Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][N:17](CC4C=CC=CC=4)[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)=O.CO.[Pd]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][NH:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: COC(=O)[C@@H]1CNC[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
trans-3-(3-Cyclopentoxy-4-methoxyphenyl)-4-methoxycarbonyl-1-(phenylmethyl)pyrrolidine (3.5 g, 8.6 mmol) was dissolved in 20 mL of 4% HCO2H:methanol. While stirring at room temperature, 10% Pd/C (450 mg) was added in small portions. After several hours the reaction was diluted with methanol. Filtration through Celite followed by concentration under reduced pressure yielded a yellow oil residue. This residue was partitioned between CH2Cl2 and sat. NaHCO3. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×). The organic layers were combined, dried (K2CO3), filtered, and concentrated under reduced pressure to afford a pale oil. Chromatography on silica gel (8:1:1, CH2Cl2 :ethyl acetate:methanol) provided trans-3-(3-cyclopentoxy-4-methoxyphenyl)-4-(methoxycarbonyl)pyrrolidine as a colorless oil (2.3 g, 84%). 1H-NMR (300 MHz): δ 2.86-3.04 (m, 2), 3.29-3.52 (m, 4), 3.68 (s, 3), 3.83 (s, 3).
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[C:15]([O:24][CH3:25])[CH:14]=1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:11][CH2:12][C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[C:15]([O:24][CH3:25])[CH:14]=1
Reactant: [H][H]
Reactant: COc1cc(CNC(=O)OCc2ccccc2)ccc1OCC(=O)O
Agent: [Pd]
Solvent: CO
Product: COc1cc(CN)ccc1OCC(=O)O
Yield: 55 %

Procedure:
A solution of 16 (0.276 g, 0.8 mmol) in MeOH (5 mL) was treated with 10% palladium on carbon (30 mg) and hydrogenated under a balloon of hydrogen for 30 min. The reaction mixture was filtrated and the filtrate was concentrated to give 17 as white solid (0.093 g, 55%) which was used to next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=O)[O:19]C4C=CC=CC=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[Br:35][C:36]1[N:37]=[CH:38][S:39][C:40]=1[CH2:41][OH:42]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:19])[O:42][CH2:41][C:40]4[S:39][CH:38]=[N:37][C:36]=4[Br:35])=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OCc1scnc1Br
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)Oc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)OCc1scnc1Br
Temperature: 100 °C

