Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N[C@H](C(O)=O)CC1C=CC=CC=1)=O)(C)(C)C.[N+:39]([C:42]1[CH:62]=[CH:61][C:45]([CH2:46][NH:47][C:48](=[O:60])[C@H:49]([CH3:59])[NH:50][C:51](=[O:58])[C@H:52]([CH2:54][CH:55]([CH3:57])[CH3:56])[NH2:53])=[CH:44][CH:43]=1)([O-:41])=[O:40].C(Cl)Cl>C(OCC)(=O)C>[N+:39]([C:42]1[CH:62]=[CH:61][C:45]([CH2:46][NH:47][C:48](=[O:60])[C@H:49]([CH3:59])[NH:50][C:51](=[O:58])[C@H:52]([CH2:54][CH:55]([CH3:56])[CH3:57])[NH:53][C:17](=[O:19])[C@H:9]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:44][CH:43]=1)([O-:41])=[O:40]
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)NCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)NCc1ccc([N+](=O)[O-])cc1
Yield: 71 %

Procedure:
Parallel syntheses for the D-isomer (R1 =H, R2 =benzyl) and L-isomer (R1 =benzyl, R2 =H) were performed. The following procedure was used for each. The procedure of Example 2, Section B was followed, using t-butoxycarbonyl-D-phenylalanine for one isomer and t-butoxycarbonyl-L-phenylalanine for the other, and using L-leucyl-L-alanine 4-nitrobenzylamide of the formula ##STR28## instead of (-)N-(L-2-hydroxy-4-methylpentanoyl)-L-alanine 4-nitrobenzyl amide. The reaction was carried out on a 2.0 mmol scale, using methylene chloride (10 mL) instead of dimethylformamide as the solvent. After the extractions, the crude product was purified by silica gel chromatography, eluting with 7:3 methylene chloride:ethyl acetate to afford the products as white solids (D-isomer: 0.83 g, 1.42 mmol, 71% yield; L-isomer: 0.77 g, 1.3 mmol, 62% yield). Verification of the structures was as follows:
Reaction SMILES: [CH3:1][NH:2][CH3:3].C1COCC1.[CH3:9][CH:10]([CH3:39])[C@@H:11]([NH:20][C:21]1[CH:22]=[C:23]([C:27]2[C:35]3[C:30](=[N:31][CH:32]=[C:33]([C:36](O)=[O:37])[CH:34]=3)[NH:29][CH:28]=2)[CH:24]=[N:25][CH:26]=1)[C:12](=[O:19])[NH:13][CH2:14][C:15]([F:18])([F:17])[F:16].CCN(C(C)C)C(C)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][N:2]([CH3:3])[C:36]([C:33]1[CH:34]=[C:35]2[C:27]([C:23]3[CH:24]=[N:25][CH:26]=[C:21]([NH:20][C@H:11]([CH:10]([CH3:39])[CH3:9])[C:12](=[O:19])[NH:13][CH2:14][C:15]([F:18])([F:16])[F:17])[CH:22]=3)=[CH:28][NH:29][C:30]2=[N:31][CH:32]=1)=[O:37]
Reactant: CNC
Reactant: CC(C)[C@@H](Nc1cncc(-c2c[nH]c3ncc(C(=O)O)cc23)c1)C(=O)NCC(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](Nc1cncc(-c2c[nH]c3ncc(C(=O)N(C)C)cc23)c1)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 0° C. solution of 2M dimethylamine/THF (58 uL, 0.115 mmol), 3-(5-(3-methyl-1-oxo-1-(2,2,2-trifluoroethylamino)butan-2-ylamino)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid 3-1b (25 mg, 0.057 mmol) and DIPEA (0.025 ml, 0.144 mmol) in DMF (0.7 ml) was slowly added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (0.078 ml, 0.115 mmol). The reaction was allowed to warm to room temperature and stir 18 hr. PyBOP (59.8 mg, 0.115 mmol) was then added and let stir 18 hr. The reaction was diluted with DMF (0.7 mL), filtered, and purified by reverse-phase HPLC. Lyophilization of pure fractions gave the title compound as a solid. LRMS (ESI) m/z 463.2 [(M+H)+; calcd for C22H25F3N6O2: 463.2].
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[O:6][C:7]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:8]=3[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC>O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[O:6][C:7]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:8]=3[CH:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[NH:10][C:4]=2[CH:3]=1
Reactant: COc1ccc2c(c1)C(c1ccncc1)=Nc1cc(Cl)ccc1O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: COc1ccc2c(c1)C(c1ccncc1)Nc1cc(Cl)ccc1O2

