Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([OH:14])=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.S(Cl)([Cl:17])=O>>[OH:1][C:2]1[C:11]([C:12]([Cl:17])=[O:14])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2ccccc2cc1O
Product: O=C(Cl)c1cc2ccccc2cc1O

Procedure:
Also, the azo pigments of Formula I illustrated in FIG. 5 may be prepared, for example, by reacting 2-hydroxy-3-naphthoic acid with thionyl chloride to obtain 2-hydroxy-3-naphthoic acid chloride. Subsequently, the formed acid chloride is added to a solution of N,N-diethylaniline and a halo aniline to yield a halo coupler compound. A 5 millimole amount of 2,7-diaminofluoren-9-one is then tetrazotized by an excess amount of a metal nitrite such as sodium nitrite in an aqueous hydrochloric acid solution at from about 0° C. to about 30° C., and the product is reacted with HBF4. An 11 millimole amount of the halo coupler compound previously prepared is then added to the resulting tetrazonium salt in a solution of dimethylformamide at from about 0° C. to about 30° C., followed by the addition of a base, such as sodium acetate in water, to the reaction mixture. The resulting precipitated product is a disazo pigment of Formula I, the specific compound obtained depending on the dihalo aniline selected during the preparation of the coupler compound. For example, 2,3-dichlloroaniline is selected as a reactant to obtain the coupler compound 2-hydroxy-3-naphtho-2',3'-dichloroanilide, which is then used to prepare 2,7-bis(1'azo-2'-hydroxy-3'naphtho-2",3"-dichloroanilide)fluoren-9-one. The azo pigments are isolated by filtration and purified by repetitive solvent washings, and may be characterized by elemental analysis, melting point, and IR spectroscopy.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:20]=[CH:19][C:18]2[C:9](=[C:10]3[C:15](=[CH:16][N:17]=2)[C:14]([NH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:13][C:12]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:11]3)[CH:8]=1)([O:3][CH2:4][CH3:5])=[O:2].Br[CH2:34][CH2:35][C:36]([OH:38])=[O:37]>[N+](C1C=CC=CC=1)([O-])=O>[C:36]([CH2:35][CH2:34][C:11]1[C:10]2[C:15](=[CH:16][N:17]=[C:18]3[C:9]=2[CH:8]=[C:7]([NH:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH:20]=[CH:19]3)[C:14]([NH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:13][C:12]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([OH:38])=[O:37]
Reactant: O=C(O)CCBr
Reactant: CCOC(=O)Nc1ccc2ncc3c(NC(=O)OCC)cc(-c4ccccc4)cc3c2c1
Solvent: O=[N+]([O-])c1ccccc1
Product: CCOC(=O)Nc1ccc2ncc3c(NC(=O)OCC)cc(-c4ccccc4)c(CCC(=O)O)c3c2c1

Procedure:
2,7-Biscarboethoxyamino-9-phenylphenanthridine (22-1, 1 equiv.), prepared by the method of Watkins (1952) J. Chem. Soc. 3059, is combined with 3-bromopropionic acid (2.5 equiv.; Aldrich Chemical Co., Milwaukee, Wis.) and is heated in nitrobenzene at 100° C. for 4-6 hours. Following cooling to room temperature the crude product is precipitated by addition of ether. The product 22-2 is isolated by filtration and used directly.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:24]C(OCCCl)=O.CO.C(OCC)C>C(Cl)Cl>[ClH:24].[F:23][C:20]([F:21])([F:22])[C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCCCl
Reactant: FC(F)(F)c1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: Cl
Product: FC(F)(F)c1ccc(C2=CCNCC2)cc1
Reaction time: 3 h
Yield: 86.7 %