Procedure:
Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (28 mg, 0.061 mmol) was mixed with (4-bromo-1,3-thiazol-5-yl)methanol (50 mg, 0.434 mmol) in pyridine (0.5 mL). The reaction mixture was heated at 100° C. overnight. The solvent was removed and the residue was purified by preparative reverse phase LC/MS to give (4-bromo-1,3-thiazol-5-yl)methyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate. 1H NMR (CDCl-d) δ 2.07(m, 4H), 3.65(m, 2H), 3.92(s, 3H), 4.13(m, 2H), 4.98(m, 1H), 5.35(s, 1H), 5.40(s, 2H), 6.97(s, 1H), 7.04(s, 1H), 7.09(m, 1H), 7.35(s, 1H), 8.17(s, 1H), 8.32(s, 1H), 8.78(s, 1H). LC/MS MH+=481.
Reaction SMILES: [CH:1]([N:4]([C:18]([C:20]1[C:21]([C:40]([F:43])([F:42])[F:41])=[CH:22][C:23]2[O:28][C:27]([CH3:30])([CH3:29])[C:26](=[O:31])[N:25]([CH2:32][CH2:33][NH:34][C:35]([O:37][CH3:38])=[O:36])[C:24]=2[CH:39]=1)=[O:19])[C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:46]N(C)C=O.CI>O>[CH:1]([N:4]([C:18]([C:20]1[C:21]([C:40]([F:41])([F:42])[F:43])=[CH:22][C:23]2[O:28][C:27]([CH3:30])([CH3:29])[C:26](=[O:31])[N:25]([CH2:32][CH2:33][N:34]([C:35]([O:37][CH3:38])=[O:36])[CH3:46])[C:24]=2[CH:39]=1)=[O:19])[C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:6]1)([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: COC(=O)NCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COC(=O)N(C)CCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl (3R)-3-(isopropyl{[4-{2-[(methoxycarbonyl)amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate (110 mg) were added sodium hydride (9.3 mg) and N,N-dimethylformamide (9 ml) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Then, to the mixture was added methyl iodide (0.02 ml), and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. The obtained ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give the title compound (110 mg) as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.[CH3:22][S:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]2[O:21][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([S:23][CH3:22])=[CH:25][CH:26]=2)=[CH:6][CH:7]=1
Reactant: CSc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(O)C1
Product: CSc1ccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(F)cc2)cc1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-4-(4-fluoro-phenyl)-3-hydroxy-piperidine-1-carboxylate [Example 3 (b)] with 4-methylthio-benzyl chloride [J.Org.Chem. (1988), 53(3), 561-569] there was obtained tert-butyl (3RS,4RS)-4-(4-fluoro-phenyl)-3-(4-methylsulphanyl-benzyloxy)-piperidine-1-carboxylate as a colourless oil; MS: 432 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[N:5]=[C:4]([NH:12][C@H:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])[C:3]=1[C:19]1[C:24]([F:25])=[CH:23][C:22]([F:26])=[CH:21][C:20]=1[F:27].[N-:28]=[N+:29]=[N-:30].[Na+]>C(#N)C>[N:28]([C:6]1[N:5]=[C:4]([NH:12][C@H:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])[C:3]([C:19]2[C:24]([F:25])=[CH:23][C:22]([F:26])=[CH:21][C:20]=2[F:27])=[C:2]([Cl:1])[N:7]=1)=[N+:29]=[N-:30]
Reactant: C[C@H](Nc1nc(S(C)(=O)=O)nc(Cl)c1-c1c(F)cc(F)cc1F)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Product: C[C@H](Nc1nc(N=[N+]=[N-])nc(Cl)c1-c1c(F)cc(F)cc1F)C(F)(F)F
Yield: 72.3 %

Procedure:
A solution of 0.5 g (1.15 mmol) of sulfone 1 and 0.11 g (1.62 mmol) of sodium azide in acetonitrile was refluxed for 2 hours. Cooling, distillative removal of the solvent and digestion of the residue with water gave 0.33 g of the title compound of m.p. 152-154° C.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]([C:7]1[C:12]([NH2:13])=[CH:11][C:10]([O:14][CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1)=[O:6].[CH:18](OCC)=O.Cl>O.O1CCCC1>[CH3:17][O:16][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[O:14][CH3:15])[N:13]=[CH:18][CH2:4][C:5]2=[O:6]
Reactant: COc1cc(N)c(C(C)=O)cc1OC
Reactant: CCOC=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(cc1OC)C(=O)CC=N2
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
Tetrahydrofuran (THF) (5.3 L) and sodium methoxide (313 g) were added to 2-amino-4,5-dimethoxyacetophenone (337 g), and the mixture was stirred at 20° C. for 30 min. Ethyl formate (858 g) was added to the reaction solution at 0° C., and the mixture was stirred at 20° C. for one hr. Water (480 mL) was added thereto at 0° C., and the mixture was neutralized with 1 N hydrochloric acid. The resultant precipitate was collected by filtration, and the filtered product was slurried in water (2 L) for washing. The slurry was filtered, and the filtered product was then dried under the reduced pressure to give 6,7-dimethoxy-4-quinolone (352 g, yield 81.50%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1.[C:16]([NH2:19])(=[S:18])[CH3:17]>>[CH3:1][O:2][C:3]([C:4]1[N:19]=[C:16]([CH3:17])[S:18][C:5]=1[C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)=[O:15]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1cccc(C)c1
Product: COC(=O)c1nc(C)sc1-c1cccc(C)c1