Procedure:
A 5.0 g. portion of 8-Chloro-2-methoxy-11-(4-pyridyl)-dibenz[b,f][1,4]oxazepine (Example 1) is added to 2.5 g. of lithium aluminum hydride in 200 ml. of ether. The mixture is stirred and heated under reflux for 4 hours. Water is added dropwise to decompose the excess lithium aluminum hydride. The ether is decanted and the residue is extracted with methylene chloride which is then combined with the ether, dried and evaporated. The residue is crystallized from acetone-hexane giving 8-chloro-10,11-dihydro-2-methoxy-11-(4-pyridyl)-dibenz[b,f][1,4]oxazepine, m.p. 186°-188° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:13]([C:21]3[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=3)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].B1([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)C2CCCC1CCC2.[OH-].[Na+]>[Pd].O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:23][CH:22]=3)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn2c(C3CCCCC3)c(-c3ccc(I)cc3)cnc12
Reactant: c1ccc(CB2C3CCCC2CCC3)cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn2c(C3CCCCC3)c(-c3ccc(Cc4ccccc4)cc3)cnc12
Reaction time: 24 h
Yield: 68.3 %

Procedure:
According to a modification of a literature procedure (Suzuki, A. et al Tetrahedron Lett. 1986, 27, 6369–6372) a mixture of 57 mg (0.12 mmol) of 7-cyclohexyl-6-(4-iodo-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester and 5 mg (0.006 mmol, 5 mol %) of Pd catalyst was placed into a carousel tube. After a vacuum and argon cycle, tetrahydrofuran (THF) (2 mL) was added, followed by 0.29 mL (0.144 mmol, 1.2 equiv) of B-Benzyl-9-BBN 0.5 M solution in THF, and 0.12 mL (0.36 mmol, 3 equiv) of 3 N NaOH solution, and the resulting mixture was heated reflux under argon overnight. Since analysis by LC-MS revealed unreacted starting material still present, 0.12 mL (0.06 mmol) of B-Benzyl-9-BBN, 5 mg (0.006 mmol, 5 mol %) of Pd catalyst, and 0.12 mL (0.36 mmol) of 3 N NaOH solution was added and heating was continued for 24 h. The reaction mixture was then diluted with ethyl acetate, washed with water, dried over sodium sulfate, passed through a small pad of Celite, and evaporated to give a brown residue (crude coupling product), which was chromatographed on silica gel (Biotage; 2% ethyl acetate in dichloromethane) to afford 36 mg (68% yield) of desired 6-(4-benzyl-phenyl)-7-cyclohexyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester as indicated by 1H NMR (containing traces of impurities); LC-MS—calcd for C28H29N3O2 [M++H]+: 440.23, found: 440.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=O)[C:5]=2[C:4]([CH3:13])([CH3:12])[CH2:3]1.[C:15](O)(=O)C.[CH:19]([NH2:21])=[NH:20]>C(O)CCC>[CH3:12][C:4]1([CH3:13])[C:5]2[C:6]3[C:7]([CH2:8][CH2:9][C:10]=2[C:2]([CH3:1])([CH3:14])[CH2:3]1)=[CH:15][N:21]=[CH:19][N:20]=3
Reactant: CC1(C)CC(C)(C)C2=C1CCCC2=O
Reactant: N=CN
Reactant: CC(=O)O
Solvent: CCCCO
Product: CC1(C)CC(C)(C)C2=C1CCc1cncnc12
Temperature: 130 °C
Reaction time: 24 h