Procedure:
1-Benzyl-4-(4-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine (2 g, 6.3 mmol) prepared in Reference Example 96 was dissolved in methylene chloride (20 ml), to which 2-chloroethyl chloroformate (1.67 g, 11.68 mmol) was added dropwise under a nitrogen atmosphere while cooling in an ice-bath, and the mixture was stirred at the same temperature for 3 hours. Methanol (20 ml) was added to the mixture, which was heated under reflux for 1 hour. The reaction mixture was allowed to return to room temperature, to which diethyl ether was added, and the resulting precipitates were collected by filtration to afford 4-(4-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride (1.44 g, yield 87%) as a colorless crystalline powder.
Reaction SMILES: Cl.[CH:2]1([CH:6]([NH2:8])[CH3:7])[CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.C1COCC1.Cl[C:22]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:23]=1[C:24]([C:26](=[CH:32]OCC)[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:25]>O>[CH:2]1([CH:6]([N:8]2[C:22]3[C:23](=[CH:36][C:37]([F:41])=[C:38]([F:40])[CH:39]=3)[C:24](=[O:25])[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32]2)[CH3:7])[CH2:5][CH2:4][CH2:3]1
Reactant: CC(N)C1CCC1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C(C)C2CCC2)c2cc(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
1.02 g of 1-cyclobutylethylamine hydrochloride and 1.05 ml of triethylamine were added under ice-cooling to a 15 ml THF solution of 2.0 g of ethyl 2-(2-chloro-4,5-difluorobenzoyl)-3-ethoxyacrylate, followed by overnight stirring at room temperature. Water was added to the resulting reaction mixture, followed by extraction with ether and washing with water and aqueous saturated sodium chloride. After drying over anhydrous magnesium sulfate, concentration under a reduced pressure was carried out. 315 mg of 55% sodium hydride was added under ice-cooling to a 30 ml dioxane solution of the resulting residue, followed by overnight stirring at 80° C. The reaction mixture was poured into 1 M hydrochloric acid, followed by extraction with chloroform and washing with water and aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate and subsequent concentration under a reduced pressure, the resulting residue was purified by silica gel column chromatography to obtain 1.13 g of ethyl 1-(1-cyclobutylethyl)-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate.
Reaction SMILES: CN(C[CH2:5][O:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10])C.[CH3:12][N:13]([CH2:15][CH2:16][OH:17])[CH3:14].C(=O)(OCC)[O:19]CC>>[CH3:12][N:13]([CH2:15][CH2:16][O:17][C:5](=[O:19])[O:6][CH2:7][CH2:8][N:9]([CH3:10])[CH3:11])[CH3:14]
Reactant: CCOC(=O)OCC
Reactant: CN(C)CCO
Reactant: CN(C)CCOCCN(C)C
Product: CN(C)CCOC(=O)OCCN(C)C

Procedure:
A process for preparing bis[2-(N,N-dimethylamino)ethyl]ether which comprises (i) contacting 2-(N,N-dimethylamino)ethanol with diethyl carbonate under conditions effective to produce bis[2-(N,N-dimethylamino)ethyl]carbonate, and (ii) contacting bis[2-(N,N-dimethylamino)ethyl]-carbonate with a magnesium:aluminum mixed metal oxide catalyst under conditions effective to produce bis[2-(N,N-dimethylamino)ethyl]ether.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][C@@H:13]2[CH2:17][C@H:16]([O:18][CH2:19][CH2:20][OH:21])[C@@H:15]([OH:22])[C@H:14]2[OH:23])[C:3]=1[N+:24]([O-])=O.[H][H].[N:29]([O-])=O.[Na+]>C(O)(=O)C.[Pt].C(OCC)(=O)C>[Cl:1][C:2]1[C:3]2[N:24]=[N:29][N:12]([C@@H:13]3[CH2:17][C@H:16]([O:18][CH2:19][CH2:20][OH:21])[C@@H:15]([OH:22])[C@H:14]3[OH:23])[C:4]=2[N:5]=[C:6]([S:8][CH2:9][CH2:10][CH3:11])[N:7]=1
Reactant: CCCSc1nc(Cl)c([N+](=O)[O-])c(N[C@@H]2C[C@H](OCCO)[C@@H](O)[C@H]2O)n1
Reactant: [H][H]
Reactant: O=N[O-]
Agent: [Pt]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCSc1nc(Cl)c2nnn([C@@H]3C[C@H](OCCO)[C@@H](O)[C@H]3O)c2n1
Reaction time: 1 h
Yield: 71.3 %

Procedure:
The solution of (1S,2S,3R,5S)-3-((6-chloro-5-nitro-2-(propylthio)pyrimidin-4-yl)amino)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (OLACIN; 0.74 g, 1.8 mmol) in acetic acid (15 mL) was hydrogenated for 5 h in the presence of platinum on carbon (5%; 0.11 g, 1.5 mol %) at 10 bar hydrogen pressure. The catalyst was filtered trough celite and washed with ethyl acetate (5 mL). The analysis of the filtrate confirmed complete conversion of the starting material and 95 area % HPLC purity of the intermediate (1S,2S,3R,5S)-3-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (OLACINA). To the filtrate was then added sodium nitrite (0.14 g, 2 mmol) while stirring in a bath at 15-20° C. After 1 h, the reaction mixture was diluted with ethyl acetate (50 mL), washed with water (2×50 mL) and evaporated under reduced pressure. The solid residue was triturated in n-hexane (10 mL) and filtered to give CLTOL as a grey powder (0.50 g, 71% yield): 96 area % by HPLC; mp 91-95° C.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][C:4]([C:6]1[N:7]=[C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:10]=12)=[O:5].[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][C:4]([C:6]1[N:7]=[C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]=12)=[O:5].[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]
Reactant: CC(C)(C)CC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC(=O)c1nc(-c2ccccc2)n2c1CNCC2
Reaction time: 2 h