Procedure:
prepared by reaction of 3-chloro-2-oxo-3-m-tolyl-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.94 min; [M+H]+=248.0.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[C:33]([NH:34][S:35]([CH2:38][CH2:39][CH3:40])(=[O:37])=[O:36])=[CH:32][CH:31]=[C:30]([F:41])[C:11]=1[C:12]([NH:14][C:15]1[CH:16]=[C:17]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:21][C:18]2=[N:19][CH:20]=1)=[O:13]>C(Cl)(Cl)Cl>[Br:1][C:23]1[C:17]2[C:18](=[N:19][CH:20]=[C:15]([NH:14][C:12](=[O:13])[C:11]3[C:30]([F:41])=[CH:31][CH:32]=[C:33]([NH:34][S:35]([CH2:38][CH2:39][CH3:40])(=[O:37])=[O:36])[C:10]=3[F:9])[CH:16]=2)[NH:21][C:22]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(-c4ccccc4)cc3c2)c1F
Solvent: ClC(Cl)Cl
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(-c4ccccc4)c(Br)c3c2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
N-Bromosuccinimide (1.1 eq.) was added to a slurry of 2,6-difluoro-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (11 mg, 1.0 eq.) in CHCl3 (1.0 mL), and the reaction mixture stirred at ambient temperature for 16 hours. The reaction mixture was filtered, and the solids were washed with CH2Cl2. The resulting solids were then purified by silica gel chromatography (eluting with 5% MeOH/CH2Cl2) to afford N-(3-bromo-2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide as a solid (9 mg, 69%). 1H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 11.08 (s, 1H), 9.82 (s, 1H), 8.47-8.44 (m, 1H), 8.39-8.37 (m, 1H), 7.95-7.91 (m, 2H), 7.61-7.53 (m, 3H), 7.51-7.45 (m, 1H), 7.32-7.26 (m, 1H), 3.16-3.11 (m, 2H), 1.83-1.74 (m, 2H), 1.03-0.98 (m, 3H); m/z (APCI-neg) M−1=549.1.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:19]1([C:22]#[CH:23])[CH2:21][CH2:20]1>C(NCC)C.C(Cl)CCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:23]#[C:22][CH:19]3[CH2:21][CH2:20]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#CC1CC1
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: ClCCCl
Product: CN1Cc2c(C#CC3CC3)ncn2-c2cccc(Cl)c2C1=O

Procedure:
3.37 g (10 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to 75° for 16 hours with 1.47 g of cyclopropylacetylene, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 20 mg of copper(I) iodide in 20 ml of diethylamine and 10 ml of ethylene chloride. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there was obtained a mixture of product and starting material. In order to remove the starting material, the mixture was heated under reflux for 4 hours with 1 ml of 2-methyl-3-butyn-2-ol, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 20 mg of copper(I) iodide in 10 ml of diethylamine and 10 ml of ethylene chloride. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate the byproduct can be separated from the desired product. After crystallization from ethyl acetate there was obtained 7-chloro-3-(cyclopropylethynyl)-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 177°-178°.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.C1(C)C=CC([C:17]#[N:18])=CC=1>>[C:17]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1)#[N:18]
Reactant: N#CCc1ccc(I)cc1
Reactant: Cc1ccc(C#N)cc1
Product: N#CCc1ccc(C#N)cc1
Yield: 34.2 %

Procedure:
4-bromomethylbenzonitrile (white crystal), 2.0 g (yield: 51.0%), were obtained according to the same method as that of synthesis of 4-iodophenylacetonitrile of Example 5 except that 2.34 g (20 mmole) of p-tolunitrile (purchased from Tokyo Kasei) were used. Subsequently, 438 mg (yield: 34.2%) of light yellow crystals of 4-cyanophenylacetonitrile were obtained according to the same method as that of synthesis of 4-iodophenylacetonitrile of Example 5 except that 1.76 g (9.0 mmole) of the above 4-bromomethylbenzonitrile were used and that purification was performed according to silica gel column chromatography and recrystallization.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([OH:10])=O.C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([Cl:14])=[O:10]
Reactant: CC1CCCCC1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1CCCCC1C(=O)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.3 %