Procedure:
A 100 mL reaction flask is charged with 1,1,3,3-tetramethyl-1,2,3,5,6,7-hexahydro-inden-4-one (prepared as described in U.S. Pat. No. 3,927,083) (10 g, 0.05 mol), formamidine acetate (27 g, 0.26 mol), and butanol (C4H9OH) (50 mL). The reaction mixture is heated to 130° C. and stirred for 24 hours. The crude mass is washed once with aqueous sulfuric acid (H2SO4) (10%, 100 mL) followed by twice with brine (30 mL). Butanol is recovered by roto-evaporation. The crude product is further purified with liquid chromatography (Biotage® system) and then crystallized. Product 1,1,3,3-tetramethyl-2,3,4,5-tetrahydro-1H-7,9-diaza-cyclopenta[a]naphthalene (˜5 g) is obtained.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[OH:9][C:10]1[C:19]2[C:14](=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=[C:17]([CH3:20])[CH:18]=2)[N:13]=[CH:12][C:11]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]>ClCCCl>[Br:1][CH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=1)[N:13]=[CH:12][C:11]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:10]2[OH:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cc(C)cc2c1O
Solvent: ClCCCl
Product: CCOC(=O)c1cnc2c([N+](=O)[O-])cc(CBr)cc2c1O

Procedure:
N-Bromosuccinimide (3.52 g) is added to a solution of ethyl 4-hydroxy-6-methyl-8-nitro-3-quinolinecarboxylate (2.76 g) in 1,2 dichloroethane (250 mL). The refluxing solution is irradiated with a sun lamp (625 watt) for 20 min. The crude ethyl 6-bromomethyl-4-hydroxy-8-nitro-3-quinolinecarboxylate thus formed is reacted with morpholine (5 mL). After evaporation, the product is partitioned between ethyl acetate and water. Evaporation of the ethyl acetate gives a solid, which is dissolved in chloroform and is chromatographed on silica gel with 1% methanol/chloroform as the initial eluant. Elution of the column with 10% methanol/chloroform gives the title compound, which is crystallized from methanol. Physical characteristics: M.p. 214-216° C. 1H NMR (CDCl3) δ1.41, 2.50, 3.68, 3.74, 4.42, 8.69, 8.73, 8.78, 11.6. Anal. Found: C, 56.30; H, 5.32; N, 11.56.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:10]=[C:9]3[O:12][CH2:13][O:14][C:8]3=[CH:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].[N+:26](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>CN(C)C=O>[NH2:26][N:5]1[C:6]2[CH:7]=[C:8]3[O:14][CH2:13][O:12][C:9]3=[CH:10][C:11]=2[C:2](=[O:1])[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4]1
Reactant: CCOC(=O)c1cnc2cc3c(cc2c1O)OCO3
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(N)c2cc3c(cc2c1=O)OCO3
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a stirred mixture of 12.8 g (0.049 mole) of ethyl 8-hydroxy-1,3-dioxolo[4,5-g]quinoline-7-carboxylate and 13.5 g (0.098 mole) of potassium carbonate in 500 ml of dimethylformamide was added 11.7 g (0.059 mole) of O-(2,4-dinitrophenyl)hydroxylamine. The reaction mixture was stirred overnight at room temperature. An additional 5.0 g of O-(2,4-dinitrophenyl)hydroxylamine and 300 ml of dimethylformamide were then added and stirring was continued again overnight. The solvent was removed in vacuo, the residue stirred in 500 ml of water, and the product was collected by filtration and recrystallized from dimethylformamide to give 7.6 g of ethyl 5-amino-5,8-dihydro-8-oxo-1,3-dioxolo[4,5-g]quinoline-7-carboxylate, pale orange crystals, m.p. 251°-253° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10](C(O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P([N:38]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C(N(CC)CC)C.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[NH2:38][C@@H:10]1[C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](C(=O)O)[C@@H](c2ccc(Cl)c(Cl)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](c2ccc(Cl)c(Cl)c2)[C@@H](N)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
To a solution of the compound (14.4 g) obtained in step 5 in toluene (120 mL) were added DPPA (16.5 g) and triethylamine (8.36 mL) at room temperature, and the mixture was stirred at 100° C. for 2 hr. The reaction mixture was cooled, 8N aqueous sodium hydroxide solution (50 mL) was added, and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and brine and dried, and the solvent was evaporated under reduced pressure to give crude tert-butyl (3R*,4S*)-3-amino-4-(3,4-dichlorophenyl)pyrrolidine-1-carboxylate (13.3 g, 100%) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](O)[CH:6]=1.C(N([CH2:18][CH3:19])CC)C.[OH2:20]>CC(C)=O>[C:3](=[O:2])([O:20][C:19]1[CH:18]=[CH:7][CH:6]=[CH:5][C:10]=1[C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([NH:4][C:3]([O:2][CH3:1])=[O:12])[CH:6]=1)[NH2:4]
Reactant: COC(=O)Nc1cccc(O)c1
Reactant: CCN(CC)CC
Reactant: O
Solvent: CC(C)=O
Product: COC(=O)Nc1cccc(-c2ccccc2OC(N)=O)c1
Reaction time: 0.5 h