Procedure:
Intermediate 26B (0.08 g, 0.20 mmol) was dissolved in DCM and TFA was added. The resulting mixture was stirred for 2 hours. The mixture was concentrated, diluted with water and acetonitrile and lyophilized to produce the desired product as a TFA salt. The residue was dissolved in methanol and filtered through a SPE SCX tube column, eluting with 2N ammonia in methanol to provide Compound 291 (0.055 g, 90%) as a free base. 1H-NMR (400 MHz, CD3OD) δ: 1.05 (s, 9H), 2.87 (s, 2H), 3.15 (t, 2H), 4.07 (t, 2H), 4.35 (s, 2H), 7.52 (m, 3H), 7.67 9m, 2H); LCMS (+ESI) m/z 298.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:15]1([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([CH3:14])([OH:12])[CH2:13][N:18]2[CH2:17][CH2:16][N:15]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=3)[CH2:20][CH2:19]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: FC(F)(F)c1ccc(NN2CCNCC2)cc1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Product: C[C@](O)(CN1CCN(Nc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 86.2 %

Procedure:
Using (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (0.610 g, 2.82 mmol) and N-(piperazin-1-yl)-4-trifluoromethylaniline (0.760 g, 3.09 mmol) gave (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethylphenylamino)piperazin-1-yl]propan-2-ol (1.125 g, yield 86%) as a colorless solid in the same manner as in Example 496.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([C@H:15]([CH3:24])[CH2:16][NH:17]C(=O)C(F)(F)F)[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:17][CH2:16][C@H:15]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[CH:7][N:6]=[C:5]2[C:3]([NH:2][CH3:1])=[O:4])[CH3:24]
Reactant: CNC(=O)c1ncnc2c([C@H](C)CNC(=O)C(F)(F)F)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CNC(=O)c1ncnc2c([C@H](C)CN)cccc12

Procedure:
As shown in step 12-iii of Scheme 12, a solution of (S)—N-methyl-8-(1-(2,2,2-trifluoroacetamido)propan-2-yl)quinazoline-4-carboxamide (200 mg, 0.588 mmol), K2CO3 (406 mg, 2.94 mmol) in MeOH (10 mL) and water (0.5 mL) was heated at 60° C. for 1 hour. The reaction mixture concentrated under reduced pressure and dried under high vacuum to provide (S)-8-(1-aminopropan-2-yl)-N-methylquinazoline-4-carboxamide (compound 2054). LC-MS: 245.09 (M+), which was used in the following reaction as is.
Reaction SMILES: [BH4-].[Na+].[O:3]1[CH2:7][CH2:6][O:5][CH:4]1[CH2:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH:16]2[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[CH2:12][CH2:11]1>C(O)(C)C.Cl>[O:3]1[CH2:7][CH2:6][O:5][CH:4]1[CH2:8][CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]2)[CH2:14][CH2:15]1
Reactant: O=C1CCC([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: O[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 2.97 g of sodium borohydride in 300 ml of isopropanol was treated dropwise at -70° C. while gassing with nitrogen with a solution of 11 g of 4-[trans-4-[2-(1,3-dioxolan-2-yl)ethyl]cyclohexyl]cyclohexanone in 200 ml of isopropanol. After about 1 hour the reaction mixture was left to warm to room temperature, diluted with 500 ml of 0.1N hydrochloric acid and extracted three times with 300 ml of methylene chloride each time. The organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. Crystallization of the residue (11 g) from 500 ml of ethyl acetate/petroleum ether (vol. 3:5) gave 6.6 g of pure trans-4-[trans-4-[2-(1,3-dioxolan-2-yl)ethyl]cyclohexyl]cyclohexanol with m.p. 129.5° C.
Reaction SMILES: [CH:1]1([CH:4]=[O:5])[CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:24][C:25]([Si](C)(C)C)([F:27])[F:26]>O1CCCC1>[CH:1]1([CH:4]([OH:5])[C:25]([F:27])([F:26])[F:24])[CH2:3][CH2:2]1
Reactant: O=CC1CC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(C1CC1)C(F)(F)F
Yield: 26.8 %