Procedure:
To a solution of 2-methylcyclohexanecarboxylic acid (6.00 mL, 42.6 mmol, mixture of cis and trans) in DCM (60 mL) was added oxalyl chloride (4.80 mL, 55.3 mmol) followed by DMF (0.03 mL, 0.4 mmol). The reaction mixture was stirred at ambient temperature for about 4 h before it was concentrated under reduced pressure to constant weight to afford 2-methylcyclohexanecarbonyl chloride (mixture of diastereomers) as a yellow oil (7.0 g, 97%): 1H NMR (400 MHz, CDCl3) δ 2.98-2.94 (m, 1H), 2.39-2.35 (m, 1H), 1.91-1.82 (m, 1H), 1.79-1.72 (m, 1H), 1.69-1.60 (m, 2H), 1.57-1.47 (m, 2H), 1.42-1.36 (m, 1H), 1.34-1.26 (m, 1H), 1.04-0.96 (m, 3H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][N:8]2[N:7]=[C:6]1[CH:15]([N:18]([CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[CH2:16][CH3:17].O[NH:41][C:42](=[NH:44])[CH3:43].[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[C:35]([O:34][C:32](=[O:33])[NH:31][CH2:30][CH2:29][CH2:28][N:18]([C:19](=[O:27])[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1)[CH:15]([C:6]1[N:5]([CH2:4][C:3]2[O:2][N:44]=[C:42]([CH3:43])[N:41]=2)[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][N:8]2[N:7]=1)[CH2:16][CH3:17])([CH3:37])([CH3:38])[CH3:36]
Reactant: CCC(c1nn2cccc2c(=O)n1CC(=O)OC)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Reactant: CC(=N)NO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(c1nn2cccc2c(=O)n1Cc1nc(C)no1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a mixture of (±)-(2-{1-[(3-tert-butoxycarbonylaminopropyl)-(4-methylbenzoyl) amino]propyl}-4-oxo-4H-pyrrolo[2,1-f][1,2,4]triazin-3-yl)acetic acid methyl ester (Example 7 A, 26 mg, 0.05 mmol) and N-hydroxyacetamidine (Tyger Scientific, 6 mg, 0.08 mmol) in DMF (1 mL), under Ar, was treated with sodium hydride (6.5 mg as 60% dispersion in mineral oil, 0.15 mmol) and stirred at ambient temperature overnight before being diluted with ethyl acetate. The organic layer was washed twice with water and once with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The crude product was purified by preparative HPLC (YMC S5 ODS, 20×250 mm, 30 minute gradient from 66–90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined, neutralized with saturated aqueous sodium bicarbonate, and then concentrated in vacuo to remove methanol. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed once each with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to yield the title compound (5 mg, 18%): 1H NMR (CDCl3) δ 7.45 (m, 1H), 7.21–7.08 (m, 4H), 7.07 (m, 1H), 6.59 (m, 1H), 5.97 (m, 1H), 5.83 (m, 1H), 5.47 (m, 1H), 3.92 (m, 1H), 3.36 (m, 2H), 2.74 (m, 2H), 2.38 (s, 3H), 2.34 (s, 3H), 2.30–1.98 (m, 2H), 1.74–0.80 (m, 14H); MS (ESI+) 564.20 (M++H).
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#N.CC(C[AlH]CC(C)C)C.Cl.CC[O:26]CC>C(Cl)Cl>[I:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:26]
Reactant: CCOCC
Reactant: N#Cc1cc(C(F)(F)F)ccc1I
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: ClCCl
Product: O=Cc1cc(C(F)(F)F)ccc1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-iodo-5-(trifluoromethyl)benzonitrile (INTERMEDIATE 2, 42 g) in CH2Cl2 (300 mL) at −78° C. was added a solution of DIBAL in CH2Cl2 (175 mL, 1M) over 30 minutes. A precipitate formed. The reaction was warmed to 0° C. An additional 25 mL of the DIBAL solution was added dropwise over 30 minutes. The reaction was poured into 200 mL 2N aqueous HCl, diluted with ether and stirred 1 hour. TLC analysis indicates imine still present and an additional 100 mL 2N aqueous was added and the reaction stirred overnight. Imine was still present by TLC analysis and 200 mL 2N aqueous HCl was added and the mixture stirred 2 hours. The layers were separated and the aqueous layer back extracted with ether. The ether extracts were combined, washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The product was purified by silica gel chromatography eluting with 95:5 hexanes/EtOAc to give 2-Iodo-5-(trifluoromethyl)benzaldehyde as a white solid. 1H NMR (500 MHz, CDCl3): (10.00 (s, 1H), 8.12 (s, 1H), 8.11 (d, J=8 Hz, 1H), 7.53 (dd, J=2 Hz, 8 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[C:19]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:20]=1[C:21]#[N:22].O>CS(C)=O>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:19]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:20]=2[C:21]#[N:22])=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1ccc(C(=O)c2ccccc2)cc1
Temperature: 60 °C
Yield: 94.1 %