Procedure:
4.3 g (0.025 moles) of methyl-(N-3-hydroxyphenyl)-carbamate are reacted with 7.3 g (0.025 moles) of N-phenylcarbamoylbenzoic acid sulfimide (m.p.: 184°-186° C.) in 15 ml of acetone, in the presence of 2.56 g (0.025 moles) of triethyl amine, at 40° C. for 15 minutes. To the reaction mixture 40 ml of water are added and it is cooled to 5° to 10° C. The mixture is allowed to stand for 30 minutes, filtered, washed and dried. 5.5 g of 3-methoxycarbonylaminophenyl-phenyl carbamate are obtained, melting at 150° to 152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+:27]>>[OH2:19].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:21][CH2:22][C:23]([O-:25])=[O:24])[CH:9]=2)=[CH:6][CH:7]=1.[Na+:27]
Reactant: COc1ccc(-n2nc(CCC(=O)O)cc2-c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-n2nc(CCC(=O)[O-])cc2-c2ccc(Cl)cc2)cc1
Product: O
Yield: 98 %

Procedure:
To the acid 12 (1.0169 g, 2.85 mM) was added a 1.00N NaOH solution (2.85 ml, 2.85 mM) and distilled H2O (15 ml). The reaction mixture was stirred until it was homogeneous, and then lyophilized to afford 13 (1.08 g, 98%) as a white solid, with a mp greater than 300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:15])(=[O:14])[NH:12][CH3:13].[CH2:16]([C:18]1[O:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[CH:19]=1)[CH3:17]>>[CH2:16]([C:18]1[O:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[C:19]=1[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([S:11](=[O:15])(=[O:14])[NH:12][CH3:13])[CH:4]=1)[CH3:17]
Reactant: CCc1cc2ccccc2o1
Reactant: CNS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Product: CCc1oc2ccccc2c1C(=O)c1ccc(Cl)c(S(=O)(=O)NC)c1