Procedure:
According to Reference Example 8-12, by use of cyclopropanecarbaldehyde (300 mg, 4.28 mmol) dissolved in tetrahydrofuran (6 mL), a 1 mol/L solution of tetrabutylammonium fluoride in tetrahydrofuran (0.856 mL, 0.856 mmol) and (trifluoromethyl)trimethylsilane (0.759 mL, 5.14 mmol), the mixture was stirred and reacted at room temperature for 1.7 hours. Then, purification by extraction gave 1-cyclopropyl-2,2,2-trifluoroethanol (Compound EB) (161 mg, yield: 27%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2[C:26](=[CH:27]C=CC=2)[C:25]2([C:35]3=CC4OCOC=4C=[C:34]3OC2)C1=O.BrCCCCC.CC1C=CC(S(OC[C@H]2COCCO2)(=O)=O)=CC=1>>[CH2:27]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22])[CH2:26][CH2:25][CH2:35][CH3:34]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Solvent: CCCCCBr
Product: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 1-bromopentane to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, 1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (91%) as a colorless solid: mp 129-130° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.29 (ddd, J=8.0, 7.7, 1.5 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 7.04 (dd, J=7.5, 7.5 Hz, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.49 (s, 1H), 6.21 (s, 1H), 4.88 (d, J=9.0 Hz, 1H), 4.63 (d, J=9.0 Hz, 1H), 4.23-4.17 (m, 2H), 4.14-4.09 (m, 2H), 3.87-3.77 (m, 1H), 3.72-3.62 (m, 1H), 1.77-1.68 (m, 2H), 1.45-1.30 (m, 4H), 0.91 (t, J=6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ177.3, 155.3, 144.6, 142.5, 138.3, 132.7, 128.9, 124.0, 123.2, 121.3, 111.6, 108.7, 99.4, 80.2, 64.6, 64.0, 58.1, 40.4, 29.1, 27.2, 22.4, 14.1; MS (ES+) m/z 366.0 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([O:11][N:12]=[C:13]([C:39]2[N:40]=[C:41]([NH:44]C=O)[S:42][CH:43]=2)[C:14]([NH:16][C@@H:17]2[C:37](=[O:38])[N:19]3[C:20]([C:34]([O-:36])=[O:35])=[C:21]([CH2:24][N+:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:33])[NH2:32])=[CH:27][CH:26]=4)[CH2:22][S:23][C@H:18]23)=[O:15])[CH2:10][CH2:9]1.Cl.C(=O)(O)[O-].[Na+]>CO.O1CCCC1>[NH2:44][C:41]1[S:42][CH:43]=[C:39]([C:13](=[N:12][O:11][CH:8]2[CH2:9][CH2:10]2)[C:14]([NH:16][C@@H:17]2[C:37](=[O:38])[N:19]3[C:20]([C:34]([O-:36])=[O:35])=[C:21]([CH2:24][N+:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:33])[NH2:32])=[CH:27][CH:26]=4)[CH2:22][S:23][C@H:18]23)=[O:15])[N:40]=1
Reactant: NC(=O)c1cc[n+](CC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)C(=NOC4CC4)c4csc(NC=O)n4)[C@H]3SC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cc[n+](CC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)C(=NOC4CC4)c4csc(N)n4)[C@H]3SC2)cc1
Temperature: 0 °C
Yield: 11.8 %

Procedure:
A mixture of trifluoroacetic acid salt of 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(4-carbamoyl-1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) (1.6 g) and concentrated hydrochloric acid (0.76 ml) in a mixture of methanol (16 ml) and tetrahydrofuran (5 ml) was warmed at 33° to 35° C. for 1.5 hours. The mixture was poured into ice-water, adjusted to pH 2.5 with saturated aqueous solution of sodium bicarbonate and washed with ethyl acetate. The aqueous solution was subjected to column chromatography on a non-ionic adsorption resin "Diaion HP-20" (30 ml). After the column was washed with water (300 ml), 1% isopropyl alcohol (60 ml), and 3% isopropyl alcohol (60 ml) successively, the elution was carried out with 5% isopropyl alcohol (250 ml) and 10% isopropyl alcohol (150 ml) successively. The fractions containing the object compound were collected, combined, concentrated in vacuo to about 100 ml and lyophylized to give 7β-[2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetamido]-3-(4-carbamoyl-1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) (180 mg).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:33][C:34]([F:44])([F:43])[C:35]1C=CC(CN)=CC=1.F[P-](F)(F)(F)(F)F.C[N:53](C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:53][CH2:35][C:34]([F:44])([F:43])[F:33])=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCC(F)(F)F)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 18 h
Yield: 57.9 %

