post-treated in the same manner as in Example 27(b) and the produced compound was recovered and purified similarly to Example 27(b) to afford the titled compound (728 mg; 100%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH2:11])[CH:3]=1.[OH:12][CH2:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[NH2:11][C:4]1[CH:3]=[C:2]([C:18]2[CH:19]=[C:14]([CH2:13][OH:12])[CH:15]=[CH:16][CH:17]=2)[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=1
Reactant: Nc1cc(Cl)n2nccc2n1
Reactant: OCc1cccc(B(O)O)c1
Product: Nc1cc(-c2cccc(CO)c2)n2nccc2n1

Procedure:
The titled compound was prepared using a procedure analogous to that described in connection with Example 15 except that 7-chloropyrazolo[1,5-a]pyrimidin-5-amine (1E) and 3-(hydroxymethyl)phenylboronic acid were used as starting materials. 1H NMR (400 MHz, MeOD) δ ppm 4.72 (s, 2 H) 6.27-6.31 (m, 1 H) 6.47 (s, 1 H) 7.56 (t, J=7.58 Hz, 1 H) 7.62 (d, J=7.58 Hz, 1 H) 7.84 (d, J=7.33 Hz, 1 H) 7.91-7.97 (m, 2 H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][C:5]([CH3:18])=[C:4]([C:19](O)=[O:20])[C:3]1=[O:22].C(Cl)(=O)C(Cl)=O.CCN(CC)CC.[N:36]1([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37]1>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][C:5]([CH3:18])=[C:4]([C:19]([N:44]2[CH2:45][CH2:46][CH:41]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:42][CH2:43]2)=[O:20])[C:3]1=[O:22]
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)n(C)c(=O)c1C(=O)O
Reactant: C1CCN(C2CCNCC2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)n(C)c(=O)c1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
A solution of 0.16 g (0.5 mmol) of 1,4-dimethyl-2-oxo-6-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid (intermediate 5) in 5 ml of CH2Cl2 was treated at RT with two drops of DMF; then, 0.05 ml=0.074 g (0.6 mmol) of oxalyl chloride was added and the reaction mixture was stirred for 30 min at RT. After removal of the solvents by evaporation in a high vacuum, the residue was dissolved again in 10 ml of CH2Cl2 and the solution was cooled down to 0° C.; then, 0.29 ml=0.21 g (2.1 mmol) of Et3N was added while stirring, followed by 0.081 g (0.5 mmol) of 4-pyrrolidin-1-yl-piperidine. The reaction mixture was subsequently warmed up to RT. After 3 hours, it was poured into crashed ice and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 98:2 to 95:5) to give 0.20 g (85%) of the title compound as light yellow solid. MS: 448.2 (MH+).
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][C:34]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)([OH:37])[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1CCN(c2ccc(OCc3ccccc3)cc2)CC1
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2ccc(C(F)(F)F)cc2)CCN(c2ccc(OCc3ccccc3)cc2)CC1
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 73.5 %

Procedure:
Isopropylmagnesium chloride (2M tetrahydrofuran solution) (11.73 ml) was added to a tetrahydrofuran solution (20 ml) of 4-iodobenzotrifluoride (3.45 ml, 23.5 mmol) dropwise at −10° C. under an argon atmosphere. The mixture was stirred at the same temperature for 5 minutes and further stirred at room temperature for 2 hours. After cooling the mixture to −10° C., a tetrahydrofuran solution (40 ml) of 1-(4-benzyloxyphenyl)piperidin-4-one (6 g, 21.3 mmol) was added thereto dropwise. While gradually returning to room temperature, the mixture was stirred. After 10 hours, a saturated ammonium chloride aqueous solution/ice water was poured into the mixture, followed by extraction with ethyl acetate. The result was washed with water and a saturated sodium chloride aqueous solution and dried over sodium sulfate. After removing the desiccant by filtration, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25→66:34). The resultant was washed with a mixed solvent of isopropyl ether and hexane and filtered to afford the title compound as a white powder (6.69 g, 73%).