Procedure:
is obtained as described in Example 1 from 10.7 g 4-chloro-3-methylsulfamoylbenzoyl chloride and 6.4 g 2-ethylbenzo[b]furan in the form of amorphous solids having a softening point of 63° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Cl:25][CH2:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)=[O:28]>C(#N)C>[Cl-:25].[C:19]1([C:12]2([C:10]([O:9][C@@H:3]3[CH:4]4[CH2:7][CH2:8][N+:1]([CH2:26][C:27](=[O:28])[NH:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=5)([CH2:6][CH2:5]4)[CH2:2]3)=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Reactant: O=C(CCl)Nc1ccccn1
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3ccccc3)CCCCCC1)C2)Nc1ccccn1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester (Example 14e) (254 mg) in acetonitrile (5 mL) was treated with 2 -chloro-N-pyridin-2-yl-acetamide (Example 140 (146 mg) and the resulting yellow solution was stirred at room temperature overnight during which time a solid precipitated. The reaction mixture was treated with ˜2 mL of ether and the solid was filtered off, washed with ether and dried under vacuum to give the title compound as an off-white solid (217 mg). Crystallisation from refluxing acetonitrile (20 mL) gave 98 mg of the titled compound as a white crystalline solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([N:15]2[C:19]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=4)[N:22]([CH3:30])[CH:21]=3)=[N:18][NH:17][C:16]2=[O:31])=[CH:6]1.[C-:32]#[N:33].[K+]>CN(C=O)C>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][CH2:3][CH2:2][C:32]#[N:33])[CH:6]=[C:7]2[N:15]1[C:16](=[O:31])[NH:17][N:18]=[C:19]1[C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=2)[N:22]([CH3:30])[CH:21]=1
Reactant: [C-]#N
Reactant: Cn1cc(-c2n[nH]c(=O)n2-c2cn(CCCBr)c3ccc(F)cc23)c2cc(F)ccc21
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2n[nH]c(=O)n2-c2cn(CCCC#N)c3ccc(F)cc23)c2cc(F)ccc21
Temperature: 50 °C
Yield: 60.1 %

Procedure:
To a solution of the product from Example 18 (0.86 g, 1.77 mmol) in dry DMF (25 mL) was added potassium cyanide (0.18 g, 2.77 mmol) and the mixture was stirred and heated at 50° C. overnight under nitrogen. The solvent was evaporated, and the residue was distributed between ethyl acetate and water. The water phase was extracted twice with ethyl acetate, and the combined organic phases were washed with water and dried. After evaporation the crude product was chromatographed on silica gel (EtOAc) to yield 0.46 g (61%) of the title product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[CH2:9](C([Sn])=C(CCCC)CCCC)[CH2:10]CC>CN(C=O)C.C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:8][C:5]1[CH:4]=[CH:3][C:2]([CH:9]=[CH2:10])=[CH:7][N:6]=1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Cc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1ccc(C)nc1
Temperature: 100 °C
Yield: 46.3 %

Procedure:
The title compound was prepared by following general procedure 2. 5-Bromo-2-methyl pyridine (5 g, 29.0 mmol) was dissolved in DMF:THF (3:1, 35 mL): tributylvinyltin (10.2 g, 31.9 mmol) and Pd(PPh3)4 (0.44 g, 0.432 mmol) was added to this solution at RT under nitrogen and was heated at 100° C. for 2 h. After completion of the reaction (TLC), the reaction mixture was cooled to RT and diluted with water (350 mL) and extracted with ethyl acetate (3×200 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator below 40° C. The crude was purified through column chromatography (6% ethylacetate:hexane in silica 100-200 mesh, Diameter of column—2.5cm, Height of silica—approx. 5 inch) to provide 2-methyl-5-vinylpyridine as a light yellow oil (1.6 g, 47% yield).
Reaction SMILES: [O:1]1[CH2:6][C:2]1([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]#[CH:5].O>C(O)C>[CH3:5][C:4]1[O:1][CH:6]=[C:2]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]=1
Reactant: C#CCC1(c2ccccc2)CO1
Solvent: CCO
Solvent: O
Product: Cc1cc(-c2ccccc2)co1
Temperature: 23 °C
Yield: 75.9 %