Procedure:
To a solution of 11.4 g (0.0575 moles) of 4-hydroxybenzophenone dissolved in 150 ml of DMSO was added 2.3 g (0.0575 moles) of NaOH. The mixture was heated to 60° C. and 10.0 g (0.0548 moles) of 2-chloro-5-nitrobenzonitrile was added and the mixture heated at 75° C. for 3 hrs. The reaction mixture was cooled and poured into a solution of 100 ml of 2 N aqueous NaOH and 700 ml of water. The product was collected by filtration, washed well with water and dried to obtain 17.75 g of product (89.6% yield). Recrystallization from a mixture of ethanol and dimethylformamide and a second recrystallization from chloroform afforded purified 2-(4-benzoylphenoxy)-5-nitrobenzonitrile, mp 179.5°-180.5° C.
Reaction SMILES: [O:1]=[C:2]1[N:9]2[CH:4]([CH2:5][CH2:6][O:7]C2(C)C)[CH:3]1[CH:12]([CH3:14])[CH3:13].O>C(O)(=O)C>[CH:12]([CH:3]1[CH:4]([CH2:5][CH2:6][OH:7])[NH:9][C:2]1=[O:1])([CH3:14])[CH3:13]
Reactant: CC(C)C1C(=O)N2C1CCOC2(C)C
Solvent: CC(=O)O
Solvent: O
Product: CC(C)C1C(=O)NC1CCO
Temperature: 65 °C

Procedure:
8-oxo- 2,2-dimethyl-7α-isopropyl-3-oxa-1-azabicyclo[4.2.0]octane 1.0 g is dissolved in 8 ml of acetic acid and 2 ml H2O is added. The mixture is heated at 65° C. for 1.25 hrs. The acetic acid and H2O are removed under reduced pressure and the residue is taken up in C6H6 and evaporated to give 3-isopropyl-4-(2-hydroxyethyl)azetidinone.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](Cl)=[O:8].[NH2:10][CH:11]1[C:26](=[O:27])[N:13]2[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[CH2:16][S:17][C@:12]12[S:28][CH3:29].C([O-])(O)=O.[Na+]>O.CC(C)=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:10][CH:11]1[C:26](=[O:27])[N:13]2[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[CH2:16][S:17][C@:12]12[S:28][CH3:29])=[O:8]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CS[C@]12SCC(COC(C)=O)=C(C(=O)O)N1C(=O)C2N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CS[C@]12SCC(COC(C)=O)=C(C(=O)O)N1C(=O)C2NC(=O)Cc1cccs1
Temperature: 0 °C
Yield: 33.5 %

Procedure:
2-Thienylacetyl chloride (28 μl, 0.209 mMol) is added to an ice-cold, stirring mixture of 7-amino-6-methylthio-3-acetoxymethyl-ceph-3-em-4-carboxylic acid (66.4 mg., 0.209 mMol) and NaHCO3 (35 mg., 0.418 mMol) in H2O (1.5 ml.) and acetone (3.0 ml.). After stirring for 30 mins. in the cold, the mixture is evaporated under reduced pressure to remove acetone. The aqueous residue is diluted with more H2O (4.5 ml). and extracted with three portions of Et2O. The aqueous phase is acidified to pH 2.5 with 10% HCl and extracted with three portions of EtOAc. The EtOAc solution is dried over MgSO4, filtered, and evaporated in vacuo to a solid (72 mg.). This material is extracted with φH to remove 2-thienylacetic acid and the residue recrystallized from CH3CN-Et2O to provide 7-(2-thienylacetamido)-6-methylthio-3-acetoxymethyl-ceph-3-em-4-carboxylic acid (31 mg.) as an off-white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[CH3:29][C:30]1[NH:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2>>[CH3:29][C:30]1[N:31]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)[C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2
Reactant: Cc1cc2ccccc2[nH]1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Product: Cc1cc2ccccc2n1Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2C(F)(F)F)cc1
Yield: 70 %

Procedure:
Following the general method as outlined in Example 1 (Method A), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 2-methyl-1-H-indole, the title compound was isolated as a yellow solid in 70% yield (98% purity by HPLC).