Procedure:
A mixture of 0.070 g (0.16 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.027 g (0.19 mmole) of 4-trifluoromethyl-benzylamine, 0.071 g (0.19 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.136 mL (0.78 mmole) of diisopropylethyl amine and 2.0 mL of dimethylformamide was stirred for 18 hours. The mixture was diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (gradient, 80:20-0:100) to give 0.049 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(2,2,2-trifluoro-ethyl)-benzamide (I-31) as a white solid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:41][CH2:42][CH3:43])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:44](#[N:47])[CH:45]=[CH2:46]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([O:40][CH2:46][CH2:45][C:44]#[N:47])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:41][CH2:42][CH3:43])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CC#N
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(OCCC#N)CC1

Procedure:
In a manner similar to the method described in example 177, [(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-(4-hydroxy-piperidin-1-yl)-methanone (example 101) was reacted with acrylonitrile (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C37H44Cl2N5O3 [(M+H)+] 676.2816, observed 676.2815.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23]Br)[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>C(#N)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: BrCCOc1cccc2c1c1ccccc1n2Cc1ccccc1
Solvent: CC#N
Product: c1ccc(Cn2c3ccccc3c3c(OCCN4CCCC4)cccc32)cc1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A mixture of 9-benzyl-4-(2-bromoethoxy)-9H-carbazole (0.020 g, 0.0526 mmol), pyrrolidine (0.040 g, 0.562 mmol), and acetonitrile (1.0 mL) is stirred over the weekend at room temperature; much starting material remained so the mixture is heated at 75° C. in a capped vial for 24 h. After cooling and removal of the solvent, the residue is partitioned between CH2Cl2 and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate; chromatography on silica gel eluting with CH3OH—CH2Cl2 (4/96) gave 0.0165 g (85%) of the title compound as a waxy solid; 1H NMR (CDCl3) δ1.97, 3.04, 3.36, 4.59, 5.30, 6.71, 7.02, 7.12, 7.2-7.4, 8.32. Anal. Calcd for C25H26N2O: C, 81.05; H, 7.07; N, 7.56. Found: C, 79.84; H, 7.02; N, 7.44.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:29])[C@@H:19](/[CH:20]=[CH:21]/[C:22](=[O:25])[O:23][CH3:24])[C@H:18]1[C:26]([OH:28])=[O:27].[O:30]([C:37]1[S:38][C:39]([CH2:42]O)=[CH:40][N:41]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:16][C:17]1([CH3:29])[C@@H:19](/[CH:20]=[CH:21]/[C:22](=[O:25])[O:23][CH3:24])[C@H:18]1[C:26]([O:28][CH2:42][C:39]1[S:38][C:37]([O:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[N:41][CH:40]=1)=[O:27]
Reactant: COC(=O)/C=C/[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: OCc1cnc(Oc2ccccc2)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)/C=C/[C@H]1[C@@H](C(=O)OCc2cnc(Oc3ccccc3)s2)C1(C)C
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 55.8 %

Procedure:
0.1 g of 4-dimethylamino-pyridine and then 0.97 g of dicyclohexylcarbodiimide were added to a solution of 1 g of (1R,3S) 2,2-dimethyl-3-[(E) 3-oxo-3-methoxy-propen-1-yl)-cyclopropane-1-carboxylicacid in 20 ml of methylene chloride and the mixture was stirred at 20° C. for 15 minutes. A solution of 1.24 g of (2-phenoxy-5-thiazolyl)-methanol in 15 ml of methylene chloride was added dropwise at 10° C. to the mixture. The mixture was stirred at 20° C. for 4 hours and was filtered. The filtrate was treated with activated carbon, was washed with water, dried and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with an 8-2 hexane-ethyl acetate mixture yielded 1.09 g of (2-phenoxy-5-thiazolyl)-methyl (1R,3S) 2,2-dimethyl-3-[(E) 3-oxo-3-methoxy-propen-1-yl)-cyclopropane-1-carboxylate with a specific rotation of [α]D° =+60.5° (c=1.5% in benzene) and melting at 62° C.