Procedure:
To a solution of 0.5 g HgSO4 in 30 mL of 2N HgSO4 was added 4.74 g (30 mmol) of 4,5-epoxy-4-phenyl-1-pentyne in 30 mL of absolute ethanol over a 5 minute period. The reaction mixture was refluxed for 0.25 hour and cooled to 23° C. After addition to 150 mL of H2O the mixture was extracted with hexanes three times. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. Sublimination (90° C. at 15 mmHg) of the solid gave 3.6 g (76%) of 2-methyl-4-phenylfuran as a solid (m.p. 89°-91° C.) which was homogeneous by spectroscopic considerations; IR (KBr) 1599, 1545, 1440, 742 cm-1 ; 1HNMR (300 MHz, CDCl3) δ 7.62 (s, 1H), 7.50 (d, 2H, J=9.0 Hz), 7.38 (t, 2H, J=9.0 Hz), 7.28 (t, 1H, J=9.0 Hz), 6.33 (s, 1H), 2.35 (s, 3H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][O:13][C:14]1[CH:35]=[CH:34][C:17]([CH2:18][O:19][C:20]([C:22]2[N:27]3[C:28](=[O:31])[C@@H:29]([NH2:30])[C@H:26]3[S:25][CH2:24][C:23]=2[CH2:32][Cl:33])=[O:21])=[CH:16][CH:15]=1.[C:36]([O:40][C:41]([NH:43][C:44]1[S:45][CH:46]=[C:47]([C:49](=[N:53][O:54][C:55]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])([CH3:57])[CH3:56])[C:50](O)=[O:51])[N:48]=1)=[O:42])([CH3:39])([CH3:38])[CH3:37].CN1CCOCC1.P(OCl)(OCl)(OC1C=CC=CC=1)=O>ClCCl.C(N(CC)CC)C>[C:36]([O:40][C:41]([NH:43][C:44]1[S:45][CH:46]=[C:47]([C:49](=[N:53][O:54][C:55]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])([CH3:56])[CH3:57])[C:50]([NH:30][C@@H:29]2[C:28](=[O:31])[N:27]3[C:22]([C:20]([O:19][CH2:18][C:17]4[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:35][CH:34]=4)=[O:21])=[C:23]([CH2:32][Cl:33])[CH2:24][S:25][C@H:26]23)=[O:51])[N:48]=1)=[O:42])([CH3:39])([CH3:37])[CH3:38]
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=NOC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=P(OCl)(OCl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)C(=NOC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N23)cc1

Procedure:
7β-Amino-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxy-benzyl ester p-toluenesulfonate in dichloromethane is treated with triethylamine, 2-(2-t-butoxycarbonylamino-4-thiazolyl)-2-(1-t-butoxycarbonyl-1-methylethoxyimino)acetic acid, N-methylmorpholine, and phenyl dichloro phosphate to give p-methoxybenzyl 7β-[2-(2-t-butoxycarbonylamino-4-thiazolyl)-2-(1-t-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](Cl)=[N:10][C:4]=2[CH:3]=1.[CH2:18]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([N:30]3[CH2:31][CH2:32][N:27]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:28][CH2:29]3)=[N:10][C:4]=2[CH:3]=1
Reactant: ClC1=Nc2cc(Cl)ccc2Oc2ccccc21
Reactant: CCCCCCCCCN1CCNCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCCCCCCCN1CCN(C2=Nc3cc(Cl)ccc3Oc3ccccc32)CC1

Procedure:
The mixture of 8, 11-dichlorodibenz[b,f][1,4]oxazepine (0.32 g, 1.19 mmol), 1-nonylpiperazine (0.38 g, 1.79 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.72 mL, 0.73 g, 4.77 mmol) in acetonitrile (15 mL) was heated at reflux for 6 h. After the mixture was concentrated, water (20 mL) and ethyl acetate (20 mL) were added. The two phases were separated and the aqueous phase was extracted with ethyl acetate (2×20 mL). The combined ethyl acetate solution was dried over magnesium sulfate and filtered. The filtrate was then concentrated in vacuo to dryness and the residue was subjected to column chromatography using ethyl acetate/hexane (1/2) as the eluent. The title compound was obtained as a white solid (0.15 g, 28%), m.p. 64°-66° C., MS 440 (M+ +1).